U.S. patent application number 14/502792 was filed with the patent office on 2015-06-04 for nucleic acid biomarker and use thereof.
This patent application is currently assigned to Daiichi Sankyo Company, Limited. The applicant listed for this patent is Daiichi Sankyo Company, Limited, U3 Pharma GmbH. Invention is credited to Robert Allen BECKMAN, Sabine BLUM, Daniel J. FREEMAN, Xiaoping JIN, Renee Jeanne MENDELL-HARARY, Matthias SCHNEIDER.
Application Number | 20150152508 14/502792 |
Document ID | / |
Family ID | 52744734 |
Filed Date | 2015-06-04 |
United States Patent
Application |
20150152508 |
Kind Code |
A1 |
SCHNEIDER; Matthias ; et
al. |
June 4, 2015 |
NUCLEIC ACID BIOMARKER AND USE THEREOF
Abstract
The present invention is directed to methods of identifying and
treating a human subject harboring a tumor or other disease
comprising assessing HRG gene expression at an mRNA level in the
human subject and administering a treatment comprising an anti-HER3
antibody to the human subject whose HRG gene expression at an mRNA
level is assessed as high. The present invention is also directed
to methods of identifying a human subject harboring a tumor or
other disease comprising assessing HRG gene expression at an mRNA
level in the human subject and withholding a treatment comprising
an anti-HER3 antibody to the human subject whose HRG gene
expression at an mRNA level is assessed as low.
Inventors: |
SCHNEIDER; Matthias;
(Neufarn, DE) ; BLUM; Sabine; (Munchen, DE)
; MENDELL-HARARY; Renee Jeanne; (Skillman, NJ) ;
FREEMAN; Daniel J.; (Holmdel, NJ) ; BECKMAN; Robert
Allen; (Blue Bell, PA) ; JIN; Xiaoping;
(Hillsborough, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Daiichi Sankyo Company, Limited
U3 Pharma GmbH |
Tokyo
Martinsried |
|
JP
DE |
|
|
Assignee: |
Daiichi Sankyo Company,
Limited
Tokyo
JP
U3 Pharma GmbH
Martinsried
DE
|
Family ID: |
52744734 |
Appl. No.: |
14/502792 |
Filed: |
September 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61884982 |
Sep 30, 2013 |
|
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|
Current U.S.
Class: |
424/174.1 ;
435/6.12 |
Current CPC
Class: |
A61P 11/00 20180101;
C12Q 2600/158 20130101; C07K 16/2863 20130101; C07K 2317/73
20130101; G01N 2333/4704 20130101; A61P 43/00 20180101; A61K 45/06
20130101; C12Q 2600/106 20130101; C12Q 1/6886 20130101; A61K
39/39558 20130101; C07K 16/32 20130101; A61P 35/04 20180101; A61K
2039/505 20130101; A61P 35/00 20180101 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; C07K 16/28 20060101 C07K016/28 |
Claims
1.-53. (canceled)
54. A method of treating a human subject harboring a locally
advanced or metastatic non-small cell lung cancer (NSCLC) tumor
comprising administering a treatment comprising an anti-HER3
antibody to a human subject diagnosed with a locally advanced or
metastatic NSCLC whose HRG gene expression at an mRNA level is
assessed as high.
55. The method of claim 54 in which the HRG gene expression at an
mRNA level is assessed as high if a delta Ct (dCt) value is
observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
56. The method of claim 55 in which the predetermined threshold is
statistically determined, refined, adjusted and/or confirmed
through, on, or based on randomized clinical data and optionally
non-clinical data.
57. The method of claim 56 in which the predetermined threshold dCt
value is selected from the group consisting of 5.0, 4,9, 4.8, 4.7,
4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4,
3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1,
2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,
0,7, 0.6, 0.5, 0.4, 0,3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5,
-0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1,3, -1.4, -1.5, -1.6,
-1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7,
-2.8, -2.9, -3.0, -3.1, -3.2, -.3.3, -3.4, -3.5, -3.6, -3.7, -3.8,
-3.9, -4.0, -4.1, 4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9,
-5.0,-5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0,
-6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1,
-7.2 and -7.3.
58. The method of claim 56, wherein the predetermined threshold dCt
value is in a range of from about 2.7 to about 4.1.
59. The method of claim 54, wherein the subject harbors wild-type
EGFR.
60. The method of claim 54, wherein the tumor has progressed on at
least one prior systemic therapy.
61. The method of claim 54, further comprising assessing gene
expression at an mRNA level in the human subject diagnosed with the
locally advanced or metastatic NSCLC, wherein the HRG gene
expression at an mRNA level is assessed using quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR), RNA sequencing
or ISH.
62. The method of claim 55 in which the biological sample comprises
a tumor sample.
63. The method of claim 54 in which the anti-HER3 antibody is
selected from the group consisting of patritumab, duligotumab
(MEHD-7945A), seribantumab (MM-121), MM-111, LIM716, RG-7116,
tri-specific anti-EGFR/ER13133 zybody, huHER3-8, and a derivative
or fragment of any of these.
64. The method of claim 54 in which the treatment comprises
administering an anti-HER3 antibody in combination with one or more
of (i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and
(iv) an other targeted agent.
65. The method of claim 64, wherein the HER inhibitor is selected
from the group consisting of trastuzumab, T-DM1, lapatinib,
pertuzumab, cetuximab, panitumumab gefitinib, afatinib,
dacomitinib, KD-019 and erlotinib.
66. The method of claim 64, wherein the chemotherapy is selected
from the group consisting of cisplatin, carboplatin, gemcitabine,
pemetrexed, irinotecan, 5-fluoniracil, paclitaxel, docetaxel, and
capecitabine.
67. The method of claim 54, wherein the HRG gene expression is
assessed using an FDA-approved test.
68. A method of treating a human subject harboring a locally
advanced or metastatic non-small cell lung cancer (NSCLC) tumor
comprising withholding a treatment comprising an anti-HER3 antibody
to a human subject diagnosed with a locally advanced or metastatic
NSCLC whose HRG gene expression at an mRNA level is assessed as
low.
69. The method of claim 68 in which the HRG gene expression at an
mRNA level is assessed as low if a delta Ct (dCt) value is
observed, which is at or above a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
70. The method of claim 69 in which the predetermined threshold is
statistically determined, refined, adjusted and/or confirmed
through, on, or based on, randomized clinical data and optionally
non-clinical data.
71. The method of claim 70 in which the predetermined threshold dCt
value is selected from the group consisting of 5.0, 4.9, 4.8, 4.7,
4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4,
3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2,5, 2.4, 2.3, 2.2, 2.1,
2.0, 1,9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,
0,7, 0.6, 0.5, 0.4, 0,3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5,
-0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6,
-1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7,
-2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8,
-3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9,
-5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0,
-6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1,
-7.2 and -7.3.
72. The method of claim 68, wherein the subject harbors wild-type
EGFR.
73. The method of claim 68, wherein the tumor has progressed on at
least one prior systemic therapy.
74. The method of claim 69 in which the biological sample comprises
a tumor sample.
75. The method of claim 68 in which the treatment withheld
comprises an anti-HER3 antibody in combination with one or more of
(i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv)
an other targeted agent.
76. A method of receiving or undergoing a treatment for a locally
advanced or metastatic non-small cell lung cancer (NSCLC) tumor or
abstaining therefrom comprising: providing an autologous tissue
sample or consenting to a taking of same to facilitate an
assessment of HRG gene expression at an mRNA level in a human
subject diagnosed with a locally advanced or metastatic NSCLC; and
receiving or undergoing a treatment comprising an anti-HERS
antibody if the HRG gene expression at an mRNA level is assessed as
high, or abstaining from a treatment comprising an anti-HERS
antibody if the HRG gene expression at an mRNA level is assessed as
low.
77. The method of claim 76 in which (i) the HRG gene expression at
an mRNA level is assessed as high if a delta et (dCt) value is
observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC or (ii) the HRG gene expression at an
mRNA level is assessed as low if a dCt value is observed, which is
at or above the predetermined threshold, from the biological sample
taken from the subject diagnosed with the locally advanced or
metastatic NSCLC.
78. The method of claim 77 in which the predetermined threshold is
statistically determined, refined, adjusted and/or confirmed
through, on, or based on, randomized clinical data and optionally
non-clinical data.
79. The method of claim 78 in which the predetermined threshold dCt
value is selected from the group consisting of 5.0, 4.9, 4.8, 4.7,
4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4,
3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1,
2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,
0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5,
-0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6,
-1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7,
-2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8,
-3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9,
-5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0,
-6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1,
-7.2 and -7.3.
80. A method of electing a treatment for a locally advanced or
metastatic non-small cell lung cancer (NSCLC) tumor comprising:
receiving or undergoing an assessment of HRG gene expression at an
mRNA level in a human subject diagnosed with a locally advanced or
metastatic NSCLC; and electing to withhold or abstain from a
treatment comprising an anti-HERS antibody if the HRG gene
expression at an mRNA level is assessed as low, or electing to
receive or undergo a treatment comprising an anti-HER3 antibody if
the HRG gene expression at an mRNA level is assessed as high.
81. The method of claim 80 in which (i) the HRG gene expression at
an mRNA level is assessed as high if a delta Ct (dCt) value is
observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC or (ii) the HRG gene expression at an
mRNA level is assessed as low if a dCt value is observed, which is
at or above the predetermined threshold, from the biological sample
taken from the subject diagnosed with the locally advanced or
metastatic NSCLC.
82. The method of claim 81 in which the predetermined threshold is
statistically determined, refined, adjusted and/or confirmed
through, on, or based on, randomized clinical data and optionally
non-clinical data.
83. The method of claim 82 in which the predetermined threshold dCt
value is selected from the group consisting of 5.0, 4.9, 4.8, 4.7,
4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4,
3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1,
2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,
0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5,
-0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6,
-1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7,
-2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8,
-3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9,
-5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0,
-6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1,
-7.2 and -7.3.
Description
FIELD OF THE INVENTION
[0001] The field of the invention is molecular biology, oncology,
clinical diagnostics, and clinical treatment.
BACKGROUND
[0002] Most cancer drugs are effective in some patients, but not in
others. This results from genetic variation among tumors, and can
be observed even among tumors within the same patient. Variable
patient response is particularly pronounced with respect to
targeted therapeutics. Therefore, the full potential of targeted
therapies cannot be realized without suitable tests for determining
which patients will benefit from which drugs. According to the
National Institutes of Health (NIH), the term "biomarker" is
defined as "a characteristic that is objectively measured and
evaluated as an indicator of normal biologic or pathogenic
processes or pharmacological response to a therapeutic
intervention." (Biomarkers Definitions Working Group, 2001, Clin.
Pharmacol. Ther. 69:89-95)
[0003] The development of improved diagnostics based on the
discovery of biomarkers has the potential to accelerate new drug
development by identifying, in advance, those patients most likely
to show a clinical response to a given drug. This would
significantly reduce the size, length and cost of clinical trials.
Technologies such as genomics, proteomics and molecular imaging
currently enable rapid, sensitive and reliable detection of
specific gene mutations, expression levels of particular genes, and
other molecular biomarkers. In spite of the availability of various
technologies for molecular characterization of tumors, the clinical
utilization of cancer biomarkers remains largely unrealized because
few cancer biomarkers have been discovered. For example, a recent
review article states: "There is a critical need for expedited
development of biomarkers and their use to improve diagnosis and
treatment of cancer." (Cho, 2007, Molecular Cancer 6:25) Another
recent review article on cancer biomarkers contains the following
comments: "The challenge is discovering cancer biomarkers. Although
there have been clinical successes in targeting molecularly defined
subsets of several tumor types--such as chronic myeloid leukemia,
gastrointestinal stromal tumor, lung cancer and glioblastoma
multiforme--using molecularly targeted agents, the ability to apply
such successes in a broader context is severely limited by the lack
of an efficient strategy to evaluate targeted agents in patients.
The problem mainly lies in the inability to select patients with
molecularly defined cancers for clinical trials to evaluate these
exciting new drugs. The solution requires biomarkers that reliably
identify those patients who are most likely to benefit from a
particular agent. (Sawyers, 2008, Nature 452:548-552, at 548)
Comments such as the foregoing illustrate the recognition of a need
for the discovery of clinically useful biomarkers and diagnostic
methods based on such biomarkers.
[0004] There are three distinct types of cancer biomarkers: (1)
prognostic biomarkers, (2) predictive biomarkers, and (3)
pharmacodynamic biomarkers. A prognostic biomarker is used to
classify a cancer, e.g., a solid tumor, according to
aggressiveness, i.e., rate of growth and/or metastasis, and
refractiveness to treatment. This is sometimes called
distinguishing "good outcome" tumors from "poor outcome" tumors. A
predictive biomarker is used to assess the probability that a
particular patient will benefit from treatment with a particular
drug. For example, patients with breast cancer in which the ERBB2
(HER2) gene is amplified are likely to benefit from treatment with
trastuzumab (HERCEPTIN.RTM.), whereas patients without ERBB2 gene
amplification are unlikely to benefit from treatment with
trastuzumab. A pharmacodynamic biomarker is an indication of the
effect(s) of a drug on its molecular target while the patient is
taking the drug. Accordingly, pharmacodynamic biomarkers often are
used to guide dosage level and dosing frequency, during the early
stages of clinical development of a new drug. For a discussion of
cancer biomarkers, see, e.g., Sawyers, 2008, Nature
452:548-552.
[0005] Tumors driven by EGFR or HER2 often respond to treatment
with inhibitors of EGFR or HER2, but these tumors invariably
develop resistance to these inhibitors. At least one mechanism of
acquired resistance to anti-EGFR or anti-HER2 treatment is
activation of HER3 (also known as ERBB3) signaling. See, e.g.,
Engelman et al, 2006, Clin. Cancer Res. 12:4372; Ritter et al,
2007, Clin. Cancer Res. 13:4909; Sergina et al, 2007, Nature
445:437. HER3 plays an important role in development of drug
resistance, as well as being involved in tumor initiation and
maintenance, through its heterodimerization with EGFR and HER2.
Consequently, there has been interest in development of HER3
inhibitors, especially anti-HER3 antibodies, since HER3 lacks
kinase activity.
[0006] As with other types of targeted therapy, some, but not all,
tumors respond to anti-HER3 therapy. Therefore, there is a need for
diagnostic methods based on predictive biomarkers that can be used
to identify patients with tumors that are likely (or unlikely) to
respond to treatment with a HER3 inhibitor such as an anti-HER3
antibody.
SUMMARY
[0007] The present invention is directed to methods of treating a
human subject harboring a locally advanced or metastatic non-small
cell lung cancer (NSCLC) tumor comprising administering a treatment
comprising an anti-HER3 antibody to a human subject diagnosed with
a locally advanced or metastatic NSCLC whose HRG gene expression at
an mRNA level is assessed as high.
[0008] Some embodiments comprise assessing HRG gene expression at
an mRNA level in a human subject diagnosed with a locally advanced
or metastatic NSCLC and administering a treatment comprising an
anti-HER3 antibody to a human subject whose HRG gene expression at
an mRNA level is assessed as high.
[0009] Some embodiments comprise ordering an assessment of HRG gene
expression at an mRNA level in a human subject diagnosed with a
locally advanced or metastatic NSCLC and administering a treatment
comprising an anti-HER3 antibody to the human subject whose HRG
gene expression at an mRNA level is assessed as high.
[0010] In a particular embodiment of the invention, the HRG gene
expression at an mRNA level is assessed as high if a delta Ct (dCt)
value is observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
[0011] In some embodiments, the predetermined threshold is chosen
statistically to minimize undesirable effects of false positives
and false negatives. In some embodiments, the predetermined
threshold dCt value is in a range of from about 2.7 to about 4.1.
In a preferred embodiment, the predetermined threshold dCt value is
selected from the group consisting of 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,
2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,
3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0.
[0012] In some embodiments, the subject harbors wild-type EGFR. In
preferred embodiments, the subject has also progressed on at least
one prior systemic therapy. In more preferred embodiments, a tumor
tissue or fragment thereof for or with which the HRG gene
expression is assessed has been removed from the subject prior to
any (systemic) therapy.
[0013] Some embodiments comprise assessing HRG gene expression at
an mRNA level in a human subject diagnosed with a locally advanced
or metastatic NSCLC, where HRG gene expression at an mRNA level is
assessed using quantitative reverse transcriptase polymerase chain
reaction (qRT-PCR).
[0014] In some embodiments, the biological sample comprises a tumor
sample.
[0015] In some embodiments, the anti-HER3 antibody is selected from
the group consisting of patritumab, duligotumab (MEHD-7945A),
seribantumab (MM-121), MM-111, LJM716, RG-7116, tri-specific
anti-EGFR/ERBB3 zybody, huHER3-8, or a derivative or fragment of
any of these.
[0016] In some embodiments, the treatment comprises an anti-HER3
antibody in combination with one or more of (i) a HER inhibitor,
(ii) a chemotherapy, (iii) radiation, and (iv) an other targeted
agent.
[0017] For example, in some embodiments the HER inhibitor is
selected from the group consisting of trastuzumab, T-DM1,
lapatinib, pertuzumab, cetuximab, panitumumab gefitinib, afatinib,
dacomitinib, KD-019 and erlotinib.
[0018] In some embodiments, the chemotherapy is selected from the
group consisting of cisplatin, carboplatin, gemcitabine,
pemetrexed, irinotecan, 5-fluoruracil, paclitaxel, docetaxel, and
capecitabine. However, other chemotherapies can be applied.
[0019] The present invention is also directed to methods of
treating a human subject harboring a locally advanced or metastatic
non-small cell lung cancer (NSCLC) tumor comprising assessing HRG
gene expression at an mRNA level in a human subject diagnosed with
a locally advanced or metastatic NSCLC, and withholding a treatment
comprising an anti-HER3 antibody to a human subject whose HRG gene
expression at an mRNA level is assessed as low.
[0020] Some embodiments comprise ordering an assessment of an HRG
gene expression at an mRNA level in a human subject diagnosed with
a locally advanced or metastatic NSCLC and withholding a treatment
comprising an anti-HER3 antibody to the human subject whose HRG
gene expression at an mRNA level is assessed as low.
[0021] In some embodiments, the HRG gene expression at an mRNA
level is assessed as low if a delta Ct (dCt) value is observed,
which is at or above a predetermined threshold, from a biological
sample taken from the subject diagnosed with a locally advanced or
metastatic NSCLC.
[0022] In some embodiments, the predetermined threshold is chosen
statistically to minimize undesirable effects of false positives
and false negatives. In some embodiments, the predetermined
threshold dCt value is in a range of from about 2.7 to about 4.1.
In some embodiments, the predetermined threshold dCt value is
selected from the group consisting of 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,
2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,
3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0.
[0023] In some embodiments, the subject harbors wild-type EGFR. In
preferred embodiments, the tumor has progressed on at least one
prior systemic therapy. In more preferred embodiments, a tumor
tissue or fragment thereof for or with which the HRG gene
expression is assessed has been removed from the subject prior to
any (systemic) therapy.
[0024] In some embodiments, HRG gene expression at an mRNA level is
assessed using quantitative reverse transcriptase polymerase chain
reaction (qRT-PCR).
[0025] In some embodiments, the biological sample comprises a tumor
sample.
[0026] In some embodiments, the treatment withheld comprises an
anti-HER3 antibody in combination with one or more of (i) a HER
inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv) an other
targeted agent.
[0027] Some embodiments comprise treating a human subject whose HRG
gene expression at an mRNA level is assessed as low with a HER
inhibitor selected from the group consisting of trastuzumab, T-DM1,
lapatinib, pertuzumab, cetuximab, panitumumab gefitinib, afatinib,
dacomitinib, KD-019 and erlotinib.
[0028] Some embodiments comprise treating a human subject whose HRG
gene expression at an mRNA level is assessed as low with a
chemotherapy selected from the group consisting of cisplatin,
carboplatin, gemcitabine, pemetrexed, irinotecan, 5-fluoruracil,
paclitaxel, docetaxel, and capecitabine. However, other
chemotherapies can be applied.
[0029] Some embodiments comprise treating a human subject whose HRG
gene expression at an mRNA level is assessed as low or high with
crizotinib. In some embodiments, the subject treated with
crizotinib has an ALK gene rearrangement or fusion.
[0030] The invention is also directed to kits for facilitating an
assessment of HRG gene expression at an mRNA level.
[0031] The invention is also directed to methods of identifying a
human patient diagnosed with a locally advanced or metastatic
non-small cell lung cancer (NSCLC) who is likely to benefit from a
treatment comprising an anti-HER3 antibody comprising obtaining a
biological sample from a human patient diagnosed with a locally
advanced or metastatic NSCLC, using the sample, determining a value
for HRG gene expression at an mRNA level in the human patient, and
recording the value determined.
[0032] Some embodiments comprise receiving a biological sample from
a human patient diagnosed with a locally advanced or metastatic
NSCLC; using the sample, determining a value for HRG gene
expression at an mRNA level in the human subject; and, optionally,
recording the value determined.
[0033] Some embodiments comprise assessing if the value determined
is below, at, or above a predetermined threshold value. In some
embodiments, the predetermined threshold dCt value is in a range of
from about 2.7 to about 4.1. In preferred embodiments, the
predetermined threshold dCt value is selected from the group
consisting of 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,
3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,
4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0.
[0034] Some embodiments involve characterizing the HRG gene
expression at an mRNA level as high if the value determined is
below the predetermined threshold value.
[0035] Some embodiments involve characterizing the HRG gene
expression at an mRNA level as low if the value determined is at or
above the predetermined threshold value.
[0036] Some embodiments comprise reporting the value determined to
an attending physician or other medical practitioner.
[0037] In some embodiments, the sample comprises a cancer tissue
sample.
[0038] In some embodiments, the subject does not harbor an
epidermal growth factor receptor (EGFR) sensitizing mutation. In
preferred embodiments, the subject harbors wild-type EGFR. In even
more preferred embodiments, the subject has progressed on at least
one prior systemic therapy. In more preferred embodiments, a tumor
tissue or fragment thereof for or with which the HRG gene
expression is assessed has been removed from the subject prior to
any (systemic) therapy.
[0039] In some embodiments, the treatment comprises an anti-HER3
antibody in combination with one or more of (i) an EGFR inhibitor
or a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv)
an other targeted agent.
[0040] The invention is also directed to methods where HRG gene
expression is assessed as high based on randomized clinical
data.
[0041] The invention is also directed to methods of receiving or
undergoing a treatment for a locally advanced or metastatic
non-small cell lung cancer (NSCLC) tumor or abstaining therefrom.
In some embodiments, the methods comprise providing an autologous
tissue sample or consenting to a taking of same to facilitate an
assessment of HRG gene expression at an mRNA level in a human
subject diagnosed with a locally advanced or metastatic NSCLC; and
receiving a treatment comprising an anti-HER3 antibody if HRG gene
expression at an mRNA level is assessed as high, or abstaining from
a treatment comprising an anti-HER3 antibody if HRG gene expression
at an mRNA level is assessed as low.
[0042] The invention is also directed to methods of electing a
treatment for a locally advanced or metastatic non-small cell lung
cancer (NSCLC) tumor. In some embodiments, the methods comprise
receiving an assessment of HRG gene expression at an mRNA level in
a human subject diagnosed with a locally advanced or metastatic
NSCLC; and electing to withhold a treatment comprising an anti-HER3
antibody if HRG gene expression at an mRNA level is assessed as
low, or electing to administer a treatment comprising an anti-HER3
antibody if HRG gene expression at an mRNA level is assessed as
high.
[0043] The present invention includes the following (1) to (97),
but is not limited thereto.
[0044] (1) A method of treating a human subject harboring a locally
advanced or metastatic non-small cell lung cancer (NSCLC) tumor
comprising:
[0045] assessing HRG gene expression at an mRNA level in a human
subject diagnosed with a locally advanced or metastatic NSCLC; and
[0046] administering a treatment comprising an anti-HER3 antibody
to a human subject whose HRG gene expression at an mRNA level is
assessed as high.
[0047] (2) The method of (1) in which the HRG gene expression at an
mRNA level is assessed as high if a delta Ct (dCt) value is
observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
[0048] (3) The method of (2) in which the predetermined threshold
is chosen statistically to minimize undesirable effects of false
positives and false negatives.
[0049] (4) The method of (2) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0050] (5) The method of (1), wherein the subject harbors wild-type
EGFR.
[0051] (6) The method of (5), wherein the tumor has progressed on
at least one prior systemic therapy.
[0052] (7) The method of (1) in which HRG gene expression at an
mRNA level is assessed using quantitative reverse transcriptase
polymerase chain reaction (qRT-PCR), RNA sequencing or ISH.
[0053] (8) The method of (2) in which the biological sample
comprises a tumor sample.
[0054] (9) The method of (1) in which the anti-HER3 antibody is
selected from the group consisting of patritumab, duligotumab
(MEHD-7945A), seribantumab (MM-121), MM-111, LJM716, RG-7116,
tri-specific anti-EGFR/ERBB3 zybody, huHER3-8, or a derivative or
fragment of any of these.
[0055] (10) The method of (1) in which the treatment comprises an
anti-HER3 antibody in combination with one or more of (i) a HER
inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv) an other
targeted agent.
[0056] (11) The method of (10), wherein the HER inhibitor is
selected from the group consisting of trastuzumab, T-DM1,
lapatinib, pertuzumab, cetuximab, panitumumab gefitinib, afatinib,
dacomitinib, KD-019 and erlotinib.
[0057] (12) The method of (10), wherein the chemotherapy is
selected from the group consisting of cisplatin, carboplatin,
gemcitabine, pemetrexed, irinotecan, 5-fluoruracil, paclitaxel,
docetaxel, and capecitabine.
[0058] (13) A method of treating a human subject harboring a
locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor comprising:
[0059] assessing HRG gene expression at an mRNA level in a human
subject diagnosed with a locally advanced or metastatic NSCLC; and
[0060] withholding a treatment comprising an anti-HER3 antibody to
a human subject whose HRG gene expression at an mRNA level is
assessed as low.
[0061] (14) The method of (13) in which the HRG gene expression at
an mRNA level is assessed as low if a delta Ct (dCt) value is
observed, which is at or above a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
[0062] (15) The method of (14) in which the predetermined threshold
is chosen statistically to minimize undesirable effects of false
positives and false negatives.
[0063] (16) The method of (14) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0064] (17) The method of (13), wherein the subject harbors
wild-type EGFR.
[0065] (18) The method of (17), wherein the tumor has progressed on
at least one prior systemic therapy.
[0066] (19) The method of (13) in which HRG gene expression at an
mRNA level is assessed using quantitative reverse transcriptase
polymerase chain reaction (qRT-PCR), RNA sequencing or ISH.
[0067] (20) The method of (14) in which the biological sample
comprises a tumor sample.
[0068] (21) The method of (13) in which the treatment withheld
comprises an anti-HER3 antibody in combination with one or more of
(i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv)
an other targeted agent.
[0069] (22) The method of (13) further comprising treating a human
subject whose HRG gene expression at an mRNA level is assessed as
low with a HER inhibitor selected from the group consisting of
trastuzumab, T-DM1, lapatinib, pertuzumab, cetuximab, panitumumab
gefitinib, afatinib, dacomitinib, KD-019 and erlotinib.
[0070] (23) The method of (13), further comprising treating a human
subject whose HRG gene expression at an mRNA level is assessed as
low with a chemotherapy selected from the group consisting of
cisplatin, carboplatin, gemcitabine, pemetrexed, irinotecan,
5-fluoruracil, paclitaxel, docetaxel, and capecitabine.
[0071] (24) A kit for facilitating an assessment of HRG gene
expression at an mRNA level.
[0072] (25) A method of identifying a human patient diagnosed with
a locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor who is likely to benefit from a treatment comprising an
anti-HER3 antibody comprising:
[0073] obtaining a biological sample from a human patient diagnosed
with a locally advanced or metastatic NSCLC;
[0074] using the sample, determining a value for HRG gene
expression at an mRNA level in the human patient; and
[0075] recording the value determined.
[0076] (26) The method of (25) further comprising assessing if the
value determined is below, at, or above a predetermined threshold
value.
[0077] (27) The method of (26) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0078] (28) The method of (26), further comprising characterizing
the HRG gene expression at an mRNA level as high if the value
determined is below the predetermined threshold value.
[0079] (29) The method of (26), further comprising characterizing
the HRG gene expression at an mRNA level as low if the value
determined is at or above the predetermined threshold value.
[0080] (30) The method of (25), further comprising reporting the
value determined to an attending physician or other medical
practitioner.
[0081] (31) The method of (25) in which the sample comprises a
cancer tissue sample.
[0082] (32) The method of (25), wherein the subject does not harbor
an epidermal growth factor receptor (EGFR) sensitizing
mutation.
[0083] (33) The method of (25), wherein the subject harbors
wild-type EGFR.
[0084] (34) The method of (33), wherein the tumor has progressed on
at least one prior systemic therapy.
[0085] (35) The method of (25), wherein the treatment comprises an
anti-HER3 antibody in combination with one or more of (i) a HER
inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv) an other
targeted agent.
[0086] (36) The method of any of (1) to (35), wherein HRG gene
expression is assessed as high based on randomized clinical
data.
[0087] (37) The method of (1), wherein the predetermined threshold
dCt value is in a range of from about 2.7 to about 4.1.
[0088] (38) The method of (13), wherein the predetermined threshold
dCt value is in a range of from about 2.7 to about 4.1.
[0089] (39) The method of (26), wherein the the predetermined
threshold dCt value is in a range of from about 2.7 to about
4.1.
[0090] (40) A method of receiving or undergoing a treatment for a
locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor or abstaining therefrom comprising:
[0091] providing an autologous tissue sample or consenting to a
taking of same to facilitate an assessment of HRG gene expression
at an mRNA level in a human subject diagnosed with a locally
advanced or metastatic NSCLC; and
[0092] receiving or undergoing a treatment comprising an anti-HER3
antibody if HRG gene expression at an mRNA level is assessed as
high, or
[0093] abstaining from a treatment comprising an anti-HER3 antibody
if HRG gene expression at an mRNA level is assessed as low.
[0094] (41) A method of electing a treatment for a locally advanced
or metastatic non-small cell lung cancer (NSCLC) tumor
comprising:
[0095] receiving or undergoing an assessment of HRG gene expression
at an mRNA level in a human subject diagnosed with a locally
advanced or metastatic NSCLC; and
[0096] electing to withhold or abstain from a treatment comprising
an anti-HER3 antibody if HRG gene expression at an mRNA level is
assessed as low, or
[0097] electing to receive or undergo a treatment comprising an
anti-HER3 antibody if HRG gene expression at an mRNA level is
assessed as high.
[0098] (42) A method of identifying a human patient diagnosed with
a locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor who is likely to benefit from a treatment comprising an
anti-HER3 antibody comprising:
[0099] receiving a biological sample from a human patient diagnosed
with a locally advanced or metastatic NSCLC;
[0100] using the sample, determining a value for HRG gene
expression at an mRNA level in the human subject; and
[0101] optionally, recording the value determined.
[0102] (43) A method of treating a human subject harboring a
locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor comprising:
[0103] ordering an assessment of HRG gene expression at an mRNA
level in a human subject diagnosed with a locally advanced or
metastatic NSCLC; and
[0104] administering a treatment comprising an anti-HER3 antibody
to the human subject whose HRG gene expression at an mRNA level is
assessed as high.
[0105] (44) A method of withholding a treatment of a human subject
harboring a locally advanced or metastatic non-small cell lung
cancer (NSCLC) tumor comprising:
[0106] ordering an assessment of an HRG gene expression at an mRNA
level in a human subject diagnosed with a locally advanced or
metastatic NSCLC; and
[0107] withholding a treatment comprising an anti-HER3 antibody to
the human subject whose HRG gene expression at an mRNA level is
assessed as low.
[0108] (45) A method of treating a human subject harboring a
locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor comprising administering a treatment comprising an anti-HER3
antibody to a human subject diagnosed with a locally advanced or
metastatic NSCLC whose HRG gene expression at an mRNA level is
assessed as high.
[0109] (46) The method of (45) in which the HRG gene expression at
an mRNA level is assessed as high if a delta Ct (dCt) value is
observed, which is below a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
[0110] (47) The method of (46) in which the predetermined threshold
is chosen statistically to minimize undesirable effects of false
positives and false negatives.
[0111] (48) The method of (46) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0112] (49) The method of (45), wherein the subject harbors
wild-type EGFR.
[0113] (50) The method of (49), wherein the tumor has progressed on
at least one prior systemic therapy.
[0114] (51) The method of (45), further comprising assessing gene
expression at an mRNA level in the human subject diagnosed with the
locally advanced or metastatic NSCLC, wherein HRG gene expression
at an mRNA level is assessed using quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR), RNA sequencing
or ISH.
[0115] (52) The method of (46) in which the biological sample
comprises a tumor sample.
[0116] (53) The method of (45) in which the anti-HER3 antibody is
selected from the group consisting of patritumab, duligotumab
(MEHD-7945A), seribantumab (MM-121), MM-111, LJM716, RG-7116,
tri-specific anti-EGFR/ERBB3 zybody, huHER3-8, or a derivative or
fragment of any of these.
[0117] (54) The method of (45) in which the treatment comprises
administering an anti-HER3 antibody in combination with one or more
of (i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and
(iv) an other targeted agent.
[0118] (55) The method of (54), wherein the HER inhibitor is
selected from the group consisting of trastuzumab, T-DM1,
lapatinib, pertuzumab, cetuximab, panitumumab gefitinib, afatinib,
dacomitinib, KD-019 and erlotinib.
[0119] (56) The method of (55), wherein the chemotherapy is
selected from the group consisting of cisplatin, carboplatin,
gemcitabine, pemetrexed, irinotecan, 5-fluoruracil, paclitaxel,
docetaxel, and capecitabine.
[0120] (57) A method of treating a human subject harboring a
locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor comprising:
[0121] withholding a treatment comprising an anti-HER3 antibody to
a human subject diagnosed with a locally advanced or metastatic
NSCLC whose HRG gene expression at an mRNA level is assessed as
low.
[0122] (58) The method of (57) in which the HRG gene expression at
an mRNA level is assessed as low if a delta Ct (dCt) value is
observed, which is at or above a predetermined threshold, from a
biological sample taken from the subject diagnosed with a locally
advanced or metastatic NSCLC.
[0123] (59) The method of (58) in which the predetermined threshold
is chosen statistically to minimize undesirable effects of false
positives and false negatives.
[0124] (60) The method of (58) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0125] (61) The method of (57), wherein the subject harbors
wild-type EGFR.
[0126] (62) The method of (61), wherein the tumor has progressed on
at least one prior systemic therapy.
[0127] (63) The method of (57), further comprising assessing HRG
gene expression at an mRNA level in the human subject diagnosed
with the locally advanced or metastatic NSCLC, wherein HRG gene
expression at an mRNA level is assessed using quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR), RNA sequencing
or ISH.
[0128] (64) The method of (58) in which the biological sample
comprises a tumor sample.
[0129] (65) The method of (57) in which the treatment withheld
comprises an anti-HER3 antibody in combination with one or more of
(i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv)
an other targeted agent.
[0130] (66) The method of (57) further comprising treating a human
subject whose HRG gene expression at an mRNA level is assessed as
low with a HER inhibitor selected from the group consisting of
trastuzumab, T-DM1, lapatinib, pertuzumab, cetuximab, panitumumab
gefitinib, afatinib, dacomitinib, KD-019 and erlotinib.
[0131] (67) The method of (57), further comprising treating a human
subject whose HRG gene expression at an mRNA level is assessed as
low with a chemotherapy selected from the group consisting of
cisplatin, carboplatin, gemcitabine, pemetrexed, irinotecan,
5-fluoruracil, paclitaxel, docetaxel, and capecitabine.
[0132] (68) A kit for facilitating an assessment of HRG gene
expression at an mRNA level.
[0133] (69) A method of identifying a human patient diagnosed with
a locally advanced or metastatic non-small cell lung cancer (NSCLC)
tumor who is likely to benefit from a treatment comprising an
anti-HER3 antibody comprising:
[0134] obtaining a biological sample taken from a human patient
diagnosed with a locally advanced or metastatic NSCLC;
[0135] using the sample, determining a value for HRG gene
expression at an mRNA level in the human patient; and
[0136] optionally, recording the value determined.
[0137] (70) The method of (69) further comprising assessing if the
value determined is below, at, or above a predetermined threshold
value.
[0138] (71) The method of (70) in which the predetermined threshold
dCt value is selected from the group consisting of 2.0, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,
4.9, and 5.0.
[0139] (72) The method of (70), further comprising characterizing
the HRG gene expression at an mRNA level as high if the value
determined is below the predetermined threshold value.
[0140] (73) The method of (70), further comprising characterizing
the HRG gene expression at an mRNA level as low if the value
determined is at or above the predetermined threshold value.
[0141] (74) The method of (69), further comprising reporting the
value determined to an attending physician or other medical
practitioner.
[0142] (75) The method of (69) in which the sample comprises a
cancer tissue sample.
[0143] (76) The method of (69), wherein the subject does not harbor
an epidermal growth factor receptor (EGFR) sensitizing
mutation.
[0144] (77) The method of (69), wherein the subject harbors
wild-type EGFR.
[0145] (78) The method of (77), wherein the tumor has progressed on
at least one prior systemic therapy.
[0146] (79) The method of (69), wherein the treatment comprises an
anti-HER3 antibody in combination with one or more of (i) a HER
inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv) an other
targeted agent.
[0147] (80) The method of any of (1) to (79), wherein HRG gene
expression is assessed as high based on randomized clinical
data.
[0148] (81) The method of (46), wherein the predetermined threshold
dCt value is in a range of from about 2.7 to about 4.1.
[0149] (82) The method of (58), wherein the predetermined threshold
dCt value is in a range of from about 2.7 to about 4.1.
[0150] (83) The method of (70), wherein the the predetermined
threshold dCt value is in a range of from about 2.7 to about
4.1.
[0151] (84) A method of any of the preceding claims, wherein HRG
gene expression is assessed using an regulatory authority-approved
test.
[0152] (85) The method of (84), wherein the regulatory
authority-approved test is an FDA (Food and Drug Administration,
the United States)-approved, EMA (European Medicines Agency,
European Union)-approved or PMDA (Pharmaceuticals and Medical
Devices Agency, Japan)-approved test.
[0153] (86) The method of (2) in which the predetermined threshold
dCt value is selected from the group consisting of 5.0, 4.9, 4.8,
4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5,
3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2,
2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4,
-0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5,
-1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6,
-2.7, -2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7,
-3.8, -3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8,
-4.9, -5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, --5.8, -5.9,
-6.0, -6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0,
-7.1, -7.2 and -7.3.
[0154] (87) The method of (14) in which the predetermined threshold
dCt value is selected from the group consisting of 5.0, 4.9, 4.8,
4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5,
3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2,
2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4,
-0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5,
-1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6,
-2.7, -2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7,
-3.8, -3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8,
-4.9, -5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9,
-6.0, -6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0,
-7.1, -7.2 and -7.3.
[0155] (88) The method of (26) in which the predetermined threshold
dCt value is selected from the group consisting of 5.0, 4.9, 4.8,
4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5,
3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2,
2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4,
-0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5,
-1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6,
-2.7, -2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7,
-3.8, -3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8,
-4.9, -5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9,
-6.0, -6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0,
-7.1, -7.2 and -7.3.
[0156] (89) The method of (6) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
[0157] (90) The method of (18) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
[0158] (91) The method of (34) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
[0159] (92) The method of (2) in which the predetermined threshold
dCt value is in a range of from about -7.3 to about 5.0.
[0160] (93) The method of (14) in which the predetermined threshold
dCt value is in a range of from about -7.3 to about 5.0.
[0161] (94) The method of (26) in which the predetermined threshold
dCt value is in a range of from about -7.3 to about 5.0.
[0162] (95) The method of (50) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
[0163] (96) The method of (62) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
[0164] (97) The method of (78) in which a tumor tissue or fragment
thereof for or with which the HRG gene expression is assessed has
been removed from the subject prior to any therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0165] FIG. 1 depicts progression-free survival (showing high- and
low-dose patritumab+erlotinib vs. placebo+erlitonib) for all
subjects from the study in Example 2.
[0166] FIG. 2 depicts overall survival (showing high- and low-dose
patritumab+erlotinib vs. placebo+erlitonib) for all subjects from
the study in Example 2.
[0167] FIG. 3 depicts progression free survival (showing high- and
low-dose patritumab+erlotinib vs. placebo+erlitonib) for subjects
from the study in Example 3 assessed as having high HRG gene
expression at an mRNA level.
[0168] FIG. 4 depicts progression free survival (showing pooled
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 3 assessed as having high HRG gene expression at
an mRNA level.
[0169] FIG. 5 depicts overall survival (showing high- and low-dose
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 4 assessed as having high HRG gene expression at
an mRNA level.
[0170] FIG. 6 depicts overall survival (showing pooled
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 4 assessed as having high HRG gene expression at
an mRNA level.
[0171] FIG. 7 depicts progression free survival (showing high- and
low-dose patritumab+erlotinib vs. placebo+erlitonib) for subjects
from the study in Example 6 assessed as having low HRG gene
expression at an mRNA level.
[0172] FIG. 8 depicts progression free survival (showing pooled
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 6 assessed as having low HRG gene expression at an
mRNA level.
[0173] FIG. 9 depicts overall survival (showing high- and low-dose
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 6 assessed as having low HRG gene expression at an
mRNA level.
[0174] FIG. 10 depicts overall survival (showing pooled
patritumab+erlotinib vs. placebo+erlitonib) for subjects from the
study in Example 6 assessed as having low HRG gene expression at an
mRNA level.
[0175] FIG. 11 depicts progression free survival (showing high- and
low-dose patritumab+erlotinib vs. placebo+erlitonib) for subjects
from the study in Example 7 assessed as having high HRG gene
expression at an mRNA level and for subjects assessed as having low
HRG gene expression at an mRNA level.
[0176] FIG. 12 depicts optimized cut-off values for high HRG and
low HRG groups.
[0177] FIG. 13 depicts progression free survival for subjects from
the study in Example 8 assessed as having high HRG gene expression
at an mRNA level and EGFR wild type.
[0178] FIG. 14 depicts efficacy determined in vitro by measuring
reduction of phospho-HER3 and phospho-AKT levels by Western
blotting.
[0179] FIG. 15 depicts Western blots showing that U3-1287 can block
ligand-dependent basal HER3 phosphorylation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0180] As used herein, unless indicated otherwise, when referring
to a numerical value, the term "about" means plus or minus 10% of
the enumerated value.
[0181] As used herein, "cancer" and "tumor" are
interchangeable.
[0182] As used herein, "treatment" means a medical care given to a
subject or patient, or administration of a dose of a medicine. In
some embodiments, "treatment" could be "pharmaceutical
composition", "medicament" or "agent" that could comprise a HER
inhibitor such as anti-HER3 antibody. In some embodiments,
"treatment" could be a "chemotherapy", "immune therapy",
"immunotherapy" or "radiotherapy".
[0183] As used herein, "EGFR mutation" means any mutation in an
EGFR gene. "EGFR mutation" can be, for example, an EGFR exon 19
deletion and/or an exon 21 (L858R) substitution mutation. However,
"EGFR mutation" is not limited thereto.
[0184] As used herein, "HER" is one selected from the group
consisting of HER1 (EGFR), HER2, HER3 and HER4.
[0185] As used herein, "HER3" means the human protein encoded by
the gene identified by Entrez Gene ID No. 2065, and allelic
variants thereof.
[0186] As used herein, "HER inhibitor" means a molecule (small
molecule or macromolecule, e.g., an antibody or antigen binding
fragment thereof) that inhibits, neutralizes, prevents or
eliminates at least a portion of the biological activity of a HER.
Preferably, a HER inhibitor binds to the HER. However, "HER
inhibitor" can be a molecule that does not directly bind to the
HER, as long as said molecule inhibits, neutralizes, prevents or
eliminates at least a portion of the biological activity of the
HER. Examples of HER1 inhibitors (EGFR inhibitor) include
lapatinib, erlotinib, cetuximab, gefitinib, afatinib, dacomitinib,
panitumumab and KD-019. Examples of HER2 inhibitors include
trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1).
[0187] As used herein, "HER3 inhibitor" means a molecule (small
molecule or macromolecule, e.g., an antibody or antigen binding
fragment thereof) that inhibits, neutralizes, prevents or
eliminates at least a portion of the biological activity of HER3.
Preferably, the HER3 inhibitor binds to HER3. However, "HER3
inhibitor" can be a molecule that does not directly bind to HER3,
as long as said molecule inhibits, neutralizes, prevents or
eliminates at least a portion of the biological activity of HER3.
The effect on "biological activity" can be direct or indirect, such
as downstream signal transduction and heterodimerization with other
HER family molecules such as EGFR, HER2 and HER4. For example, the
HER3 inhibitor can be an inhibitor of EGFR/HER3, HER2/HER3 or
HER4/HER3 heterodimerization, or an inhibitor of a signal
transduction derived from any of these heterodimerizations. In this
context, "HER3 inhibitor" can include, for example pertuzumab,
nimotuzumab, MM-111 and cetuximab. Further, without being bound by
theory it is believed that HER3 forms a heterodimer with non-HER
receptors, such as MET (c-MET). Thus, in some embodiments "HER3
inhibitor" can include, for example, a MET inhibitor such as
onartuzumab and/or tivantinive.
[0188] As used herein, "HRG" (also known as neuregulin-1, NRG1,
heregulin, and HRG1) means the human protein encoded by the gene
identified by Entrez Gene ID No. 3084, and allelic variants
thereof.
[0189] As used herein, "non-small cell lung cancer" and "non-small
cell lung carcinoma" are interchangeable.
[0190] As used herein, "predetermined threshold (value)" means the
threshold numeric value at which a classifier gives the desirable
balance between (the cost of) false negatives and false
positives.
[0191] Preferably, "predetermined threshold (value)" means the
potential threshold numeric value to divide the entire population
(of patients or subjects) into two (or more) subgroups so that it
can bring clinical benefit to patients with the threshold or higher
(HRG) gene expression (used herein as "high HRG" subgroup),
compared to patients with the lower (HRG) gene expression than the
threshold (used herein as "low HRG" subgroup).
[0192] In case a threshold value is a dCt, preferably,
"predetermined threshold (value)" means the potential threshold
numeric value to divide the entire population (of patients or
subjects) into two (or more) subgroups so that it can bring
clinical benefit to patients with the threshold or lower (HRG) gene
expression (used herein as "high HRG" subgroup), compared to
patients with the higher (HRG) gene expression than the threshold
(used herein as "low HRG" subgroup).
[0193] In some embodiments, "predetermined threshold" is
statistically (and clinically) determined, refined, adjusted and/or
confirmed through, on, or based on, a clinical study and analyses
of outcome thereof (collectively, "clinical data"), and/or a
preclinical or non-clinical study (collectively, "non-clinical
data"), in order to minimize undesirable effects of false positives
and false negatives.
[0194] In some embodiments, "predetermined threshold" is
statistically (and clinically) determined, refined, adjusted and/or
confirmed on, or based on, clinical data (and optionally
non-clinical data), further more preferably randomized clinical
data (and optionally non-clinical data), to ensure all patients
that benefit from treatment are included in the HRG high
subgroup.
[0195] More preferably, "predetermined threshold" is determined,
refined, adjusted and/or confirmed through, on, or based on
pharmacological characteristics (i.e., mechanism of action),
preclinical or non-clinical study data, clinical study data, and
commercial sample data purchased from external companies or the
like, in order to maximize clinical benefit from "high HRG"
subgroup compared with "low HRG" subgroup. Some statistical method
such as Adaptive Biomarker Threshold Design (i.e., maximum
likelihood approach), Jiang W, Freidlin B, Simon R.
Biomarker-Adaptive Threshold Design: A Procedure for Evaluating
Treatment With Possible Biomarker-Defined Subset Effect, J Natl
Cancer Inst. 2007;99(13):1036-43, and the like is used to
determine, refine, adjust and/or confirm the threshold using the
all available data of pre/non-clinical studies, clinical studies,
commercial sample, etc. (to ensure all patients that benefit from
treatment are included in the HRG high subgroup). In some
embodiments, "predetermined threshold" is determined so that high
HRG subgroup can be larger or can include all patients that drive
benefit from treatment.
[0196] As used herein, "subject," "human subject," and "patient"
are interchangeable.
[0197] As used herein, "subject suffering from a cancer" and
"subject harboring a cancer" are interchangeable.
[0198] In some preferred embodiments, when a group of patients
suffering from a cancer are treated by administering a HER3
inhibitor or placebo with or without a further medicament, and said
group is divided into "high HRG" subgroup and "low HRG" subgroup
using the predetermined threshold, average anti-cancer efficacy of
the administered HER3 inhibitor is better than that of control
(e.g. placebo) with clinical(ly) (meaningful) benefit in the "high
HRG" subgroup, while average anti-cancer efficacy of the
administered HER3 inhibitor is slightly better or not better than
that of control (e.g. placebo) with no clinical(ly) (meaningful)
benefit in the "low HRG" subgroup. In more preferred embodiments,
average anti-cancer efficacy of the administered HER3 inhibitor is
statistically significantly better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit in "high HRG"
subgroup, while average anti-cancer efficacy of the administered
HER3 inhibitor is not statistically significantly better than that
of control (e.g. placebo) with no clinical(ly) (meaningful) benefit
in the "low HRG" subgroup.
[0199] In other preferred embodiments, when a group of patients
suffering from a cancer is divided into a "high HRG" subgroup and a
"low HRG" subgroup using the predetermined threshold, and each
group is treated by administering a HER3 inhibitor or placebo with
or without a further medicament, average anti-cancer efficacy of
the administered HER3 inhibitor is better than that of a control
(e.g. placebo) with clinical(ly) (meaningful) benefit in the "high
HRG" subgroup, while average anti-cancer efficacy of the
administered HER3 inhibitor is slightly better or not better than
that of control (e.g. placebo) with no clinical(ly) (meaningful)
benefit in the "low HRG" subgroup. In more preferred embodiments,
average anti-cancer efficacy of the administered HER3 inhibitor is
statistically significantly better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit in the "high HRG"
subgroup, while average anti-cancer efficacy of the administered
HER3 inhibitor is not statistically significantly better than that
of control (e.g. placebo) with no clinical(ly) (meaningful) benefit
in the "low HRG" subgroup.
[0200] In other embodiments, "predetermined threshold" can be the
median of HRG levels which are measured in pre-/non-clinical study,
clinical study and/or commercial sample, for example with a group
of patients suffering from a cancer whose HRG levels are
measureable (can be measured) or detectable. In other preferred
embodiments, when a group of patients suffering from a cancer, such
as non-small cell lung cancer (NSCLC), are treated by administering
a HER3 inhibitor or placebo with or without a further medicament,
and the group is divided into a high HRG subgroup and low HRG
subgroup using the median HRG level of the patients as the
predetermined threshold, average anti-cancer efficacy of the
administered HER3 inhibitor is better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit in the "high HRG"
subgroup, while average anti-cancer efficacy of the administered
HER3 inhibitor is slightly better or not better than that of
control (e.g. placebo) with no clinical(ly) (meaningful) benefit in
the "low HRG" subgroup. In more preferred embodiments, average
anti-cancer efficacy of the administered HER3 inhibitor is
statistically significantly better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit in the "high HRG"
subgroup, while average anti-cancer efficacy of the administered
HER3 inhibitor is not statistically significantly better than that
of control (e.g. placebo) with no clinical(ly) (meaningful) benefit
in the "low HRG" subgroup. In some embodiments, the predetermined
threshold is the median of HRG level of a group of patients
suffering from a cancer, and said threshold can be refined or
adjusted, (to ensure all patients that benefit from treatment are
included in the HRG high sub group).
[0201] In other preferred embodiments, when a group of patients
suffering from a cancer is divided into a "high HRG" subgroup and
"low HRG" subgroup using the predetermined threshold, and the "high
HRG" subgroup is treated by administering a HER3 inhibitor or
placebo with or without a further medicament, average anti-cancer
efficacy of the administered HER3 inhibitor is better than that of
a control (e.g. placebo) with clinical(ly) (meaningful) benefit in
the "high HRG" subgroup. In more preferred embodiments, average
anti-cancer efficacy of the administered HER3 inhibitor is
statistically significantly better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit in the "high HRG"
subgroup.
[0202] In other preferred embodiments, when "high HRG" patients
suffering from a cancer are identified using the predetermined
threshold, and the patients are treated by administering a HER3
inhibitor or placebo with or without a further medicament, average
anti-cancer efficacy of the administered HER3 inhibitor is better
than that of a control (e.g. placebo) with clinical(ly)
(meaningful) benefit. In more preferred embodiments, average
anti-cancer efficacy of the administered HER3 inhibitor is
statistically significantly better than that of control (e.g.
placebo) with clinical(ly) (meaningful) benefit.
[0203] As used herein, "further medicament" means any therapeutic
or prophylactic molecule other than the HER3 inhibitor which is to
be used in combination with said molecule. In some embodiments,
"further medicament" is one or more of a HER inhibitor, a
chemotherapy, or a radiation therapy.
[0204] In some embodiments, an indicator (index) of "anti-cancer
efficacy" can be progression-free survival (PFS) or overall
survival (OS), but is not limited thereto. The indicator can be any
surrogate marker of anti-cancer efficacy of a HER3 inhibitor.
[0205] As used herein, "high HRG" is a numerical value
representing, or represents, a level of HRG gene expression at or
above a predetermined threshold. In the present invention, "high
HRG", "high HRG (sub)group" and "high HRG patient (or subject)"
mean a level of HRG gene expression at or above a (predetermined)
threshold, (sub)group having level(s) of HRG gene expression at or
above a (predetermined) threshold, and, patient (or subject) having
a level of HRG gene expression at or above a (predetermined)
threshold, respectively. The HRG classification can be based on HRG
gene expression at an RNA level, for example.
[0206] As used herein, "low HRG" is a numerical value representing,
or represents, a level of HRG gene expression at or below a
predetermined threshold. In the present invention, "low HRG", "low
HRG (sub)group" and "low HRG patient (or subject)" mean a level of
HRG gene expression at or below a (predetermined) threshold,
(sub)group having level(s) of HRG gene expression at or below a
(predetermined) threshold, and, patient (or subject) having a level
of HRG gene expression at or below a (predetermined) threshold,
respectively. The HRG classification can be based on HRG gene
expression at an RNA level, for example.
[0207] As used herein, "response" or "responding" to treatment
means, with regard to a treated tumor, that the tumor displays: (a)
slowing of growth, (b) cessation of growth, or (c) regression.
[0208] The methods disclosed herein can be used for identifying a
subject, for example a human subject, harboring or diagnosed with a
tumor or cancer cells. In some embodiments, the subject harbors
solid or liquid tumors that may be driven by the HER3 pathway, or
that may have resistance to other therapies mediated by the HER3
pathway. In some embodiments, the subject harbors lung cancer,
colorectal cancer, head and neck cancer, breast cancer,
gastrointestinal cancer, pancreatic cancer, prostate cancer,
ovarian cancer, endometrial cancer, salivary gland cancer, renal
cancer, colon cancer, gastric cancer (stomach cancer), thyroid
cancer, bladder cancer, glioma, melanoma, metastatic breast cancer,
epidermal carcinoma, esophageal cancer, cervical cancer, squamous
cell carcinoma, small-cell lung cancer, or non-small cell lung
cancer. In some embodiments, the methods disclosed herein can be
used to identify a subject harboring a locally advanced or
metastatic tumor, such as a locally advanced or metastatic NSCLC
(tumor) or locally advanced or metastatic head and neck cancer. In
some embodiments, methods disclosed herein can be used to identify
a subject, such as a subject harboring a locally advanced or
metastatic NSCLC (tumor), that is likely to benefit from a
treatment comprising an anti-HER3 antibody or HER3 inhibitor having
a low molecular weight. In some embodiments, the subject is
harboring a Stage III, e.g., Stage IIIb, or Stage IV tumor. Methods
of identifying a subject can comprise, for example, assessing HRG
gene expression at an mRNA level in a human subject diagnosed with
a tumor or cancer.
[0209] In some embodiments, methods disclosed herein can be used to
identify a subject harboring a locally advanced or metastatic NSCLC
(tumor), that is likely to benefit from a treatment comprising
(administering) an anti-HER3 antibody or HER3 inhibitor having a
low molecular weight, provided that, any subject who having an ALK
gene fusion or rearrangement is excluded from those to whom the
methods are applied.
[0210] In some embodiments, the methods disclosed herein can be
used to treat a subject identified as harboring a tumor or cancer
cells. In some embodiments, methods of identifying or treating a
human subject harboring a locally advanced or metastatic NSCLC
(tumor) can comprise assessing HRG gene expression at an mRNA level
in a human subject diagnosed with a locally advanced or metastatic
NSCLC. In some embodiments, the subject does not harbor an
epidermal growth factor receptor (EGFR) sensitizing mutation. In
some embodiments, the subject harbors wild-type EGFR. In some
embodiments, the subject does not harbor an ALK gene fusion or
rearrangement. In some embodiments, the disease or tumor has
progressed on at least one prior systemic therapy, such as
chemotherapy. Some embodiments comprise administering a treatment
comprising an anti-HER3 antibody to a human subject whose HRG gene
expression at an mRNA is assessed as high. In some embodiments,
treatment comprises (administering) an anti-HER3 antibody in
combination with at least one agent that inhibits a HER family
receptor other than HER3. In some embodiments, treatment comprises
(administering) an anti-HER3 antibody in combination with at least
one agent that inhibits a non-HER family tyrosine kinase receptor.
In some embodiments, an anti-HER3 antibody is administered in
combination with non-specific chemotherapy.
[0211] In some preferred embodiments, patients to whom the methods
disclosed herein can be applied are heregulin high, EGFR wild-type
subjects with locally advanced or metastatic non-small cell lung
cancer who have progressed on at least one prior systemic therapy.
In some embodiments, the patients are HER inhibitor naive. In
preferred embodiments, a tumor tissue or fragment thereof for or
with which the HRG gene expression is assessed has been removed
from the subject or patient prior to any (systemic) therapy.
[0212] In some preferred embodiments, patients to whom the methods
disclosed herein can be applied include a subject with a first-line
metastatic or locally advanced head and neck cancer that will be
concurrently treated with one or more of cetuximab, cisplatin,
panitumumab, 5-fluoruracil, radiotherapy, and radiation therapy
(locally advanced only).
[0213] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with a second-line
metastatic NSCLC or other cancer that will be concurrently treated
with docataxel.
[0214] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with a NSCLC or other
cancer that will be concurrently treated with an immune
therapy.
[0215] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with a third line, HER2
positive, (metastatic) breast cancer that will be concurrently
treated with a PI3K pathway inhibitor.
[0216] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with HER2 negative
(metastatic) breast cancer that will be concurrently treated with a
hormone therapy or PI3K pathway inhibitor.
[0217] In the present invention, PI3K pathway inhibitors include
PI3K inhibitors, mTOR inhibitors and AKT inhibitors.[0096] In some
embodiments, patients to whom the methods disclosed herein can be
applied include a subject with a first-line metastatic
EGFR-sensitizing mutant positive for NSCLC or other cancer that
will be concurrently treated with one or more of erlotinib,
gefitinib, and afitinib.
[0218] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with a first-line
metastatic NSCLC or other cancer that will be concurrently treated
with platinum-based chemotherapy.
[0219] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject with RAS wild-type
colorectal cancer that will be concurrently treated with one or
more of cetuximab, panitumumab, and chemotherapy.
[0220] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject that with HER2 positive
first line metastatic breast cancer or other cancer that will be
concurrently treated with one or more of trastuzumab, paclitaxel,
docataxel, T-DM1 and pertuzumab.
[0221] In some embodiments, patients to whom the methods disclosed
herein can be applied include a subject that with HER2 positive
second or later line metastatic breast cancer or other cancer that
will be concurrently treated with one or more of lapatinib,
capecitabine, trastuzumab, and paclitaxel.
[0222] In some embodiments, patients to whom the methods disclosed
herein can be applied have not failed with an earlier line of
therapy. In some embodiments, patients to whom the methods
disclosed herein can be applied have not failed with an earlier
line of therapy and the patients have been classified as "high
HRG."
[0223] In some embodiments, the methods disclosed herein can be
used to identify and/or treat HRG high, EGFR wild-type subjects
with locally advanced or metastatic NSCLC who will benefit from
treatment of patritumab in combination with a HER inhibitor.
[0224] In some embodiments, the methods disclosed herein can be
used to identify and/or treat HRG high, EGFR wild-type subjects
with locally advanced or metastatic NSCLC who will benefit from
treatment of patritumab in combination with chemotherapy.
[0225] In some embodiments, the methods disclosed herein can be
used to identify and/or treat HRG high, EGFR mutated subjects, for
example subjects with locally advanced or metastatic NSCLC who will
benefit from treatment of patritumab in combination with a HER
inhibitor.
[0226] In some embodiments, the methods disclosed herein can be
used to identify and/or treat HRG high, EGFR mutated subjects with
locally advanced or metastatic NSCLC who will benefit from
treatment of patritumab in combination with chemotherapy.
[0227] In some embodiments, the methods disclosed herein can be
used to identify and/or treat a "HRG high" patient suffering from a
cancer who will benefit from treatment of patritumab in combination
with an immune therapy or immunotherapy. Such cancers include
NSCLC.
[0228] In some embodiments, the methods disclosed herein can be
used to identify and/or treat a "HRG high" patient suffering from a
cancer who will benefit from treatment of patritumab in combination
with a hormone therapy or PI3K (phosphoinositide 3-kinase) pathway
inhibitor. Such cancers include breast cancer, preferably,
HER2-negative breast cancer. Such PI3K pathway inhibitors include
PI3K inhibitors, AKT inhibitors and mTOR (mammalian Target Of
Rapamycin) inhibitors.
[0229] In some embodiments, the methods disclosed herein can be
used to identify and/or treat a "HRG high" patient suffering from a
cancer who will benefit from treatment of patritumab in combination
with a PI3K inhibitor. Such cancers include breast cancer,
preferably, HER2-positive breast cancer.
[0230] In some embodiments, the methods disclosed herein can be
used to identify and/or treat a "HRG high" patient suffering from a
cancer who will benefit from treatment of patritumab in combination
with a ALK inhibitor. Such cancers include NSCLC. Such ALK
(anaplastic lymphoma kinase) inhibitor includes crizotinib
(Xalkori).
[0231] In some embodiments, the methods disclosed herein can be
used to identify and/or treat acute respiratory distress syndrome,
pulmonary fibrosis, schizophrenia, heart disease, atherosclerosis,
and Duchenne's muscular dystrophy.
HER3 Antibodies
[0232] Antibodies suitable for treatment are not particularly
limited, and can be any protein or ligand that can bind to HER3. In
some embodiments, the antibodies can be binding proteins or
fragments thereof that bind to HER3. In some preferred embodiments,
the antibodies can inhibit, neutralize, prevent or eliminate at
least a portion of the biological activity of HER3.
[0233] HER3 antibodies can be, for example, one or more of
patritumab, duligotumab (MEHD-7945A), seribantumab (MM-121),
MM-111, LJM716, RG-7116 (glyco engineered anti-HER3 monoclonal
antibody), tri-specific anti-EGFR/ERBB3 zybody, huHER3-8, or a
derivative or fragment of any of these that can bind to HER3.
[0234] Antibody fragments include, for example, Fab fragments, Fab'
fragments, F(ab).sub.2 fragments, Fv fragments, diabodies
(Hollinger et al. (1993) Proc. Natl. Acad. Sci. U.S.A.
90:6444-6448), single chain antibody molecules (Pluckthun in: The
Pharmacology of Monoclonal Antibodies 113, Rosenburg and Moore,
eds., Springer Verlag, N.Y. (1994), 269-315), scFv fragments, and
other fragments that can inhibit HER3.
[0235] Derivatives of antibodies or antibody fragments can include,
for example, a bispecific antibody, a multispecific antibody, a
biscFv fragment, a diabody, a nanobody, an antibody-drug conjugate,
an immunotoxin, and/or an immunocytokine, but are not limited
thereto.
[0236] Further examples of suitable antibodies can be found, for
example, in U.S. Pat. No. 7,705,130, which is herein incorporated
by reference in its entirety.
[0237] According to the present invention, an isolated binding
protein that is capable of binding to HER3 interacts with at least
one epitope in the extracellular part of HER3. The epitopes are
preferably located in domain L1, which is the amino terminal
domain, in domain S1 and S2, which are the two Cysteine-rich
domains, or in domain L2, which is flanked by the two Cysteine-rich
domains. The epitopes may also be located in combinations of
domains such as but not limited to an epitope comprised by parts of
L1 and S1.
Biological Sample
[0238] A biological sample taken from a subject, such as a subject
diagnosed with a locally advanced or metastatic NSCLC, can be used
as a source of RNA, so the level of HRG gene expression at the RNA
level in the sample can be determined. The biological sample can
comprise, for example, blood, e.g., whole blood or blood
derivatives including exosomes, tissue, cells, and/or circulating
tumor cells. In some embodiments, the biological sample can be
taken from a tumor.
[0239] The biological sample can be obtained by any known methods,
such as venipuncture or with conventional tumor biopsy instruments
and procedures. Endoscopic biopsy, excisional biopsy, incisional
biopsy, fine needle biopsy, punch biopsy, shave biopsy and skin
biopsy are examples of recognized medical procedures that can be
used by one of skill in the art to obtain tumor samples. The
biological sample should be large enough to provide sufficient RNA
or thin sections for measuring HRG gene expression.
[0240] In some embodiments, the methods described herein comprise
providing an autologous tissue sample or consenting to the taking
of an autologous tissue sample, e.g., to facilitate an assessment
of HRG gene expression at an mRNA level in a human subject
diagnosed with a locally advanced or metastatic NSCLC.
[0241] The biological sample can be in any form that allows
measurement of HRG expression or content. In other words, the
sample must be sufficient for RNA extraction or preparation of thin
sections. Accordingly, the sample can be fresh, preserved through
suitable cryogenic techniques, or preserved through non-cryogenic
techniques. For example, a standard process for handling clinical
biopsy specimens is to fix the tissue sample in formalin and then
embed it in paraffin. Samples in this form are commonly known as
formalin-fixed, paraffin-embedded (FFPE) tissue. Suitable
techniques of tissue preparation for subsequent analysis are
well-known to those of skill in the art.
HRG Gene Expression
[0242] As described herein, determining or measuring the level of
HRG gene expression in a biological sample can be performed by any
suitable method. Several such methods are known in the art. For
example, determining HRG gene expression can be done by measuring
the level or amount of HRG RNA, e.g., mRNA, in a sample.
[0243] HRG gene expression can be detected by any known methods.
For example, primers can be designed to cover the EGF-like domain
and/or Neuregulin domain of HRG isoforms. These primers can be
based on sequences commonly found on mRNA of, for example,
HRG-.alpha., HRG-.beta.1, HRG-.beta.1b, HRG-.beta.1c, HRG-.beta.1d,
HRG-.beta.2, HRG-.beta.2b, ndf43, ndf43b and/or ndf43c.
[0244] For example, gene expression can be measured by using a
TaqMan probe (Life Technologies Corporation; code Hs01101537 ml) to
amplify and detect a nucleotide sequence consisting of total 72
nucleotides in GenBank Accession No. NM.sub.--013964.3. The
center/middle of the amplified nucleotide sequence can be located
at the 1318.sup.th nucleotide of the NM.sub.--013964.3. The
amplified sequence can be one that is commonly found on mRNA of
HRG-.alpha., HRG-.beta.1, HRG-.beta.1b, HRG-.beta.1c, HRG-.beta.1d,
HRG-.beta.2, HRG-.beta.2b, ndf43, ndf43b and/or ndf43c.
[0245] The nucleotide sequence can consist of the nucleotides No,
1221 to 1780 of the NM.sub.--013964.3 that is commonly found on
mRNA of HRG variants. Therefore, the primers and/or probe for
detecting HRG can be designed to amplify full-length or any partial
sequence of the nucleotides No. 1221 to 1780 of the
NM.sub.--013964.3.
[0246] The primers and/or probes of PCR or microarray can be
designed on the 3' end of mRNA because, without being bound by
theory, it is believed to lead to higher preservation (stability)
through experimental procedures like RNA isolation or cDNA
synthesis. In some embodiments, the probes can be designed based on
a sequence of interest to detect particular form of transcript
variant.
[0247] Non-limiting examples of suitable detection methods are
described below.
RNA Analysis
[0248] Conventional microarray analysis and quantitative polymerase
chain reaction (PCR) are examples of methods for determining the
level of HRG gene expression at the mRNA level. In some
embodiments, RNA is extracted from the cells, tumor or tissue of
interest using standard protocols. In other embodiments, RNA
analysis is performed using techniques that do not require RNA
isolation.
[0249] Methods for rapid and efficient extraction of eukaryotic
mRNA, i.e., poly(a) RNA, from tissue samples are well established
and known to those of skill in the art. See, e.g., Ausubel et al,
1997, Current Protocols of Molecular Biology, John Wiley &
Sons. The tissue sample can be fresh, frozen or fixed
paraffin-embedded (FFPE) samples such as clinical study tumor
specimens. In general, RNA isolated from fresh or frozen tissue
samples tends to be less fragmented than RNA from FFPE samples.
FFPE samples of tumor material, however, are more readily
available, and FFPE samples are suitable sources of RNA for use in
methods of the present invention. For a discussion of FFPE samples
as sources of RNA for gene expression profiling by RT-PCR, see,
e.g., Clark-Langone et al, 2001, BMC Genomics 8:279. Also see, De
Andres et al, 1995, Biotechniques 18:42044; and Baker et al, U.S.
Patent Application Publication No. 2005/0095634.
[0250] The use of commercially available kits with vendor's
instructions for RNA extraction and preparation is widespread and
common. Commercial vendors of various RNA isolation products and
complete kits include Qiagen (Valencia, Calif.), Invitrogen
(Carlsbad, Calif.), Ambion (Austin, Tex.) and Exiqon (Woburn,
Mass.).
[0251] In general, RNA isolation begins with tissue/cell
disruption. During tissue/cell disruption it is desirable to
minimize RNA degradation by RNases. One approach to limiting RNase
activity during the RNA isolation process is to ensure that a
denaturant is in contact with cellular contents as soon as the
cells are disrupted. Another common practice is to include one or
more proteases in the RNA isolation process. Optionally, fresh
tissue samples are immersed in an RNA stabilization solution, at
room temperature, as soon as they are collected. The stabilization
solution rapidly permeates the cells, stabilizing the RNA for
storage at 4.degree. C., for subsequent isolation. One such
stabilization solution is available commercially as RNAlater.RTM.
(Ambion, Austin, Tex.).
[0252] In some protocols, total RNA is isolated from disrupted
tumor material by cesium chloride density gradient centrifugation.
In general, mRNA makes up approximately 1% to 5% of total cellular
RNA. Immobilized Oligo(dT), e.g., oligo(dT) cellulose, is commonly
used to separate mRNA from ribosomal RNA and transfer RNA. If
stored after isolation, RNA must be stored under RNase-free
conditions. Methods for stable storage of isolated RNA are known in
the art. Various commercial products for stable storage of RNA are
available.
Microarray
[0253] The mRNA expression level of HRG can be measured using
conventional DNA microarray expression profiling technology. A DNA
microarray is a collection of specific DNA segments or probes
affixed to a solid surface or substrate such as glass, plastic or
silicon, with each specific DNA segment occupying a known location
in the array. Hybridization with a sample of labeled RNA, usually
under stringent hybridization conditions, allows detection and
quantitation of RNA molecules corresponding to each probe in the
array. After stringent washing to remove non-specifically bound
sample material, the microarray is scanned by confocal laser
microscopy or any other suitable detection method. Modern
commercial DNA microarrays, often known as DNA chips, typically
contain tens of thousands of probes, and thus can measure
expression of tens of thousands of genes simultaneously. Such
microarrays can be used in practicing the present invention.
Alternatively, custom chips containing as few probes as those
needed to measure HRG, plus necessary controls or standards, e.g.,
for data normalization, can be used in practicing the disclosed
methods.
[0254] To facilitate data normalization, a two-color microarray
reader can be used. In a two-color (two-channel) system, samples
are labeled with a first fluorophore that emits at a first
wavelength, while an RNA or cDNA standard is labeled with a second
fluorophore that emits at a different wavelength. For example, Cy3
(570 nm) and Cy5 (670 nm) often are employed together in two-color
microarray systems.
[0255] DNA microarray technology is well-developed, commercially
available, and widely employed. Therefore, in performing disclosed
methods, a person of ordinary skill in the art can use microarray
technology to measure expression levels of genes encoding biomarker
proteins without undue experimentation. DNA microarray chips,
reagents (such as those for RNA or cDNA preparation, RNA or cDNA
labeling, hybridization and washing solutions), instruments (such
as microarray readers) and protocols are well known in the art and
available from various commercial sources. Commercial vendors of
microarray systems include Agilent Technologies (Santa Clara,
Calif.) and Affymetrix (Santa Clara, Calif.), but other array
systems can be used.
Quantitative PCR
[0256] The level of mRNA encoding HRG can be measured using
conventional quantitative reverse transcriptase polymerase chain
reaction (qRT-PCR) technology. Advantages of qRT-PCR include
sensitivity, flexibility, quantitative accuracy, and ability to
discriminate between closely related mRNAs. Guidance concerning the
processing of tissue samples for quantitative PCR is available from
various sources, including manufacturers and vendors of commercial
instruments and reagents for qRT-PCR (e.g., Qiagen (Valencia,
Calif.) and Ambion (Austin, Tex.)). Instruments and systems for
automated performance of qRT-PCR are commercially available and
used routinely in many laboratories. An example of a well-known
commercial system is the Applied Biosystems 7900HT Fast Real-Time
PCR System (Applied Biosystems, Foster City, Calif.).
[0257] Once mRNA is isolated, the first step in gene expression
measurement by RT-PCR is the reverse transcription of the mRNA
template into cDNA, which is then exponentially amplified in a PCR
reaction. Two commonly used reverse transcriptases are avian
myeloblastosis virus reverse transcriptase (AMV-RT) and Moloney
murine leukemia virus reverse transcriptase (MMLV-RT). The reverse
transcription reaction typically is primed with specific primers,
random hexamers, or oligo(dT) primers. Suitable primers are
commercially available, e.g., GeneAmp.RTM. RNA PCR kit (Perkin
Elmer, Waltham, Mass.). The resulting cDNA product can be used as a
template in the subsequent polymerase chain reaction.
[0258] The PCR step is carried out using a thermostable
DNA-dependent DNA polymerase. The polymerase most commonly used in
PCR systems is a Thermus aquaticus (Taq) polymerase. The
selectivity of PCR results from the use of primers that are
complementary to the DNA region targeted for amplification, i.e.,
regions of the cDNAs reverse transcribed from genes encoding
proteins of interest. Therefore, when qRT-PCR is employed in the
present invention, primers specific to each marker gene are based
on the cDNA sequence of the gene. Commercial technologies such as
SYBR.RTM. green or TagMan.RTM. (Applied Biosystems, Foster City,
Calif.) can be used in accordance with the vendor's instructions.
Messenger RNA levels can be normalized for differences in loading
among samples by comparing the levels of housekeeping genes such as
beta-actin or GAPDH. The level of mRNA expression can be expressed
relative to any single control sample such as mRNA from normal,
non-tumor tissue or cells. Alternatively, it can be expressed
relative to mRNA from a pool of tumor samples, or tumor cell lines,
or from a commercially available set of control mRNA.
[0259] Suitable primer sets for PCR analysis of expression of HRG
genes can be designed and synthesized by one of skill in the art,
without undue experimentation.
[0260] Alternatively, PCR primer sets for practicing the present
invention can be purchased from commercial sources, e.g., Applied
Biosystems. PCR primers preferably are about 17 to 25 nucleotides
in length. Primers can be designed to have a particular melting
temperature (Tm), using conventional algorithms for Tm estimation.
Software for primer design and Tm estimation are available
commercially, e.g., Primer Express.TM. (Applied Biosystems), and
also are available on the internet, e.g., Primer3 (Massachusetts
Institute of Technology). By applying established principles of PCR
primer design, a large number of different primers can be used to
measure the expression level of any given gene, including HRG.
gNPA.TM.
[0261] In some embodiments, RNA analysis is performed using a
technology that does not involve RNA extraction or isolation. One
such technology is quantitative nuclease protection assay, which is
commercially available under the name gNPA.TM. (High Throughput
Genomics, Inc., Tucson, Ariz.). This technology can be advantageous
when the tumor tissue samples to be analyzed are in the form of
FFPE material. See, e.g., Roberts et al, 2007, Laboratory
Investigation 87:979-997.
Nanostring
[0262] In some embodiments, RNA analysis is performed using
nanostring technology. Methods of Nanostring use labeled reporter
molecules, referred to as labeled "nanoreporters," that are capable
of binding individual target molecules. Through the nanoreporters'
label codes, the binding of the nanoreporters to target molecules
results in the identification of the target molecules. Methods of
Nanostring are described in U.S. Pat. No. 7,473,767.
Assessing HRG Gene Expression
[0263] HRG gene expression can be assessed in a biological sample
from a human patient, such as a biological sample obtained from,
taken from, or received from a human patient. Some embodiments
comprise ordering or receiving an assessment of HRG gene expression
at an mRNA level. Some embodiments comprise determining a value for
HRG gene expression at an mRNA level and, optionally, recording the
value determined.
[0264] HRG Gene Expression levels can be interpreted with respect
to a predetermined threshold. An HRG gene expression level that is
equal to or higher than the threshold score can be interpreted as
predictive of the likelihood that a subject would respond to
treatment with a HER3 inhibitor, e.g., an anti-HER3 antibody. In
some embodiments, HRG gene expression levels lower than the
threshold score can be interpreted as predictive of a tumor being
resistant (non-responsive) to treatment with a HER3 inhibitor.
[0265] In some embodiments, HRG gene expression can be assessed as
"high HRG" or "low HRG" based on a numerical value representing the
level of HRG gene expression in a biological sample. A subject can
be assessed as high HRG or low HRG based on, for example, HRG
expression at a mRNA level.
[0266] The expression level can be assessed by any known methods,
such as those described above. For example, an HRG assessment can
be based on Ct value from a qRT-PCR assay. In some embodiments, HRG
assessment can be based on the expression of additional genes that
serve as controls or standards, e.g., for data normalization, or
may be otherwise informative.
[0267] In some embodiments, HRG expression at an mRNA level is
assessed using a regulatory authority-approved test. In some
embodiments, the regulatory authority-approved test is an
FDA-approved test, an EMA-approved test, or a JPMA-approved
test.
[0268] Ct value and HRG gene expression are inversely related.
Therefore, a lower Ct value translates to higher HRG gene
expression. In some embodiments, HRG expression is assessed as high
HRG if a delta Ct (dCt) value is observed that is below a
predetermined threshold. The predetermined threshold can be chosen
statistically to minimize undesirable effects of false positives
and false negatives and can be, for example, about more than 20,
20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10.0, 9.9, 9.8, 9.7, 9.6,
9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3,
8.2, 8.1, 8.0, 7.9, 7.8, 7.7, 7.6, 7.5, 7.4, 7.3, 7.2, 7.1, 7.0,
6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7,
5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4,
4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1,
3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8,
1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9, 0.8, 0.7, 0.6, 0.5,
0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5, -0.6, -0.7,
-0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8,
-1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9,
-3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8, -3.9, -4.0,
-4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9, -5.0, -5.1,
-5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0, -6.1, -6.2,
-6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1, -7.2, -7.3,
-7.4, -7.5, -7.6, -7.7, -7.8, -7.9, -8.0, -8.1, -8.2, -8.3, -8.4,
-8.5, -8.6, -8.7, -8.8, -8.9, -9.0, -9.1, -9.2, -9.3, -9.4, -9.5,
-9.6, -9.7, -9.8, -9.9, -10.0, -11, -12, -13, -14, -15, -16, -17,
-18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29, -30,
-35, -40, -45, -50, -60, -70, -80, -90, -100 or less. In some
embodiments, HRG expression can be assessed as "high HRG" if the
dCt value is less than about 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4,
4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1,
3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8,
1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9, 0.8, 0.7, 0.6, 0.5,
0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5, -0.6, -0.7,
-0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8,
-1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9,
-3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8, -3.9, -4.0,
-4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9, -5.0,-5.1,
-5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0, -6.1, -6.2,
-6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1, -7.2 or -7.3.
In some embodiments, HRG expression is assessed as "low HRG" if the
dCt values is equal to or more than about 5.0, 4.9, 4.8, 4.7, 4.6,
4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3,
3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0,
1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9, 0.8, 0.7,
0.6, 0.5, 0.4, 0.3, 0.2, 0,1, 0, -0.1, -0.2, -0.3, -0.4, -0.5,
-0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6,
-1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4, -2.5, -2.6, -2.7,
-2.8, -2.9, -3.0, -3.1, -3.2, -3.3, -3.4, -3.5, -3.6, -3.7, -3.8,
-3.9, -4.0, -4.1, -4.2, -4.3, -4.4, -4.5, -4.6, -4.7, -4.8, -4.9,
-5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0,
-6.1, -6.2, -6.3, -6.4, -6.5, -6.6, -6.7, -6.8, -6.9, -7.0, -7.1,
-7.2 or -7.3. In some embodiments, the predetermined threshold is
between about -20 and about 20, about -10 and about 10, about -7.3
and about 7.3, about -7.3 to 5.0, about 2.0 and about 5.0, about
2.7 and about 4.1, about 3.0 to about 4.1, about 3.0 to about 4.0,
about 3.0 to about 3.9, about 3.4 to about 4.1, about 3.5 to about
4.0, about 3.5 to about 3.9, about 3.6 to about 3.9, about 3.5 to
about 4.2, about 3.5 to about 4.5, about 3.6 to about 4.4, or about
3.5 to about 5.0. In some embodiments, the predetermined threshold
can be a continuum.
[0269] In some embodiments, the predetermined threshold is set, for
example at 3.9, so that 50% of the patient population is "high
HRG." In some embodiments, the predetermined threshold is set, for
example at 3.7, so that 48% of the patient population is "high
HRG." In some embodiments, the predetermined threshold is set, for
example at 3.5, so that 45% of the patient population is "high
HRG." In some embodiments, the predetermined threshold is set, for
example at 3.3, so that 40% of the patient population is "high
HRG." In some embodiments, the predetermined threshold is set, for
example at 3.0, so that 33% of the patient population is "high
HRG." In some embodiments, the predetermined threshold is set, for
example at 2.7, so that 25% of the patient population is "high
HRG."
[0270] In some embodiments, higher HRG gene expression is
correlated with better hazard ratios and p-values.
Treatment
[0271] In some embodiments, the subject can be treated by
administering a treatment comprising an anti-HER3 antibody to a
subject suffering from a cancer or other disease with HRG gene
expression assessed as high. In some embodiments, the subject can
be treated by withholding a treatment comprising an anti-HER3
antibody from a subject suffering from a cancer or other disease
with HRG gene expression assessed as low.
[0272] In some embodiments, the subject can be treated by receiving
or undergoing a treatment comprising an anti-HER3 antibody if HRG
gene expression at an mRNA level is assessed as high or abstaining
from a treatment comprising an anti-HER3 antibody if HRG gene
expression at an mRNA level is assessed as low.
[0273] In some embodiments, the subject can be treated by electing
to withhold or abstain from a treatment comprising an anti-HER3
antibody if HRG gene expression at an mRNA level is assessed as low
or electing to administer a treatment comprising an anti-HER3
antibody if HRG gene expression at an mRNA level is assessed as
high.
[0274] The anti-HER3 antibody can be any protein or ligand that can
bind to HER3, such as those discussed above. In some embodiments,
the anti-HER3 antibody is one or more of patritumab (U3-1287),
duligotumab (MEHD-7945H), MM-111, LJM716, RG-7116, tri-specific
anti-EGFR/ERBB3 zybody, huHER3-8 and seribantumab (MM-121).
[0275] The anti-HER3 antibody can be administered at any suitable
dose. For example, the antibody can be administered at about 9
mg/kg or more, about 12 mg/kg or more, about 15 mg/kg or more, or
about 18 mg/kg or more. In some embodiments, the antibody can be
administered at about 9 mg/kg or less, about 12 mg/kg or less,
about 15 mg/kg or less, or about 18 mg/kg or less.
[0276] The anti-HER3 antibody can be administered by any suitable
method. For example, in some embodiments the antibody is
administered intravenously. However, the administration route is
not limited to the intravenous one, but can be any other suitable
one as well.
[0277] In some embodiments, the anti-HER3 antibody is administered
one or more times every week or more frequently, or, every two
weeks, or every three weeks, or less frequently.
[0278] In some embodiments, the treatment comprises administering
an anti-HER3 antibody in combination with a tyrosine kinase
inhibitor or HER inhibitor, such as an epidermal growth factor
receptor inhibitor. The treatment can comprise administering an
anti-HER3 antibody in combination with, for example, one or more of
trastuzumab, T-DM1, lapatinib, pertuzumab, cetuximab, panitumumab
gefitinib, afatinib, dacomitinib, KD-019 and erlotinib.
[0279] In some embodiments, the treatment comprises administering
an anti-HER3 antibody in combination with a chemotherapy. The
treatment can comprise administering an anti-HER3 antibody in
combination with, for example, one or more of such as cisplatin,
5-fluoruracil, paclitaxel, capecitabine, and other
chemotherapies.
[0280] In some embodiments, the treatment comprises administering
an anti-HER3 antibody in combination with both a tyrosine kinase
inhibitor or HER inhibitor and chemotherapy. The treatment can
comprise administering an anti-HER3 antibody in combination with,
for example, one or more of trastuzumab, T-DM1, lapatinib,
pertuzumab, cetuximab, panitumumab, gefitinib, dacomitinib, KD-019,
afatinib, dacomitinib, KD-019 and erlotinib, and one or more of
cisplatin, carboplatin, gemcitabine, permetrexed, irinotecan,
5-fluoruracil, paclitaxel, docetaxel, capecitabine, and other
chemotherapies.
[0281] In some embodiments, the treatment comprises administering
an anti-HER3 antibody in combination with radiotherapy. In some
embodiments, treatment comprises administering an anti-HER3
antibody in combination with radiotherapy and one or more of a
tyrosine kinase inhibitor, HER inhibitor, and chemotherapy.
[0282] In some embodiments, anti-HER3 antibodies can be
administered in combination with first-line treatments for
metastatic or locally advanced head and neck cancer, such as
radiotherapy or radiation therapy, cetuximab, cisplatin, and/or
5-fluoruracil.
[0283] In some embodiments, anti-HER3 antibodies can be
administered in combination with first-line treatments for NSCLC,
such as erlotinib or platinum-based chemotherapy.
[0284] In some embodiments, anti-HER3 antibodies can be
administered in combination with second-line treatments for NSCLC,
such as docetaxel.
[0285] In some embodiments, anti-HER3 antibodies can be
administered in combination with treatments for RAS wild-type
cancer colorectal cancer and other cancer, such as cetuximab,
panitumumab, and/or chemotherapy.
[0286] In some embodiments, anti-HER3 antibodies can be
administered in combination with radiation, cisplatin, cetuximab,
5-fluoruracil, and/or other HER inhibitors or chemotherapies.
[0287] In some embodiments, anti-HER3 antibodies can be
administered in combination with one or more of trastuzumab,
paclitaxel, lapatinib, capecitabine, and/or other HER inhibitors or
chemotherapies.
Test Kits
[0288] Also disclosed is a diagnostic test kit comprising certain
components for performing methods of the invention. A diagnostic
test kit enhances convenience, speed and reproducibility in the
performance of diagnostic assays. For example, in an exemplary
qRT-PCR-based embodiment, a basic diagnostic test kit includes PCR
primers for analyzing expression of HRG. In other embodiments, a
more elaborate test kit contains not only PCR primers, but also
buffers, reagents and detailed instructions for measuring HRG
expression levels, using PCR technology. In some embodiments, the
kit includes a test protocol and all the consumable components
needed for the test, except the RNA sample(s).
[0289] In an exemplary DNA microarray-based embodiment, a test kit
includes a micro fluidic card (array) designed for use with a
particular instrument. Optionally, the micro fluidic card is a
custom made device designed specifically for measurement of HRG.
Such custom micro fluidic cards are commercially available. For
example, the TaqMan Array is a 384-well micro fluidic card (array)
designed for use with the Applied Biosystems 7900HT Fast Real Time
PCR System (Applied Biosystems, Foster City, Calif.).
[0290] In some embodiments, one or more TaqMan probes (Life
Technologies Corporation; code Hs01101537_ml) can be used to
amplify and detect the nucleotide sequence consisting of 72
nucleotides in GenBank Accession No. NM.sub.--013964.3. The
center/middle of the amplified nucleotide sequence is located at
the 1318.sup.th nucleotide of the NM.sub.--013964.3. The amplified
sequence is commonly found on mRNA of HRG-.alpha., HRG-.beta.1,
HRG-.beta.1b, HRG-.beta.1c, HRG-.beta.1d, HRG-.beta.2,
HRG-.beta.2b, ndf43, ndf43b, and ndf43c.
[0291] The nucleotide sequence consisting of the nucleotides No.
1221 to 1780 of the NM.sub.--013964.3 is commonly found on the mRNA
of many HRG variants. Therefore, the primers and/or probe for
detecting HRG can be designed to amplify full-length or any partial
sequence of the nucleotides No. 1221 to 1780 of the
NM.sub.--013964.3.
[0292] Probes of PCR or microarray can be designed on the 3' end of
mRNA or can be designed on a sequence of interest to detect
particular form of transcript variant.
EXAMPLES
[0293] The invention is further illustrated by the following
examples. The examples are provided for illustrative purposes only,
and are not to be construed as limiting the scope or content of the
invention in any way.
[0294] Abbreviations: AE--adverse event; CI--confidence interval;
CR--complete response; DLT--dose limiting toxicity; FAS--full
analysis set; FFPE--formalin-fixed, paraffin-embedded; HR--hazard
ratio; IN--intravenous; ITT--intent to treat; MTD--maximum
tolerated dose; NE--not evaluated; OS--overall survival;
PD--progressive disease; PFS--progression-free survival;
PH--proportional hazards; PO--oral; PR--partial response;
SD--stable disease.
Example 1
Phase 1b/2 Clinical Trial
[0295] This and other examples provide the results of a randomized,
placebo-controlled, double-blind Phase 1b/2 study designed to
evaluate the safety and efficacy of patritumab in combination with
erlotinib in EGFR-inhibitor treatment-naive subjects with Stage
IIIb/IV NSCLC who had progressed after at least 1 prior
chemotherapy regimen. Unblinded data from the study is presented in
Appendix A.
[0296] The study comprised a Phase 1b open-label, single-arm
portion to assess safety and tolerability of patritumab in
combination with erlotinib, and to determine the dosage for the
Phase 2 portion, followed by a randomized, placebo-controlled Phase
2 portion to assess efficacy and safety of the combination therapy
relative to erlotinib plus placebo. Based on Phase 1 study results
in which a maximum tolerated dose was not reached, the preliminary
human pharmacokinetic profile supported intravenous patritumab
administration at or above 9 mg/kg once every 3 weeks to achieve
circulating levels exceeding those showing maximal efficacy and
pharmacodynamics in experimental animal models. A higher
maintenance dose level of 18 mg/kg was also included to accommodate
the possible effect of reduced tumor tissue penetration in the
clinical setting relative to animal models. Due to the lack of dose
limiting toxicity in a monotherapy Phase 1 study, the Phase 1b was
designed as a dose-de-escalation study, with once daily oral
administration of 150 mg of erlotinib and IV administration of 18
mg/kg patritumab every three weeks, with a provision for dose
de-escalation from this maximal dose if it exceeded the MTD. As no
DLTs were seen in this Phase 1b cohort, doses at this level and
below were allowed in the Phase 2 portion.
[0297] In both portions of the study, subjects received 150 mg of
erlotinib orally once daily. At the beginning of every 3 weeks
treatment cycle, subjects received an IV infusion of patritumab or
placebo (in Phase 2 portion). Three treatment regimens were
evaluated: the combination of 150 mg erlotinib daily and 18 mg/kg
patritumab every 3 weeks ("high dose"); the combination of 150 mg
erlotinib daily and 18 mg/kg patritumab loading with 9 mg/kg
patritumab maintenance every 3 weeks ("low dose"); and the
combination of 150 mg erlotinib daily and placebo every 3 weeks
("placebo"). Tumors were to be assessed every 6 weeks (.+-.3 days)
up to the first 24 weeks of the study, then every 12 weeks (.+-.7
days) independent of treatment cycle.
[0298] Based on blinded samples with respect to treatment group and
clinical outcomes, an "HRG high" subject was defined as a subject
with a delta Ct value of less than 3.9, the median value of the
sample set. The delta Ct value was calculated using a mean of Ct
values for three reference genes, and expression levels of HRG were
determined based on the difference between the mean Ct value for
HRG and the mean Ct value for the reference genes. All samples were
assayed in triplicate.
[0299] HRG mRNA expression was measured by a qRT-PCR validated
assay developed by MolecularMD. Total mRNA was first extracted from
FFPE using Qiagen RNeasy FFPE, and cDNA was then obtained using a
RT-PCR reaction. The cDNA was used in four PCR reactions including
HRG and three reference genes (HMBS, EIF2B1, and IPO8). The average
PCR efficiency and linearity was within 90 to 110% and
.gtoreq.0.99, respectively. Intra-assay and inter-assay precision
was conducted among 6 different FFPE samples starting from mRNA
extraction from FFPE samples.
[0300] During assessment of intra-assay precision, RNA was
extracted from FFPE samples once and six replicates were run in one
run starting from RT-PCR reaction. During the PCR reaction,
duplicate wells were run for each cDNA. The standard deviation of
delta Ct in the intra-assay precision ranged from 0.11 to 0.89. The
sample which had an standard deviation delta Ct of 0.89 appeared to
include an outlier among its six data points.
[0301] During assessment of inter-assay precision, five separate
RNA extractions were conducted for each sample for a total of six
FFPE samples (a total of 30 RNA extractions). 30 RNA samples were
run in five different batches. Each RNA proceeded to an RT-PCR
reaction followed by a PCR reaction. Duplicate wells were run in a
PCR reaction for each RNA sample. The standard deviation of delta
Ct ranged from 0.06 to 0.58.
[0302] In the study, 188 tissue samples were collected from 215
randomized subjects; from these samples, reportable HRG qRT-PCR
data were obtained for 102 subjects. The remaining 86 subjects had
non-reportable HRG qRT-PCR results: 42 samples lacked sufficient
tumor/tissue material, 38 lacked sufficient RNA, and 6 samples
yielded non-reportable Ct values.
[0303] The sample size for the Phase 2 portion was calculated based
on a one-sided log-rank test with 80% power to detect a 50%
improvement (that is, HR of 0.667) in median PFS of 3.3 vs 2.2
months between any patritumab arm compared to the control at a
significance level of one-sided alpha=0.1.
[0304] The primary analyses for this study occurred when 162 PFS
events (and 110 PFS events per comparison of patritumab 18
mg/kg+erlotinib and control arms, and of patritumab 9
mg/kg+erlotinib and control arms) had been observed. At the point
of primary analysis, the treatment assignment for all subjects was
unblinded to designated study personnel for analysis after data
were reconciled and cleaned, and a snapshot of the clean database
was created. To minimize potential bias, individual treatment
assignment was not divulged to subjects or Investigators until
study closure.
[0305] All efficacy analyses were performed on the full analysis
set, which includes all subjects in the randomized analysis set who
received at least one dose of randomized study medication. The
primary efficacy endpoint was PFS. PFS is defined as the time from
the date of randomization to the earlier of the dates of the first
objective documentation of radiographic disease progression or
death due to any cause. A subject who was alive with no objective
documentation of (radiographic) disease progression by the data
cut-off date was to be censored at the date of the last evaluable
tumor assessment. The key secondary efficacy endpoint, overall
survival, was defined as the time from the date of randomization to
death due to any cause and was analyzed in the same manner as the
primary efficacy endpoint PFS.
[0306] The primary analysis for PFS used a stratified log-rank
linear trend test for the dose-response relationship, followed by
pair-wise comparisons of each patritumab arm and the control using
the stratified log-rank test, accounting for the stratification
factors at randomization: histology (Adenocarcinoma vs
Non-Adenocarcinoma) and best response to prior therapy (CR/PR vs SD
vs PD). Kaplan-Meier curves were generated for PFS and used to
calculate medians and 95% CIs for each treatment group. Estimates
of the HR between each patritumab arm and the control along with
95% CIs were calculated using a stratified Cox's proportional
hazards model.
[0307] The primary analysis for PFS in HRG-high group on the FAS
used a stratified log-rank test for the comparisons of each
patritumab arm and the control and the comparison of the combined
patritumab arm and the control. The stratification factors included
histology (Adenocarcinoma vs Non-Adenocarcinoma) and best response
to prior therapy (CR/PR/SD vs PD). Estimates of the HR between each
patritumab arm and the control and between the combined patritumab
arm and the control along with 95% CIs were calculated using a
stratified Cox's proportional hazards model with the same
stratification factors used for the stratified log-rank test.
[0308] Unless otherwise indicated, log-rank p-values and HRs for
PFS and OS were based on the primary analysis adjusted for the
stratification factors at randomization as described above.
[0309] The Phase 1b portion of the trial enrolled 7 subjects (4
male; median age [range], 68 years [48-78]) all of whom received
the combination of 150 mg erlotinib daily and 18 mg/kg patritumab
every 3 weeks. AEs grade .gtoreq.3 occurred in 2 subjects: one
grade 3 case each of pain, fatigue, headache, dehydration,
diarrhea, and blood creatinine increase; none were related to
patritumab. Three subjects had four serious AEs: grade 3 pain
(unrelated to study treatment), grade 3 dehydration
(erlotinib-related), and grade 1 decreased appetite (erlotinib- and
patritumab-related) and grade 1 pyrexia (unrelated) in one subject.
Most reported AEs were grade 1 or 2 and were considered
erlotinib-related. The only patritumab-related AE reported in
.gtoreq.2 subjects was decreased appetite (2 subjects).
[0310] No response was recorded and stable disease was noted in
four subjects (83, 87, 90, and 117 days). All 7 subjects
discontinued from study treatment due to disease progression; 6
subjects were followed until death, and 1 subject withdrew consent
for follow-up.
[0311] No DLTs were reported during the phase 1b study. Therefore,
the Phase 2 dose regimens were a patritumab 18 mg/kg loading dose,
with subsequent administration of either a 9 mg/kg patritumab or 18
mg/kg patritumab maintenance dose every 3 weeks. Subjects were also
administered 150 mg/day erlotinib during the phase 2 trial.
[0312] For the Phase 2 portion, 3 subjects were randomized but not
treated, thus there were 212 subjects in the FAS and safety
analysis set. The analysis results presented below are based on
primary analyses of efficacy data (except for OS) from the locked
database (as of data cut-off date Oct. 30, 2012). OS data was not
mature yet at the time of primary analysis, and the preliminary
results from updated OS analysis based on a data cut-off date of
Apr. 19, 2013 are presented below.
[0313] Dispositions of the 215 subjects enrolled into the
randomized Phase 2 portion of the study are summarized in Table 1.
Demographic information for the full analysis set is summarized in
Table 2. There was no meaningful difference among treatment groups
with respect to demographic characteristics.
TABLE-US-00001 TABLE 1 Phase 2 Subject Disposition Placebo + 18
mg/kg + 9 mg/kg + Total erlotinib erlotinib erlotinib Phase 2
Subject Accounting (N = 71) (N = 72) (N = 72) (N = 215)
Enrolled/Randomized but Not Dosed 0 2 (2.8%) 1 (1.4%) 3 (1.4%)
Treatment Status Ongoing on the Study Treatment 5 (7.0%) 5 (6.9%) 6
(8.3%) 16 (7.4%) Discontinued from Study Treatment 66 (93.0%) 65
(90.3%) 65 (90.3%) 196 (91.2%) Primary Reason for Adverse Event 5
(7.0%) 7 (9.7%) 6 (8.3%) 18 (8.4%) Discontinuing Study Lost to
Follow-up 0 0 0 0 Treatment Death 4 (5.6%) 11 (15.3%) 2 (2.8%) 17
(7.9%) Protocol Violation 0 0 0 0 Subject Withdrew Consent 3 (4.2%)
2 (2.8%) 4 (5.6%) 9 (4.2%) Study Terminated by Sponsor 0 0 0 0
Progressive Disease (Radiographic Progression) 50 (70.4%) 42
(58.3%) 45 (62.5%) 137 (63.7%) Other 4 (5.6%) 3 (4.2%) 8 (11.1%) 15
(7.0%) On-Study Death.sup.[a] 13 (18.3%) 20 (27.8%) 9 (12.5%) 42
(19.5%) Primary Cause of Adverse Event 5 (7.0%) 11 (15.3%) 4 (5.6%)
20 (9.3%) On-Study Death Disease Progression 8 (11.3%) 8 (11.1%) 4
(5.6%) 20 (9.3%) Unknown 0 0 1 (1.4%) 1 (0.5%) Other 0 1 (1.4%) 0 1
(0.5%) Notes: Percentages are based on the number of subjects in
the Enrolled/Randomized Analysis Set. .sup.[a]On-Study Death = Y if
the date of death occurred on or after the date of first drug
administration and within the AE collection period (up to 53 days
after the last dose of patritumab or more than 30 days after the
last dose of erlotinib, whichever is later).
TABLE-US-00002 TABLE 2 Demographic and Baseline Characteristics
(Full Analysis Set) Placebo + 18 mg/kg + 9 mg/kg + erlotinib
erlotinib erlotinib Total (N = 71) (N = 70) (N = 71) (N = 212) Age
(yrs) [a] Median 60.0 62.0 65.0 62.5 Minimum 35 41 44 35 Maximum 88
82 84 88 <60 33 (46.5%) 28 (40.0%) 24 (33.8%) 85 (40.1%) >=60
38 (53.5%) 42 (60.0%) 47 (66.2%) 127 (59.9%) Gender Male 43 (60.6%)
38 (54.3%) 48 (67.6%) 129 (60.8%) Female 28 (39.4%) 32 (45.7%) 23
(32.4%) 83 (39.2%) Race White 69 (97.2%) 68 (97.1%) 71 (100.0%) 208
(98.1%) Black or 1 (1.4%) 1 (1.4%) 0 2 (0.9%) African American
Asian 0 1 (1.4%) 0 1 (0.5%) Other/ 1 (1.4%) 0 0 1 (0.5%) Specify
Weight (kg) n 71 70 71 212 Mean 74.68 73.59 72.34 73.53 SD 14.337
17.506 14.369 15.422 Median 74.00 72.00 72.30 72.55 Minimum 42.6
44.0 42.0 42.0 Maximum 108.6 121.0 114.0 121.0 Smoking Status Never
5 (7.0%) 10 (14.3%) 11 (15.5%) 26 (12.3%) Current 13 (18.3%) 12
(17.1%) 9 (12.7%) 34 (16.0%) Former 53 (74.6%) 48 (68.6%) 51
(71.8%) 152 (71.7%) Pack Years (PY) <=15 PY 11 (15.5%) 9 (12.9%)
7 (9.9%) 27 (12.7%) >15 PY 50 (70.4%) 43 (61.4%) 47 (66.2%) 140
(66.0%) Missing 10 (14.1%) 18 (25.7%) 17 (23.9%) 45 (21.2%) Notes:
Denominator for percentages is the number of subjects in the FAS.
[a]: Age in years is calculated using the informed consent date and
the birth date
[0314] Subject baseline characteristics with regard to NSCLC
history and prior therapy are shown in Table 3. Subjects generally
appeared to be well balanced among treatment groups.
TABLE-US-00003 TABLE 3 Baseline Prognostic and Disease
Characteristics (Full Analysis Set) Placebo + 18 mg/kg + 9 mg/kg +
erlotinib erlotinib erlotinib Total (N = 71) (N = 70) (N = 71) (N =
212) Baseline ECOG Performance Status 0 Fully Active 25 (35.2%) 33
(47.1%) 30 (42.3%) 88 (41.5%) 1 Restricted in Physically Strenuous
Activity 46 (64.8%) 37 (52.9%) 41 (57.7%) 124 (58.5%) Histology
Adenocarcinoma 42 (59.2%) 46 (65.7%) 44 (62.0%) 132 (62.3%)
Squamous 21 (29.6%) 19 (27.1%) 23 (32.4%) 63 (29.7%) Other 8
(11.3%) 5 (7.1%) 4 (5.6%) 17 (8.0%) NSCLC Tumor Staging at Study
Entry (CRF) IIIB 7 (9.9%) 5 (7.1%) 9 (12.7%) 21 (9.9%) IV 64
(90.1%) 65 (92.9%) 62 (87.3%) 191 (90.1%) Time from Initial
Diagnosis of NSCLC to Study Treatment (months) <6 months 10
(14.1%) 16 (22.9%) 14 (19.7%) 40 (18.9%) 6-12 months 37 (52.1%) 33
(47.1%) 35 (49.3%) 105 (49.5%) >12 months 24 (33.8%) 21 (30.0%)
22 (31.0%) 67 (31.6%) Number of Prior NSCLC Therapies 0 0 0 0 0 1
47 (66.2%) 50 (71.4%) 48 (67.6%) 145 (68.4%) 2 24 (33.8%) 19
(27.1%) 22 (31.0%) 65 (30.7%) 3 0 1 (1.4%) 1 (1.4%) 2 (0.9%) Best
Response to Prior Chemotherapy.sup.[a] CR/PR 23 (32.4%) 19 (27.1%)
17 (23.9%) 59 (27.8%) SD 29 (40.8%) 28 (40.0%) 34 (47.9%) 91
(42.9%) PD 19 (26.8%) 23 (32.9%) 20 (28.2%) 62 (29.2%) Exposure to
Prior Platinum Therapy Yes 70 (98.6%) 70 (100.0%) 70 (98.6%) 210
(99.1%) No 1 (1.4%) 0 1 (1.4%) 2 (0.9%) Prior Radiation Therapy Yes
24 (33.8%) 25 (35.7%) 22 (31.0%) 71 (33.5%) No 47 (66.2%) 45
(64.3%) 49 (69.0%) 141 (66.5%) Notes: Percentages reflect
proportion of subjects in Full Analysis Set (FAS). Baseline = last
non-missing value before initial administration of study treatment.
.sup.[a]If a subject has two lines of prior chemotherapy regimens,
the best response to the most recent chemotherapy regimen
(excluding `Not Applicable`) was used.
[0315] Possible predictive/prognostic biomarker data for the FAS
are shown in Table 4. Treatment groups appeared to be balanced with
respect to expression levels of HER3 and HRG and EGFR mutation
status.
TABLE-US-00004 TABLE 4 Baseline Possible Predictive/Prognostic
Biomarkers (Full Analysis Set) Placebo + 18 mg/kg + 9 mg/kg +
erlotinib erlotinib erlotinib Total (N = 71) (N = 70) (N = 71) (N =
212) Possible Predictive/ Prognostic Biomarkers HER3.sup.[a]
Positive 21 (29.6%) 31 (44.3%) 24 (33.8%) 76 (35.8%) Extreme
Overexpression 0 3 (4.3%) 1 (1.4%) 4 (1.9%) Negative 30 (42.3%) 21
(30.0%) 25 (35.2%) 76 (35.8%) Unknown 20 (28.2%) 18 (25.7%) 22
(31.0%) 60 (28.3%) HRG.sup.[b] High 19 (26.8%) 17 (24.3%) 16
(22.5%) 52 (24.5%) Low 16 (22.5%) 19 (27.1%) 15 (21.1%) 50 (23.6%)
Unknown 36 (50.7%) 34 (48.6%) 40 (56.3%) 110 (51.9%) EGFR Mutation
Status from tissue or plasma Sensitizing Only 2 (2.8%) 0 3 (4.2%) 5
(2.4%) Resistance Only 0 1 (1.4%) 0 1 (0.5%) Both Sensitizing and
Resistance 0 0 0 0 Wild Type 47 (66.2%) 45 (64.3%) 47 (66.2%) 139
(65.6%) Unknown 22 (31.0%) 24 (34.3%) 21 (29.6%) 67 (31.6%) EGFR
Mutation Status from tissue Sensitizing Only 2 (2.8%) 0 2 (2.8%) 4
(1.9%) Wild Type 23 (32.4%) 17 (24.3%) 21 (29.6%) 61 (28.8%)
Unknown 46 (64.8%) 53 (75.7%) 48 (67.6%) 147 (69.3%) Notes:
Denominator for percentages is the number of subjects in the Full
Analysis Set (FAS). The baseline value is defined as the last
non-missing value before initial administration of study treatment,
.sup.[a]HER3 positive is defined as membrane staining H-score
>0; HER3 negative is defined as a membrane staining H-score = 0;
HER3 extreme overexpression is defined as a membrane staining
H-score >100. .sup.[b]HRG high is defined as delta Ct value
<3.9; HRG low is defined as a delta Ct value .gtoreq.3.9.
[0316] Demographic information for subjects with tumors expressing
high HRG levels are summarized in Table 5. There was no meaningful
difference among treatment groups with respect to demographic
characteristics; however, 3 of 16 subjects were never-smokers in
the low dose group, one of the 17 subjects was a never-smoker in
the high dose group and none of 19 subjects was a never-smoker in
the placebo group. An analysis performed eliminating the never
smokers did not change the results stated below.
TABLE-US-00005 TABLE 5 Demographic and Baseline Characteristics in
Subjects with Tumors Expressing High Heregulin (HRG) Levels Placebo
+ 18 mg/kg + 9 mg/kg + erlotinib erlotinib erlotinib Total (N = 18)
(N = 17) (N = 16) (N = 51) Age (yrs).sup.[a] Median 60.0 63.0 66.0
64.0 Minimum 46 50 57 46 Maximum 76 74 77 77 <60 9 (50.0%) 6
(35.3%) 3 (18.8%) 18 (35.3%) .gtoreq.60 9 (50.0%) 11 (64.7%) 13
(81.3%) 33 (64.7%) Gender Male 12 (66.7%) 11 (64.7%) 9 (56.3%) 32
(62.7%) Female 6 (33.3%) 6 (35.3%) 7 (43.8%) 19 (37.3%) Race White
18 (100.0%) 17 (100.0%) 16 (100.0%) 51 (100.0%) Weight (kg) Mean
73.39 64.97 71.29 69.93 SD 12.891 15.407 14.053 14.317 Median 72.50
63.00 72.50 69.70 Minimum 48.2 44.0 42.0 42.0 Maximum 90.0 99.0
90.0 99.0 Smoking Status Never 0 1 (5.9%) 3 (18.8%) 4 (7.8%)
Current 5 (27.8%) 4 (23.5%) 2 (12.5%) 11 (21.6%) Former 13 (72.2%)
12 (70.6%) 11 (68.8%) 36 (70.6%) Pack Years (PY) .ltoreq.15 PY 3
(16.7%) 4 (23.5%) 0 7 (13.7%) >15 PY 14 (77.8%) 11 (64.7%) 11
(68.8%) 36 (70.6%) Missing 1 (5.6%) 2 (11.8%) 5 (31.3%) 8 (15.7%)
Notes: Denominator for percentages is the number of subjects with
high HRG expression tumors in the Full Analysis Set. High HRG
expression is defined as delta Ct value <3.9. .sup.[a]Age in
years is calculated using the informed consent date and the birth
date.
[0317] Subject baseline characteristics with regard to NSCLC
history and prior therapy are shown in Table 6. Subjects generally
appeared to be well balanced among treatment groups with respect to
baseline characteristics; however, there were 3 (18.8%) subjects in
the low dose group, no subject in the high dose group and 6 (31.6%)
subjects in the placebo group with best response to most recent
prior therapy being CR/PR. For subjects with 2 prior therapies,
there were 8 (50%) subjects in the low dose group, 4 (23.5%)
subjects in the high dose and 5 (26.3%) subjects in the placebo
group.
TABLE-US-00006 TABLE 6 Baseline Prognostic and Disease
Characteristics in Subjects with Tumors Expressing High Heregulin
(HRG) Levels Placebo + 18 mg/kg + 9 mg/kg + erlotinib erlotinib
erlotinib Total (N = 18) (N = 17) (N = 16) (N = 51) Baseline ECOG
Performance Status 0--Fully Active 9 (50.0%) 9 (52.9%) 7 (43.8%) 25
(49.0%) 1--Restricted in Physically Strenuous 9 (50.0%) 8 (47.1%) 9
(56.3%) 26 (51.0%) Activity Histology Adenocarcinoma 8 (44.4%) 8
(47.1%) 8 (50.0%) 24 (47.1%) Squamous 10 (55.6%) 8 (47.1%) 7
(43.8%) 25 (49.0%) Other 0 1 (5.9%) 1 (6.3%) 2 (3.9%) NSCLC Tumor
Staging at Study Entry (CRF) IIIB 0 2 (11.8%) 3 (18.8%) 5 (9.8%) IV
18 (100.0%) 15 (88.2%) 13 (81.3%) 46 (90.2%) Time from Initial
Diagnosis of NSCLC to Study Treatment (months) <6 months 0 3
(17.6%) 3 (18.8%) 6 (11.8%) 6-12 months 12 (66.7%) 7 (41.2%) 7
(43.8%) 26 (51.0%) >12 months 6 (33.3%) 7 (41.2%) 6 (37.5%) 19
(37.3%) Number of Prior NSCLC Therapies 0 0 0 0 0 1 13 (72.2%) 13
(76.5%) 8 (50.0%) 34 (66.7%) 2 5 (27.8%) 4 (23.5%) 8 (50.0%) 17
(33.3%) Best Response to Prior Chemotherapy.sup.[a] CR/PR 5 (27.8%)
0 3 (18.8%) 8 (15.7%) SD 8 (44.4%) 11 (64.7%) 8 (50.0%) 27 (52.9%)
PD 5 (27.8%) 6 (35.3%) 5 (31.3%) 16 (31.4%) Exposure to Prior
Platinum Therapy Yes 18 (100.0%) 17 (100.0%) 16 (100.0%) 51
(100.0%) No 0 0 0 0 Prior Radiation Therapy Yes 4 (22.2%) 7 (41.2%)
4 (25.0%) 15 (29.4%) No 14 (77.8%) 10 (58.8%) 12 (75.0%) 36 (70.6%)
Notes: Denominator for percentages is the number of subjects with
high HRG-expressing tumors in the Full Analysis Set. High HRG
expression is defined as delta Ct value <3.9. .sup.[a]If a
subject has two lines of prior chemotherapy regimens, the best
response to the most recent chemotherapy regimen (excluding `Not
Applicable`) will be used.
[0318] Possible predictive/prognostic biomarker values for subjects
with tumors expressing high levels of HRG are summarized in Table
7. Treatment groups appeared to be balanced with respect to
expression level of HER3. A single subject in the low dose group, a
single subject in the placebo group and no subject in the high dose
group had known EGFR mutations. A slightly larger proportion of
subjects in the high-dose group had unknown EGFR mutational status
as compared to the placebo group and the low dose group.
TABLE-US-00007 TABLE 7 Baseline Possible Predictive/Prognostic
Biomarkers in Subjects with Tumors Expressing High Heregulin (HRG)
Levels Placebo + 18 mg/kg + 9 mg/kg + erlotinib erlotinib erlotinib
Total (N = 18) (N = 17) (N = 16) (N = 51) HER3.sup.[a] High 10
(55.6%) 10 (58.8%) 8 (50.0%) 28 (54.9%) Expression Extreme 0 2
(11.8%) 0 2 (3.9%) Overexpression Low 8 (44.4%) 5 (29.4%) 8 (50.0%)
21 (41.2%) Expression Unknown 0 2 (11.8%) 0 2 (3.9%) EGFR Mutation
Status from tissue or plasma Sensitizing 1 (5.6%) 0 1 (6.2%) 2
(3.9%) Only Resistance 0 1 (5.9%) 0 1 (2.0%) Only Both 0 0 0 0
Sensitizing and Resistance Wild Type 14 (77.8%) 9 (52.9%) 11
(68.8%) 34 (66.7%) Unknown 3 (16.7%) 7 (41.2%) 4 (25.0%) 14 (27.5%)
EGFR Mutation Status from tissue Sensitizing 1 (5.5%) 0 1 (6.2%) 2
(3.9%) Only Wild Type 9 (50.0%) 5 (29.4%) 7 (43.8%) 21 (41.2%)
Unknown 8 (44.4%) 12 (70.6%) 8 (50.0%) 28 (54.9%) Notes:
Denominator for percentages is the number of subjects with high
HRG-expressing tumors in the Full Analysis Set. High HRG expression
is defined as delta Ct value <3.9. .sup.[a]HER3 high expression
is defined as membrane staining H-score >0; HER3 low expression
is defined as a membrane staining H-score = 0; HER3 extreme
overexpression is defined as a membrane staining H-score
>100.
Example 2
Progression Free Survival and Overall Survival in Full Analysis
Set
[0319] The primary analysis of PFS for the FAS is presented in
Table 8. Kaplan-Meier estimates of progression-free survival in the
FAS are presented in FIG. 1 (showing high- and low-dose
patritumab+erlotinib vs. placebo+erlitonib). Overall Survival (OS)
results in the unselected FAS are presented in Table 9 and FIG. 2
(showing high- and low-dose patritumab+erlotinib vs.
placebo+erlitonib). There was no significant improvement in PFS or
OS for the combination of patritumab with erlotinib as compared to
erlotinib plus placebo in the full analysis set, and the study was
considered as negative for the unselected ITT population.
[0320] The number of subjects with the response being CR/PR in low-
and high-dose patritumab treatment groups were respectively 9
(12.9%) and 5 (7.1%) vs placebo 4 (5.6%).
TABLE-US-00008 TABLE 8 Analysis of Progression-Free Survival in
Full Analysis Set Placebo + 18 mg/kg + 9 mg/kg + erlotinib
erlotinib erlotinib (N = 71) (N = 70) (N = 71) Subjects (%) with
events 59 (83.1%) 58 (82.9%) 52 (73.2%) Subjects (%) without 12
(16.9%) 12 (17.1%) 19 (26.8%) events (censored) Time to event
(months).sup.[a] Median 1.6 1.4 2.5 95% CI for Median [1.4; 2.6]
[1.3; 2.7] [1.5; 3.0] Stratified Logrank 0.9735 0.1512
P-Value.sup.[b] Hazard Ratio 0.978 0.770 (relative to
Placebo).sup.[b] 95% CI [0.674; 1.420] [0.523; 1.131] 80% CI
[0.767; 1.248] [0.598; 0.990] P-value for Hazard Ratio 0.9075
0.1828 Notes: PFS is defined as the time from the randomization
date to the date of the first objective documentation of disease
progression or death resulting from any cause, whichever comes
first. .sup.[a]Kaplan-Meier Estimate. CI for median was computed
using the Brookmeyer-Crowley method. .sup.[b]Stratified log-rank
and stratified Cox PH were stratified by best response to prior
therapy and histology subtype (Adenocarcinoma vs.
Non-Adenocarcinoma).
TABLE-US-00009 TABLE 9 Analysis of Overall Survival in Full
Analysis Set Placebo + 18 mg/kg + 9 mg/kg + erlotinib erlotinib
erlotinib (N = 71) (N = 70) (N = 71) Subjects (%) with events 48
(67.6%) 54 (77.1%) 46 (64.8%) Subjects (%) without 23 (32.4%) 16
(22.9%) 25 (35.2%) events (censored) Time to event (months).sup.[a]
Median 7.2 5.3 6.3 95% CI for Median [5.4; 10.6] [4.0; 6.9] [5.4;
9.3] Stratified Logrank 0.3823 0.3673 P-Value.sup.[b] Hazard Ratio
1.208 0.858 (relative to Placebo).sup.[b] 95% CI [0.807; 1.808]
[0.566; 1.301] 80% CI [0.928; 1.572] [0.653; 1.127] P-value for
Hazard Ratio 0.3585 0.4712 Notes: OS is defined as the time from
the randomization date to the date of death. .sup.[a]Kaplan-Meier
Estimate. CI for median was computed using the Brookmeyer-Crowley
method. .sup.[b]Stratified log-rank and stratified Cox PH were
stratified by best response to prior therapy and histology subtype
(adenocarcinoma vs. non-adenocarcinoma).
Example 3
Progression Free Survival in Subjects with Tumors Expressing High
HRG Levels
[0321] Secondary analyses of PFS for the prospective subpopulation
of subjects with tumors expressing high levels of HRG are presented
in Table 10 and Table 11. Kaplan-Meier estimates of
progression-free survival in subjects with tumors expressing high
HRG at an mRNA level, defined as dCt <3.9, are presented in FIG.
3 (showing high- and low-dose patritumab+erlotinib vs.
placebo+erlitonib) and FIG. 4 (showing pooled patritumab+erlotinib
vs. placebo+erlotinib).
TABLE-US-00010 TABLE 10 Analysis of Progression-Free Survival in
Subjects with Tumors Expressing High HRG Levels Placebo + 18 mg/kg
+ 9 mg/kg + Doses erlotinib erlotinib erlotinib Combined (N = 18)
(N = 17) (N = 16) (N = 33) Subjects (%) with events 16 (88.9%) 13
(76.5%) 12 (75.0%) 25 (75.8%) Subjects (%) without events
(censored) 2 (11.1%) 4 (23.5%) 4 (25.0%) 8 (24.2%) Time to event
(months).sup.[a] Median 1.4 3.4 3.0 3.0 95% CI for Median [1.2;
2.3] [1.2; 5.7] [1.5; 5.7] [1.4; 4.3] PFS Rate at 8 Weeks (%) 31.3%
56.3% 67.7% 62.1% 95% CI [11.4; 53.6] [29.5; 76.2] [38.8; 85.2]
[42.9; 76.4] PFS Rate at 14 Weeks (%) 18.8% 50.0% 33.9% 42.5% 95%
CI [4.6; 40.2] [24.5; 71.0] [12.4; 57.0] [25.1; 58.8] PFS Rate at
26 Weeks (%) 0.0% 15.6% 20.3% 18.4% 95% CI [0.0; 0.0] [2.8; 38.2]
[5.0; 42.9] [7.0; 34.0] Stratified Logrank P-Value.sup.[b] 0.0283
0.0027 0.0013 Stratified Analysis.sup.[b] Hazard Ratio (relative to
Placebo) 0.369 0.288 0.324 95% CI [0.161; 0.846] [0.125; 0.663]
[0.156; 0.672] 80% CI [0.215; 0.635] [0.167; 0.497] [0.201; 0.522]
P-value for Hazard Ratio 0.0185 0.0034 0.0024 Notes: PFS is defined
as the time from the randomization date to the date of the first
objective documentation of disease progression or death resulting
from any cause, whichever comes first. .sup.[a]Kaplan-Meier
Estimate. CI for median was computed using the Brookmeyer-Crowley
method. .sup.[b]Stratified log-rank and stratified Cox PH were
stratified by best response to prior therapy (CR, PR, SD vs PD) and
histology subtype (adenocarcinoma vs non-adenocarcinoma).
TABLE-US-00011 TABLE 11 Supportive Analyses of Progression-Free
Survival in Subjects with Tumors Expressing High HRG Levels 9 mg/kg
+ 18 mg/kg + erlotinib erlotinib Doses Combined (N = 17) (N = 16)
(N = 33) Logrank P-value (unstratified) 0.0583 0.0122 0.0089
Stratified Logrank P-Value.sup.[a] 0.0199 0.0009 0.0005 Stratified
Analysis.sup.a Hazard Ratio (relative to Placebo) 0.332 0.252 0.287
95% CI [0.141; 0.781] [0.107; 0.595] [0.135; 0.613] 80% CI [0.190;
0.581] [0.144; 0.442] [0.175; 0.472] P-value for Hazard Ratio
0.0115 0.0017 0.0013 Unadjusted Analysis (treatment group only)
Hazard Ratio (relative to Placebo) 0.462 0.395 0.426 95% CI [0.215;
0.991] [0.183; 0.853] [0.221; 0.823] 80% CI [0.280; 0.761] [0.239;
0.654] [0.277; 0.655] P-value for Hazard Ratio 0.0474 0.0181 0.0111
Adjusted analysis (alternative Cox PH model).sup.[b] Hazard Ratio
(relative to Placebo) 0.400 0.361 0.378 95% CI [0.177; 0.902]
[0.165; 0.789] [0.190; 0.752] 80% CI [0.235; 0.681] [0.217; 0.602]
[0.241; 0.593] P-value for Hazard Ratio 0.0272 0.0106 0.0056
Adjusted analysis (alternative Cox PH model).sup.[c] Hazard Ratio
(relative to Placebo) 0.400 0.356 0.375 95% CI [0.178; 0.899]
[0.163; 0.778] [0.189; 0.746] 80% CI [0.235; 0.679] [0.213; 0.594]
[0.239; 0.588] P-value for Hazard Ratio 0.0265 0.0096 0.0051 Notes:
PFS is defined as the time from the randomization date to the date
of the first objective documentation of disease progression or
death resulting from any cause, whichever comes first.
.sup.[a]Stratified log-rank and stratified Cox PH were stratified
by best response to prior therapy (CR, PR, SD vs PD) and histology
subtype (squamous vs non-squamous). .sup.[b]The model included
treatment and stratification factors (best response to prior
therapy [CR, PR, SD vs PD] and histology subtype [adenocarcinoma vs
non-adenocarcinoma]) as covariates. .sup.[c]The model included
treatment and stratification factors (best response to prior
therapy [CR, PR, SD vs PD] and histology subtype [squamous vs
non-squamous]) as covariates.
Example 4
Overall Survival in Subjects with Tumors Expressing High HRG
Levels
[0322] Preliminary OS results in the subset of subjects with tumors
expressing high levels of HRG at an mRNA level, defined as dCt
<3.9, are presented in Table 12 and Table 13, and in FIG. 5
(showing high- and low-dose patritumab+erlotinib vs.
placebo+erlitonib) and FIG. 6 (showing pooled patritumab+erlotinib
vs. placebo+erlitonib).
TABLE-US-00012 TABLE 12 Analysis of Overall Survival in Subjects
with Tumors Expressing High HRG Levels Placebo + 18 mg/kg + 9 mg/kg
+ erlotinib erlotinib erlotinib Combined (N = 18) (N = 17) (N = 16)
(N = 33) Subjects (%) with events 11 (61.1%) 12 (70.6%) 9 (56.3%)
21 (63.6%) Subjects (%) without events (censored) 7 (38.9%) 5
(29.4%) 7 (43.8%) 12 (36.4%) Time to event (months).sup.[a] Median
5.0 6.1 10.6 9.7 95% CI for Median [3.0; NA] [2.1; 11.5] [4.6; NA]
[4.6; 17.4] OS Rate at 6 Months (%) 49.4% 50.7% 68.8% 59.6% 95% CI
[25.2; 69.7] [25.1; 71.6] [40.5; 85.6] [40.7; 74.2] OS Rate at 9
Months (%) 49.4% 44.3% 56.3% 50.2% 95% CI [25.2; 69.7] [20.2; 66.1]
[29.5; 76.2] [32.0; 65.8] OS Rate at 1 Year (%) 32.4% 22.2% 49.2%
35.8% 95% CI [10.5; 57.0] [5.7; 45.3] [23.6; 70.6] [19.5; 52.5]
Stratified Logrank P-Value.sup.[b] 0.8698 0.1082 0.2707 Stratified
Analysis.sup.[b] Hazard Ratio (relative to Placebo) 0.875 0.487
0.647 95% CI [0.363; 2.111] [0.192; 1.239] [0.297; 1.411] 80% CI
[0.492; 1.556] [0.265; 0.897] [0.389; 1.078] P-value for Hazard
Ratio 0.7661 0.1311 0.2742 Notes: OS is defined as the time from
the randomization date to the date of death. .sup.[a]Kaplan-Meier
Estimate. CI for median was computed using the Brookmeyer-Crowley
method, .sup.[b]Stratified log-rank and stratified Cox PH were
stratified by best response to prior therapy (CR, PR, SD vs PD) and
histology subtype (adenocarcinoma vs non-adenocarcinoma).
TABLE-US-00013 TABLE 13 Supportive Analysis of Overall Survival in
Subjects with Tumors Expressing High HRG Levels 18 mg/kg + erlotmib
9 mg/kg + erlotinib Doses Combined (N = 17) (N = 16) (N = 33)
Logrank P-value (unstratified) 0.5909 0.3077 0.7579 Stratified
Logrank P-Value.sup.[a] 0.8302 0.1744 0.3139 Stratified
Analysis.sup.[a] Hazard Ratio (relative to Placebo) 0.923 0.499
0.674 95% CI [0.386; 2.207] [0.197; 1.266] [0.311; 1.459] 80% CI
[0.522; 1.632] [0.271; 0.917] [0.407; 1.117] P-value for Hazard
Ratio 0.8563 0.1435 0.3167 Unadjusted Analysis (treatment group
only) Hazard Ratio (relative to Placebo) 1.254 0.621 0.892 95% CI
[0.552; 2.846] [0.249; 1.549] [0.427; 1.866] 80% CI [0.733; 2.143]
[0.342; 1.129] [0.551; 1.445] P-vaIue for Hazard Ratio 0.5890
0.3073 0.7617 Adjusted anaIysis (alternative Cox PH model).sup.[b]
Hazard Ratio (relative to Placebo) 0.918 0.557 0.716 95% CI [0.388;
2.173] [0.222; 1.398] [0.334; 1.534] 80% CI [0.523; 1.613] [0.305;
1.017] [0.435; 1.178] P-value for Hazard Ratio 0.8458 0.2126 0.3901
Adjusted analysis (alternative Cox PH model).sup.[c] Hazard Ratio
(relative to Placebo) 0.933 0.577 0.736 95% CI [0.395; 2.203]
[0.230; 1.446] [0.345; 1.571] 80% CI [0.532; 1.637] [0.316; 1.052]
[0.449; 1.209] P-value for Hazard Ratio 0.8747 0.2407 0.4286 Notes:
OS is defined as the time from the randomization date to the date
of death. .sup.[a]Stratified log-rank and stratified Cox PH were
stratified by best response to prior therapy (CR, PR, SD vs PD) and
histology subtype (squamous vs non-squamous). .sup.[b]The model
included treatment and stratification factors (best response to
prior therapy [CR, PR, SD vs PD] and histology subtype
[adenocarcinoma vs non-adenocarcinoma]) as covariates. .sup.[c]The
model included treatment and stratification factors (best response
to prior therapy [CR, PR, SD vs PD] and histology subtype [squamous
vs non-squamous]) as covariates.
Example 5
Objective Response Rate (ORR) and Disease Control Rate (DCR) in
Subjects with Tumors Expressing High HRG Levels
[0323] Subjects with tumors expressing high levels of HRG in the
low-dose patritumab plus erlotinib group trended toward an
improvement in objective response relative to placebo: 4 (25.0%)
subjects in the low-dose group responded, as compared to 1 (5.6%)
subject in the placebo group. No subject with a tumor expressing
high levels of HRG in the high-dose group achieved CR or PR. Given
the very small numbers, no conclusions can be drawn.
[0324] Among subjects with tumors expressing high levels of HRG,
there were significant treatment differences in disease control
rate in both patritumab plus erlotinib groups relative to the
erlotinib plus placebo group. Disease control was achieved in 4
(22.2%) subjects in the placebo plus erlotinib group, as compared
to 10 (62.5%; p=0.0068) subjects and 9 (52.9%; p=0.0129) subjects
in the 9 mg/kg patritumab plus erlotinib and 18 mg/kg patritumab
plus erlotinib groups, respectively.
Example 6
Efficacy in Subjects with Tumors Expressing Low HRG Levels
[0325] In contrast with subjects whose tumors expressed high levels
of HRG, subjects with tumors expressing low levels of HRG showed no
clear treatment difference in PFS and OS. Ad-hoc subgroup analysis
of PFS and OS for subjects with tumors expressing low levels of HRG
at an mRNA level, defined as dCt >3.9, are presented in Table 14
and Table 15. Kaplan-Meier estimates of PFS in subjects with tumors
expressing low HRG levels are presented in FIG. 7 (showing high-
and low-dose patritumab+erlotinib vs. placebo+erlitonib) and FIG. 8
(showing pooled patritumab+erlotinib vs. placebo+erlitonib).
Kaplan-Meier estimates of OS in subjects with tumors expressing low
HRG levels are presented in FIG. 9 (showing high- and low-dose
patritumab+erlotinib vs. placebo+erlitonib) and FIG. 10 (showing
pooled patritumab+erlotinib vs. placebo+erlitonib).
TABLE-US-00014 TABLE 14 Analysis of Progression-Free Survival in
Subjects with Tumors Expressing Low HRG Levels Placebo + 18 mg/kg +
9 mg/kg + Doses erlotinib erlotinib erlotinib Combined (N = 16) (N
= 19) (N = 15) (N = 34) Subjects (%) with events 13 (81.3%) 13
(68.4%) 12 (80.0%) 25 (73.5%) Subjects (%) without events
(censored) 3 (18.8%) 6 (31.6%) 3 (20.0%) 9 (26.5%) Time to event
(months).sup.[a] Median 1.4 1.4 2.1 1.9 95% CI for Median [1.3;
8.1] [1.1; 8.5] [1.4; 3.0] [1.3; 3.0] Stratified Logrank
P-Value.sup.[b] 0.8025 0.8192 0.7876 Stratified Analysis.sup.[b]
Hazard Ratio (relative to Placebo) 0.908 0.924 0.915 95% CI [0.394;
2.091] [0.385; 2.219] [0.439; 1.908] 80% CI [0.526; 1.567] [0.521;
1.639] [0.566; 1.480] P-value for Hazard Ratio 0.8204 0.8599 0.8132
Notes: PFS is defined as the time from the randomization date to
the date ot the first objective documentation of disease
progression or death resulting from any cause, whichever comes
first. .sup.[a]Kaplan-Meier Estimate. CI for median was computed
using the Brookmeyer-Crowley method. .sup.[b]Stratified log-rank
and stratified Cox PH were stratified by best response to prior
therapy (CR, PR, SD vs PD) and histology subtype (adenocarcinoma vs
non-adenocarcinoma).
TABLE-US-00015 TABLE 15 Analysis of Overall Survival in Subjects
with Tumors Expressing Low HRG Levels Placebo + 18 mg/kg + 9 mg/kg
+ Doses erlotinib erlotinib erlotinib Combined (N = 16) (N = 19) (N
= 15) (N = 34) Subjects (%) with events 11 (68.8%) 12 (63.2%) 10
(66.7%) 22 (64.7%) Subjects (%) without events (censored) 5 (31.3%)
7 (36.8%) 5 (33.3%) 12 (35.3%) Time to event (months).sup.[a]
Median 8.0 9.6 6.3 9.3 95% CI for Median [2.3; 14.2] [2.3; NA]
[2.9; 13.3] [4.0; 11.7] Stratified Logrank P-Value.sup.[b] 0.9165
0.9713 0.9402 Stratified Analysis.sup.[b] Hazard Ratio (relative to
Placebo) 0.974 0.978 0.976 95% CI [0.426; 2.229] [0.395; 2.424]
[0.467; 2.040] 80% CI [0.567; 1.674] [0.541; 1.771] [0.603; 1.580]
P-value for Hazard Ratio 0.9506 0.9625 0.9484 Notes: OS is defined
as the time from the randomization date to the date of death.
.sup.[a]Kaplan-Meier Estimate. CI for median was computed using the
Brookmeyer-Crowley method. .sup.[b]Stratified log-rank and
stratified Cox PH were stratified by best response to prior therapy
(CR, PR, SD vs PD) and histology subtype (adenocarcinoma vs
non-adenocarcinoma).
Example 7A
HRG is Both a Prognostic and a Predictive Biomarker
[0326] An exploratory analysis of treatment effect as judged by PFS
was performed for the HRG high and low groups versus their
comparative placebo groups. As shown in FIG. 11, the analysis
suggested that HRG high is a negative prognostic factor for single
agent erlotinib treatment and a positive predictive factor for
clinical benefit from the addition of patritumab.
[0327] Based on blinded samples with respect to treatment group and
clinical outcomes, an HRG high subject was defined as the subject
with mRNA expression of HRG in the tumor with delta Ct value
<3.9 (median), and key efficacy analyses were performed for HRG
high group based on such pre-specified definition. Additional
ad-hoc exploratory analyses were performed to determine the
cut-offs for HRG expression.
[0328] A post-hoc analysis used a log likelihood approach for
cut-off values based on PFS. Log partial likelihoods for stratified
Cox proportional hazards model were calculated for both HRG high
and low groups based on a variety of possible HRG cut-off
values.
Example 7B
Determination of Optimal Cut-off for HRG mRNA Expression
[0329] Based on the plot of the sum of negative log partial
likelihoods versus cut-off value, the optimized maximum likelihood
cut-off value fell within the range of 3.5 to 4.0, as shown in FIG.
12.
[0330] Data was also used to calculate hazard ratios between the
pooled dose of patritumab and placebo based on several potential
cut-off values for delta Ct. These hazard ratios are shown in Table
16. Lower dCt values represent higher HRG mRNA expression. It
appears that higher HRG expression was associated with greater
clinical benefit in terms of PFS. Lowering the cutoff from 3.9 to
3.0 results in additional improvement in the average benefit as
judged by the hazard ratio without dramatically lowering the size
of the HRG high population.
TABLE-US-00016 TABLE 16 Hazard ratio and p-values for PFS in the
HRG high group as a function of cutoff Cut-off for n HR (pooled
dose Log-rank delta Ct (#events) vs placebo) p-value 2.7 (first
quartile) 24 (18) 0.180 0.0039 3.0 33 (24) 0.177 0.0009 3.5 46 (36)
0.283 0.0009 3.9 (median) 51 (41) 0.324 0.0013 4.5 65 (50) 0.490
0.0190 5.0 (third quartile) 76 (58) 0.561 0.0429
Example 8
Treatment Efficacy in Subjects with Tumors Expressing High HRG
Levels and EGFR Wild Type
[0331] In the HRG high group, there were 2 subjects with a
sensitizing mutation (1 on placebo and 1 on low dose); 21 subjects
with wild type (9 on placebo, 7 on low dose, and 5 on high dose)
and 28 subjects with unknown/indeterminate mutation status (8 on
placebo, 12 on low dose, and 8 on high dose) (Table 17).
[0332] Ad-hoc subgroup analysis of PFS for subjects with tumors
expressing high levels of HRG and EGFR wild type are presented in
Table 17 based on un-stratified analysis and Kaplan-Meier estimates
of PFS is presented in FIG. 13 (pooled patritumab+erlotinib vs.
placebo+erlotinib). An analysis of HRG high, EGFR wild type
subjects showed that the clinical benefit with respect to PFS was
maintained with pooled dose vs placebo: HR 0.24 (95% CI: 0.08,
0.74; P-value=0.008) based on un-stratified analysis.
TABLE-US-00017 TABLE 17 Analysis of Progression-Free Survival in
Subjects with Tumors Expressing High HRG Levels and EGFR Wild Type
Placebo + 18 mg/kg + 9 mg/kg + Doses erlotinib erlotinib erlotinib
Combined (N = 9) (N = 5) (N = 7) (N = 12) Subjects (%) with events
8 (88.9%) 5 (100.0%) 6 (85.7%) 11 (91.7%) Subjects (%) without
events (censored) 1 (11.1%) 0 1 (14.3%) 1 (8.3%) Time to event
(months).sup.[a] Median 1.4 2.8 2.8 2.8 95% CI for Median [0.6;
2.3] [0.2; 4.3] [1.4; 5.7] [1.2; 4.6] Unstratified Logrank P-Value
0.0913 0.0107 0.0078 Unstratified Analysis Hazard Ratio (relative
to Placebo) 0.361 0.167 0.237 95% CI [0.099; 1.317] [0.043; 0.647]
[0.075; 0.744] 80% CI [0.155; 0.842] [0.069; 0.405] [0.112; 0.500]
P-value for Hazard Ratio 0.123 0.0096 0.0137 Notes: PFS is defined
as the time from the randomization date to the date of the first
objective documentation of disease progression or death resulting
from any cause, whichever comes first. .sup.[a]Kaplan-Meier
Estimate. CI for median was computed using the Brookmeyer-Crowley
method.
Example 9
Biomarker Identification
[0333] The HRG biomarker was identified by analysing the anti-tumor
activity of the anti-HER3 antibody U3-1287 on various human cancer
xenografts in vivo and analysis of the expression of HRG of these
cell lines in vitro. Human tumor cell lines of various indications
were grown as xenografts in mice and treated with the anti-HER3
antibody U3-1287 for several weeks. Inhibition of tumor growth was
analysed by comparing the tumor volumes of control mice and mice
treated with U3-1287. Human tumor cell lines were grown in vitro
and analysed for HRG RNA expression by PCR. The results of this
analysis are shown in Table 18. Basal activity of HER3 as measured
by Western blotting did not correlate with in vivo efficacy of
U3-1287, predominantly in FISH positive breast cancer models. In
contrast, expression of HRG correlated very well with in vivo
efficacy of U3-1287, as seen for 15 of the 17 models analyzed.
TABLE-US-00018 TABLE 18 Retrospective in vitro analysis of cell
lines used for in vivo xenografts Phospho In vivo HER HER3 HRG
efficacy Corre- Cell Line Indication (WB) (WB) (PCR) (SA) lation
Sum225 BC FISH + ve + + - No Yes MDA- BC FISH + ve + + - No Yes
MB453 BT474 BC FISH + ve + + - No Yes HCC 1569 BC FISH + ve + + -
No Yes ZR75-1 BC FISH + ve + - - No Yes MCF-7 BC FISH + ve + - - No
Yes T47D BC FISH + ve + + - No Yes NCI-H441 NSCLC + + - No Yes A549
NSCLC + + + Yes Yes Calu-3 NSCLC + + + Yes Yes NC-H1975 NSCLC + + +
Yes Yes A375 Melanoma + - - No Yes HT-144 Melanoma + - + No Yes
HT-29 Colon + + - Yes No MKN-45 Gastric + + - Yes No BxPC3 Pancreas
+ + + Yes Yes FaDu Head&Neck + + + Yes Yes
[0334] U3-1287 efficacy was determined in vitro by measuring
reduction of phospho-HER3 and phospho-AKT levels. Basal HER3
phosphorylation could be blocked in cell lines that endogenously
express heregulin (A549) as well as in cells that do not have basal
HER3 activation but were stimulated with exogenous heregulin
(CaOV3). U3-1287 efficacy results are shown in FIG. 14.
[0335] Unexpectedly, cells that have basal HER3 phosphorylation but
do not express heregulin showed no efficacy upon U3-1287 treatment
(BT474 basal) and even more surprisingly, this could be overcome by
exogenously added heregulin (BT474+HRG), as shown in FIG. 15.
INCORPORATION BY REFERENCE
[0336] The entire disclosure of each of the patent documents and
scientific articles cited herein is incorporated by reference for
all purposes.
Appendix A
[0337] The below table (Table A1) shows unblinded data from Example
1. In the table, U3-1287 corresponds to patritumab.
TABLE-US-00019 HRG Patient Cancer deltaCt PFS* OS* Best # Stage
Prior Cancer Therapy (mRNA) Treatment (days) (days) Response 1 IV
CARBOPLATIN + 4.64 U3-1287 18 41 118 PD PEMETREXED mg/kg +
Erlotinib 2 IV CARBOPLATIN + OTHER: 5.35 U3-1287 9 78 192 SD
ETOPOSIDE; mg/kg + CARBOPLATIN + Erlotinib DOCETAXEL; VINORELBINE 3
IV BEVACIZUMAB + 4.8 U3-1287 9 1(c) 46(c) NE CARBOPLATIN + mg/kg +
PEMETREXED Erlotinib 4 IV CARBOPLATIN + 3.14 U3-1287 18 37 185 PD
PACLITAXEL + mg/kg + BEVACIZUMAB Erlotinib 5 IV CISPLATIN + 3.92
Placebo + 402 562(c) PR PEMETREXED; Erlotinib CARBOPLATIN +
PACLITAXEL + BEVACIZUMAB 6 IV CARBOPLATIN + 2.52 Placebo + 37 90 PD
PACLITAXEL + Erlotinib BEVACIZUMAB 7 IV CARBOPLATIN + 4.61 Placebo
+ 40 190 PD PACLITAXEL Erlotinib 8 IV CARBOPLATIN + 2.09 U3-1287 9
426(c) 641(c) PR PACLITAXEL; mg/kg + DOCETAXEL + OTHER: Erlotinib
BIBF1120/PLACEBO 9 IV OTHER: PAZOPANIB + 5.32 Placebo + 86 432 SD
PEMETREXED Erlotinib 10 IV CARBOPLATIN + 4.82 U3-1287 18 38 38 NE
PACLITAXEL; mg/kg + PEMETREXED + OTHER: Erlotinib
PLACEBO!!!/(BIBF1120) 11 IV CARBOPLATIN + 4.45 Placebo + 33 33 NE
PACLITAXEL Erlotinib 12 IV CARBOPLATIN + 2.22 U3-1287 9 98 531 PR
PACLITAXEL mg/kg + Erlotinib 13 IV CARBOPLATIN + 3.1 U3-1287 18 182
499(c) SD PACLITAXEL + OTHER: mg/kg + OMBRABULIN/PLACEBO Erlotinib
14 IIIB CARBOPLATIN + 2 U3-1287 9 94 430(c) SD PACLITAXEL mg/kg +
Erlotinib 15 IV CARBOPLATIN + 4.49 U3-1287 9 43 66 PD PACLITAXEL
mg/kg + Erlotinib 16 IV CARBOPLATIN + 5.14 U3-1287 18 260 463(c) SD
PACLITAXEL + OTHER: mg/kg + OMBRABULIN/PLACEBO Erlotinib 17 IV
CARBOPLATIN + 3.12 U3-1287 18 13 13 NE PACLITAXEL + OTHER: mg/kg +
OMBRABULIN/PLACEBO Erlotinib 18 IV CARBOPLATIN + 0.09 U3-1287 9 42
142 PD PEMETREXED mg/kg + Erlotinib 19 IV CISPLATIN + 3.36 U3-1287
9 329(c) 510(c) PR VINORELBINE mg/kg + Erlotinib 20 IV CARBOPLATIN
+ 4.75 U3-1287 18 328(c) 524(c) PR PACLITAXEL + OTHER: mg/kg +
OMBRABULIN/PLACEBO Erlotinib 21 IV CARBOPLATIN + 3.07 Placebo + 44
114 PD GEMCITABINE; Erlotinib DOCETAXEL 22 IIIB CISPLATIN + 2.25
U3-1287 9 90 140 SD GEMCITABINE; mg/kg + DOCETAXEL Erlotinib 23 IV
CISPLATIN + 4.59 U3-1287 9 91 405 SD GEMCITABINE + OTHER: mg/kg +
SAR240550(INIPARIB = Erlotinib PARP1INHIBITOR); OTHER: BIBF1120
(VEGFINHIBITOR) + PEMETREXED 24 IV CARBOPLATIN + 2.73 Placebo + 18
18 NE PACLITAXEL Erlotinib 25 IV CARBOPLATIN + 4.35 U3-1287 18
91(c) 189 PR PACLITAXEL mg/kg + Erlotinib 26 IV CARBOPLATIN + 3.45
U3-1287 18 173 173 SD PACLITAXEL mg/kg + Erlotinib 27 IV
CARBOPLATIN + 3.89 Placebo + 49 89 PD PACLITAXEL + OTHER: Erlotinib
OMBRABULIN/PLACEBO 28 IIIB CISPLATIN + 3.53 U3-1287 18 122 122 SD
GEMCITABINE mg/kg + Erlotinib 29 IV CARBOPLATIN + 5.73 U3-1287 18
133(c) 292 SD PACLITAXEL mg/kg + Erlotinib 30 IV CARBOPLATIN + 1.83
U3-1287 18 262(c) 349 SD PACLITAXEL + OTHER: mg/kg + OMBRABULIN
Erlotinib 31 IIIB CARBOPLATIN + 5.7 Placebo + 44 165 PD PACLITAXEL
Erlotinib 32 IV CISPLATIN + 2.27 U3-1287 18 24 382(c) PD
PACLITAXEL; mg/kg + DOCETAXEL Erlotinib 33 IV CARBOPLATIN + 2.77
Placebo + 45 98 PD PACLITAXEL + OTHER: Erlotinib OMBRABULIN/PLACEBO
34 IV CARBOPLATIN + 2.72 Placebo + 1(c) 390(c) SD GEMCITABINE
Erlotinib 35 IV CARBOPLATIN + 6.09 U3-1287 9 43 60 PD PACLITAXEL +
OTHER: mg/kg + OMBRABULIN/PLACEBO Erlotinib 36 IV CISPLATIN + 2.44
U3-1287 18 44 63 PD PACLITAXEL mg/kg + Erlotinib 37 IV CISPLATIN +
3.3 U3-1287 18 38 38 NE PEMETREXED mg/kg + Erlotinib 38 IV
CISPLATIN + 4.45 U3-1287 9 43 355 PD PEMETREXED mg/kg + Erlotinib
39 IV CARBOPLATIN + 6.32 Placebo + 39 266 PD PEMETREXED + Erlotinib
BEVACIZUMAB 40 IV CARBOPLATIN + 4.09 Placebo + 178(c) 336 SD
PACLITAXEL + Erlotinib BEVACIZUMAB; PEMETREXED 41 IV CISPLATIN +
7.13 U3-1287 18 35 35 NE PEMETREXED + OTHER: mg/kg + PANITUMUMAB
Erlotinib 42 IV BEVACIZUMAB + 2.29 U3-1287 9 43(c) 375(c) PR
CARBOPLATIN + mg/kg + PEMETREXED Erlotinib 43 IV CARBOPLATIN + 2.66
Placebo + 24 363 PD GEMCITABINE Erlotinib 44 IV CISPLATIN + 2.98
Placebo + 1(c) 448(c) NE VINORELBINE Erlotinib 45 IV CARBOPLATIN +
5.12 U3-1287 18 33 33 NE PACLITAXEL mg/kg + Erlotinib 46 IV
CISPLATIN + 4.15 U3-1287 18 36 69 PD PEMETREXED mg/kg + Erlotinib
47 IV CARBOPLATIN + 3.93 U3-1287 18 34 292 PD VINORELBINE; mg/kg +
CARBOPLATIN + Erlotinib PEMETREXED; OTHER: MAGRIT(VACCINATION) 48
IV CARBOPLATIN + 5.2 U3-1287 18 99(c) 149 SD PACLITAXEL + OTHER:
mg/kg + OMRABULINVS.cndot.PLACEBO Erlotinib 49 IV CARBOPLATIN +
1.88 U3-1287 9 47 93 PD GEMCITABINE; mg/kg + DOCETAXEL Erlotinib 50
IV CISPLATIN + 2.85 U3-1287 9 48 64 PD PEMETREXED mg/kg + Erlotinib
51 IIIB CISPLATIN + 2.51 U3-1287 18 141(c) 296 SD PACLITAXEL; mg/kg
+ CISPLATIN + Erlotinib VINORELBINE 52 IV CISPLATIN + 1.51 Placebo
+ 43 456(c) PD VINORELBINE; Erlotinib CARBOPLATIN + PACLITAXEL 53
IV CISPLATIN + 4.66 U3-1287 9 168 284 SD VINORELBINE; mg/kg +
CARBOPLATIN + Erlotinib PACLITAXEL 54 IV CISPLATIN + 6.23 U3-1287
18 43 122 PD PEMETREXED mg/kg + Erlotinib 55 IV CISPLATIN + 5.62
U3-1287 9 43 179 PD PEMETREXED mg/kg + Erlotinib 56 IV CARBOPLATIN
+ 5.33 U3-1287 18 58 330(c) PD GEMCITABINE; OTHER: mg/kg +
LUCANIXVACCINE Erlotinib 57 IV CISPLATIN + 2.47 U3-1287 18 40 71 PD
CARBOPLATIN + mg/kg + GEMCITABINE Erlotinib 58 IV CARBOPLATIN +
6.37 Placebo + 66 160 PD GEMCITABINE; Erlotinib PEMETREXED 59 IV
CISPLATIN + 4.87 U3-1287 9 39 116 PD GEMCITABINE; mg/kg +
PEMETREXED Erlotinib 60 IV CISPLATIN + 5.25 U3-1287 18 25 327 PD
VINORELBINE; mg/kg + CISPLATIN + Erlotinib PEMETREXED 61 IV
CARBOPLATIN + 5.96 U3-1287 18 41 66 PD PEMETREXED mg/kg + Erlotinib
62 IV CARBOPLATIN + OTHER: 3.04 Placebo + 120 323(c) SD TAXOTERE;
Erlotinib CARBOPLATIN + GEMCITABINE 63 IV CISPLATIN + OTHER: 4.46
U3-1287 9 16 89 PD ETOPOSIDE mg/kg + Erlotinib 64 IIIB CISPLATIN +
2.15 U3-1287 9 43 267 PD CISPLATIN + mg/kg + PEMETREXED Erlotinib
65 IV CISPLATIN + OTHER: 2.81 U3-1287 9 85 323 PD
INVESTIGATIONALDRUG + mg/kg + PEMETREXED; Erlotinib DOCETAXEL 66
IIIB CARBOPLATIN + 4.4 U3-1287 9 42(c) 128(c) SD VINORELBINE; mg/kg
+ CISPLATIN + Erlotinib VINORELBINE 67 IIIB CISPLATIN + 4.21
U3-1287 9 211 333(c) SD VINORELBINE; mg/kg + DOCETAXEL Erlotinib 68
IV CARBOPLATIN + 3.42 U3-1287 18 131 333 SD PACLITAXEL mg/kg +
Erlotinib 69 IV CISPLATIN + 0.76 U3-1287 9 253(c) 372(c) SD
VINORELBINE; mg/kg + PACLITAXEL Erlotinib 70 IIIB CISPLATIN + 6.99
U3-1287 18 22 127(c) PD GEMCITABINE mg/kg + Erlotinib 71 IV
CISPLATIN + 2.3 Placebo + 40 153 PD GEMCITABINE; Erlotinib
DOCETAXEL 72 IV CISPLATIN + 2.35 U3-1287 18 255(c) 437(c) SD
GEMCITABINE mg/kg + Erlotinib 73 IV CISPLATIN + 2.59 Placebo + 43
140(c) PD GEMCITABINE Erlotinib 74 IV CISPLATIN + 5.08 U3-1287 9 65
345(c) PR GEMCITABINE mg/kg + Erlotinib 75 IV CISPLATIN + 5.39
Placebo + 44 71 PD PEMETREXED Erlotinib 76 IV CARBOPLATIN + 2.98
U3-1287 18 1(c) 52(c) NE PACLITAXEL mg/kg + Erlotinib 77 IV
CISPLATIN + 5.41 Placebo + 248 379(c) SD DOCETAXEL; Erlotinib
PEMETREXED 78 IV CARBOPLATIN + 5.78 Placebo + 42 57 PD PACLITAXEL;
Erlotinib DOCETAXEL
79 IV CARBOPLATIN + 5.06 Placebo + 247(c) 427(c) PR PACLITAXEL;
Erlotinib CISPLATIN + PEMETREXED 80 IV CISPLATIN + OTHER: 4.01
Placebo + 38 311(c) PD ETOPOSIDE Erlotinib 81 IV CISPLATIN + 3.66
Placebo + 168 330(c) PR DOCETAXEL Erlotinib 82 IV CISPLATIN + 5.85
Placebo + 27 27 NE DOCETAXEL Erlotinib 83 IV CISPLATIN + 4.58
Placebo + 173(c) 328(c) SD GEMCITABINE Erlotinib 84 IV CISPLATIN +
1.98 U3-1287 9 85 185 SD GEMCITABINE; OTHER: mg/kg + TAXOTERE
Erlotinib 85 IV CISPLATIN + 3.32 Placebo + 167 323(c) SD PEMETREXED
Erlotinib 86 IV CISPLATIN + 4.2 U3-1287 18 168(c) 321(c) SD
GEMCITABINE mg/kg + Erlotinib 87 IV CISPLATIN + 4.63 U3-1287 18 83
246(c) SD DOCETAXEL; mg/kg + CISPLATIN + Erlotinib DOCETAXEL 88 IV
CISPLATIN + 3.85 U3-1287 9 43 522(c) PD GEMCITABINE; mg/kg +
PEMETREXED Erlotinib 89 IIIB CISPLATIN + 8.1 U3-1287 9 81 174 SD
CARBOPLATIN + mg/kg + PACLITAXEL + Erlotinib BEVACIZUMAB 90 IV
CARBOPLATIN + 3.04 Placebo + 34 46 PD GEMCITABINE + Erlotinib
PACLITAXEL + DOCETAXEL 91 IIIB CISPLATIN + 5.04 Placebo + 43 221 PD
CARBOPLATIN + Erlotinib GEMCITABINE 92 IV CARBOPLATIN + 3.7 U3-1287
18 85 278(c) SD GEMCITABINE; mg/kg + DOCETAXEL Erlotinib 93 IV
CARBOPLATIN + 1.43 Placebo + 78 123 PD CISPLATIN + OTHER: Erlotinib
DOXORUBICIN + OTHER: ETOPOSIDE 94 IV CISPLATIN + OTHER: 3.43
Placebo + 70 322 PD ETOPOSIDE; OTHER: Erlotinib CAMPTOTHECIN 95 IV
CISPLATIN + OTHER: 6.71 U3-1287 18 165(c) 336(c) PR ETOPOSIDE;
OTHER: mg/kg + TAXOTER Erlotinib 96 IV CARBOPLATIN 2.3 Placebo + 44
81 PD Erlotinib 97 IV CARBOPLATIN + 3.46 U3-1287 18 129 129 SD
PACLITAXEL; mg/kg + CISPLATIN + OTHER: Erlotinib ETOPOSID,
DOXORUBICIN 98 IV CARBOPLATIN + OTHER: 2.81 U3-1287 9 173 267(c) SD
ETOPOSIDE; mg/kg + CISPLATIN + Erlotinib DOCETAXEL + OTHER:
CYCLOPHOSPHAMIDE 99 IV CISPLATIN + 3.97 U3-1287 9 171(c) 351(c) PR
PACLITAXEL; mg/kg + CARBOPLATIN + Erlotinib GEMCITABINE +
PACLITAXEL 100 IV CISPLATIN + OTHER: 2.93 U3-1287 18 7 7 NE
ETOPOSIDUM mg/kg + Erlotinib 101 IV CISPLATIN + OTHER: 0.1 U3-1287
9 141 141 SD ETOPOSID mg/kg + Erlotinib
* * * * *