U.S. patent application number 16/240316 was filed with the patent office on 2019-06-27 for treatment of pd-l1-negative melanoma using an anti-pd-1 antibody and an anti-ctla-4 antibody.
This patent application is currently assigned to Bristol-Myers Squibb Company. The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Arvin YANG.
Application Number | 20190194328 16/240316 |
Document ID | / |
Family ID | 56087499 |
Filed Date | 2019-06-27 |
United States Patent
Application |
20190194328 |
Kind Code |
A1 |
YANG; Arvin |
June 27, 2019 |
TREATMENT OF PD-L1-NEGATIVE MELANOMA USING AN ANTI-PD-1 ANTIBODY
AND AN ANTI-CTLA-4 ANTIBODY
Abstract
The invention provides a method of treating a melanoma
comprising (i) identifying a patient having a PD-L1-negative
melanoma and (ii) administering to the patient a combination of an
anti-PD-1 antibody or an antigen-binding portion thereof and an
anti-CTLA-4 antibody or an antigen-binding portion thereof. The
methods of the invention can extend progression-free survival for
over 8 months and/or reduces the tumor size at least about 10%,
about 20%, about 30%, about 40%, or about 50% compared to the tumor
size prior to the administration.
Inventors: |
YANG; Arvin; (Princeton,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Assignee: |
Bristol-Myers Squibb
Company
Princeton
NJ
|
Family ID: |
56087499 |
Appl. No.: |
16/240316 |
Filed: |
January 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15141769 |
Apr 28, 2016 |
10174113 |
|
|
16240316 |
|
|
|
|
62153973 |
Apr 28, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2039/545 20130101;
C07K 2317/92 20130101; G01N 33/577 20130101; A61K 2039/55 20130101;
G01N 2333/70503 20130101; A61P 17/00 20180101; A61K 45/06 20130101;
C07K 16/2818 20130101; A61P 43/00 20180101; A61K 2039/507 20130101;
C07K 2317/21 20130101; G01N 33/5743 20130101; A61P 35/00 20180101;
A61K 39/39558 20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28; G01N 33/577 20060101 G01N033/577; A61K 45/06 20060101
A61K045/06; A61K 39/395 20060101 A61K039/395; G01N 33/574 20060101
G01N033/574 |
Claims
1. (canceled)
2. A method for treating a melanoma comprising administering to a
patient afflicted with a melanoma tumor an anti-PD-1 antibody or an
antigen-binding portion thereof that binds specifically to a human
PD-1 ("anti-PD-1 antibody") at a flat dose of 240 mg once every two
weeks or 480 mg once every four weeks.
3. The method of claim 2 further comprising administering to the
patient an anti-CTLA-4 antibody or an antigen-binding portion
thereof that binds specifically to a human CTLA-4 ("anti-CTLA-4
antibody").
4-7. (canceled)
8. The method of claim 2, wherein the patient is characterized by
(i) extended progression-free survival for over 8 months, (ii)
tumor size reduction at least about 10%, about 20%, about 30%,
about 40%, or about 50% compared to the tumor size prior to the
administration, or (iii) both.
9-13. (canceled)
14. The method of claim 2, further comprising measuring a PD-L1
expression on the melanoma tumor prior to the administration.
15. (canceled)
16. The method of claim 14, wherein the measuring comprises
providing a test tissue sample obtained from the patient, the test
tissue sample comprising tumor cells and/or tumor-infiltrating
inflammatory cells.
17. The method of claim 16, wherein the measuring further comprises
assessing the proportion of cells in the test tissue sample that
express PD-L1 on the cell surface.
18. The method of claim 17, wherein the test tissue sample is a
formalin-fixed paraffin-embedded (FFPE) tissue sample, and wherein
the presence of PD-L1 is determined using an automated IHC
assay.
19. (canceled)
20. The method of claim 18, wherein the IHC assay is performed
using an anti-PD-L1 monoclonal antibody that specifically binds to
the PD-L1 and wherein the anti-PD-L1 monoclonal antibody comprises
a variable heavy chain region comprising the amino acid sequence
set forth in SEQ ID NO: 1 and a variable light region comprising
the amino acid sequence set forth in SEQ ID NO: 2.
21. The method of claim 2, wherein the PD-L1-positive melanoma
tumor is characterized by having at least about 5% of tumor cells
showing binding to the anti-PD-L1 antibody or an antigen-binding
portion thereof.
22-24. (canceled)
25. The method of claim 2, wherein the anti-PD-1 antibody is
nivolumab or pembrolizumab.
26-31. (canceled)
32. The method of claim 3, wherein the anti-CTLA-4 antibody is
ipilimumab.
33. (canceled)
34. The method of claim 3, wherein the anti-CTLA-4 antibody is
administered once every 2, 3 or 4 weeks.
35. The method of claim 34, wherein the anti-CTLA-4 antibody is
administered at a dose of 1 or 3 mg/kg body weight once every 3
weeks.
36. The method of claim 34, wherein the anti-CTLA-4 antibody is
administered at a flat dose of about 80 mg, about 160 mg, or about
240 mg.
37. The method of claim 3, wherein the anti-PD-1 antibody is
administered concurrently with the anti-CTLA-4 antibody.
38. The method of claim 3, wherein the anti-PD-1 antibody is
administered prior to or after the anti-CTLA-4 antibody.
39-45. (canceled)
46. The method of claim 3, further comprising administering an
anti-cancer agent.
47. (canceled)
48. The method of claim 3, wherein the anti-PD-1 antibody is
administered at a flat dose of 240 mg once every two weeks.
49. The method of claim 3, wherein the anti-PD-1 antibody is
administered at a flat dose of 480 mg once every four weeks.
50. A method for treating a melanoma in a patient afflicted with a
melanoma tumor, comprising administering to the patient nivolumab
as a monotherapy at a flat dose of 240 mg once every two weeks or
480 mg once every four weeks, wherein the patient is identified as
having a PD-L1-positive melanoma tumor prior to the administration.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/141,769 filed Apr. 28, 2016, which claims
benefit to U.S. Provisional Application No. 62/153,973 filed Apr.
28, 2015, each of which is incorporated herein by reference in its
entirety.
REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA
EFS-WEB
[0002] The instant application contains a Sequence Listing which
has been submitted in ASCII format via EFS-Web, and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Jan. 4, 2019, is named 3338_0330003 SeqListing_ST25.txt and is
3,770 bytes in size.
[0003] Throughout this application, various publications are
referenced in parentheses by author name and date, or by Patent No.
or Patent Publication No. The disclosures of these publications are
hereby incorporated in their entireties by reference into this
application in order to more fully describe the state of the art as
known to those skilled therein as of the date of the invention
described and claimed herein. However, the citation of a reference
herein should not be construed as an acknowledgement that such
reference is prior art to the present invention.
FIELD OF THE INVENTION
[0004] This invention relates to a method of treating
PD-L1-negative melanoma comprising administering a combination of
an anti-PD-1 antibody and an anti-CTLA-4 antibody.
BACKGROUND OF THE INVENTION
[0005] Human cancers harbor numerous genetic and epigenetic
alterations, generating neoantigens potentially recognizable by the
immune system (Sjoblom et al. (2006) Science 314:268-74). The
adaptive immune system, comprised of T and B lymphocytes, has
powerful anti-cancer potential, with a broad capacity and exquisite
specificity to respond to diverse tumor antigens. Further, the
immune system demonstrates considerable plasticity and a memory
component. The successful harnessing of all these attributes of the
adaptive immune system would make immunotherapy unique among all
cancer treatment modalities.
[0006] Recently, several immune checkpoint pathway inhibitors have
begun to provide new immunotherapeutic approaches for treating
cancer, including the development of an antibody (Ab), ipilimumab
(YERVOY.RTM.), that binds to and inhibits Cytotoxic T-Lymphocyte
Antigen-4 (CTLA-4) for the treatment of patients with advanced
melanoma and the development of antibodies such as nivolumab and
pembrolizumab (formerly lambrolizumab; USAN Council Statement,
(2013) Pembrolizumab: Statement on a nonproprietary name adopted by
the USAN Council (ZZ-165), Nov. 27, 2013) that bind specifically to
the Programmed Death-1 (PD-1) receptor and block the inhibitory
PD-1/PD-1 ligand pathway.
[0007] The promise of the emerging field of personalized medicine
is that advances in pharmacogenomics will increasingly be used to
tailor therapeutics to defined sub-populations, and ultimately,
individual patients in order to enhance efficacy and minimize
adverse effects. Recent successes include, for example, the
development of imatinib mesylate (GLEEVEC.RTM.), a protein tyrosine
kinase inhibitor that inhibits the bcr-abl tyrosine kinase, to
treat Philadelphia chromosome-positive chronic myelogenous leukemia
(CIVIL); crizotinib (XALKORI.RTM.) to treat the 5% of patients with
late-stage non-small cell lung cancers who express a mutant
anaplastic lymphoma kinase (ALK) gene; and vemurafenib
(ZELBORAF.RTM.), an inhibitor of mutated B-RAF protein (V600E-BRAF)
which is expressed in around half of melanoma tumors. However,
unlike the clinical development of small molecule agents that
target discrete activating mutations found in select cancer
populations, a particular challenge in cancer immunotherapy has
been the identification of mechanism-based predictive biomarkers to
enable patient selection and guide on-treatment management.
SUMMARY OF THE INVENTION
[0008] The present disclosure provides a method for treating a
melanoma comprising (i) identifying a patient having a
PD-L1-negative melanoma tumor; and (ii) administering to the
patient (a) an anti-PD-1 antibody or an antigen-binding portion
thereof that binds specifically to a human PD-1; and (b) an
anti-CTLA-4 antibody or an antigen-binding portion thereof that
binds specifically to a human CTLA-4. The present disclosure also
provides a method for treating a melanoma comprising administering
to a patient afflicted with a melanoma tumor (a) an anti-PD-1
antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4, wherein the patient is identified as having a
PD-L1-negative melanoma tumor prior to the administration.
[0009] The present disclosure further provides a method for
extending a progression-free survival period for over 8 months in a
patient afflicted with a melanoma tumor comprising administering to
the patient (a) an anti-PD-1 antibody or an antigen-binding portion
thereof that binds specifically to a human PD-1; and (b) an
anti-CTLA-4 antibody or an antigen-binding portion thereof that
binds specifically to a human CTLA-4, wherein the patient is
identified as having a PD-L1-negative melanoma tumor prior to the
administration and wherein the patient demonstrates
progression-free survival for over 8 months. In certain
embodiments, the progression-free survival of the patient is
extended after the administration for over about 11 months, about
12 months, about 13 months, about 14 months, about 15 months, about
16 months, about 17 months, about 18 months, about 2 years, about 3
years, about 4 years, about 5 years, about 6 years, about 7 years,
about 8 years, about 9 years, or about 10 years. In one particular
embodiment, the progression-free survival of the patient is
extended for over 11 months.
[0010] The present disclosure also provides a method for reducing a
tumor size at least by 10% in a patient afflicted with a melanoma
tumor comprising administering to the patient (a) an anti-PD-1
antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4, wherein the patient is identified as having a
PD-L1-negative melanoma tumor prior to the administration and
wherein the administration reduces the tumor size at least about
10%, about 20%, about 30%, about 40%, or about 50% compared to the
tumor size prior to the administration.
[0011] The present disclosure also provides a method for increasing
an objective response rate to be higher than 40% in a patient
population, each of whom is afflicted with a melanoma tumor, in a
cancer treatment comprising administering to the patient (a) an
anti-PD-1 antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4, wherein each patient is identified as having a
PD-L1-negative melanoma tumor prior to the administration and
wherein the objective response rate is higher than 40%, 45%, 50%,
55%, 60%, 65%, 70%, or 75%.
[0012] The present disclosure also provides a method for selecting
a patient suitable for an anti-PD-1 antibody and anti-CTLA-4
antibody combination therapy comprising (i) identifying a patient
having a PD-L1-negative melanoma tumor; and (ii) instructing a
healthcare provider to administer to the patient (a) an anti-PD-1
antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4.
[0013] In certain embodiments, the methods disclosed herein further
comprise identifying the patient as having a melanoma tumor that
does not express PD-L1 prior to the administration. In some
embodiments, the patient is characterized by (i) extended
progression-free survival for over 8 months, (ii) tumor size
reduction at least about 10%, about 20%, about 30%, about 40%, or
about 50% compared to the tumor size prior to the administration,
or (iii) both.
[0014] In some embodiments, the methods disclosed herein further
comprise measuring a PD-L1 expression on the melanoma tumor. In
certain embodiments, the measuring further comprises assessing the
proportion of cells in the test tissue sample that express PD-L1 on
the cell surface. In one particular embodiment, the presence of
PD-L1 is determined using an automated IHC assay.
[0015] The present disclosure further provides a kit for treating a
patient afflicted with a melanoma tumor, the kit comprising (a) a
dosage ranging from 0.1 to 10 mg/kg body weight of an anti-PD-1
antibody or an antigen-binding portion thereof; (b) a dosage
ranging from 0.1 to 10 mg/kg body weight of an anti-CTLA-4 antibody
or an antigen-binding portion thereof; and (c) instructions for
using the anti-PD-1 antibody or the antigen-binding portion thereof
and the anti-CTLA-4 antibody or the antigen-binding portion thereof
in any of the methods disclosed herein.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 shows a patient flow diagram of the randomized,
double-blind, multicenter, phase 3 trial.
[0017] FIGS. 2A-C show progression-free survival data in the
intention-to-treat population (FIG. 2A), in patients with positive
PD-L1 status (FIG. 2B), and Negative PD-L1 Status (FIG. 2C). Each
graph shows the progression free survival for patients treated with
nivolumab alone (solid line), ipilimumab alone (dashed line), or
the combination of nivolumab and ipilimumab (dotted line) in months
(FIGS. 2A-C). The number at risk in months for each of nivolumab,
nivolumab plus ipilimumab, and ipilimumab is shown below each
x-axis (FIGS. 2A-C). PD-L1 expression status is based on verified
PD-L1 assay data (FIGS. 2B-C).
[0018] FIGS. 3A and 3B show subgroup analyses of progression-free
survival among patients treated with nivolumab alone compared to
ipilimumab alone (FIG. 3A) and patients treated with nivolumab plus
ipilimumab compared to ipilimumab alone (FIG. 3B).
[0019] FIGS. 4A-4C show the tumor burden change in target lesions
in patients treated with nivolumab alone (FIG. 4A), nivolumab plus
ipilimumab (FIG. 4B), and ipilimumab alone (FIG. 4C). In each
graph, the y-axis shows the best reduction from baseline in target
lesions (%) and the x-axis represents each patient (FIGS.
4A-C).
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention relates to identifying an optimal
strategy to treat a patient having a PD-L1-negative melanoma. The
present invention shows that in a patient having a PD-L1-negative
melanoma tumor, a combination therapy of an anti-PD-1 antibody and
an anti-CTLA-4 antibody provides a better response (e.g.,
progression-free survival) than a monotherapy of either an
anti-PD-1 antibody or an anti-CTLA-4 antibody. Furthermore, the
combination therapy when given to a population of patients can
increase the objective response rate compared to the
monotherapy.
Definitions
[0021] In order that the present disclosure may be more readily
understood, certain terms are first defined. As used in this
application, except as otherwise expressly provided herein, each of
the following terms shall have the meaning set forth below.
Additional definitions are set forth throughout the
application.
[0022] The term "and/or" where used herein is to be taken as
specific disclosure of each of the two specified features or
components with or without the other. Thus, the term "and/or" as
used in a phrase such as "A and/or B" herein is intended to include
"A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the
term "and/or" as used in a phrase such as "A, B, and/or C" is
intended to encompass each of the following aspects: A, B, and C;
A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B (alone); and C (alone).
[0023] It is understood that wherever aspects are described herein
with the language "comprising," otherwise analogous aspects
described in terms of "consisting of" and/or "consisting
essentially of" are also provided.
[0024] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure is related. For
example, the Concise Dictionary of Biomedicine and Molecular
Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of
Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the
Oxford Dictionary Of Biochemistry And Molecular Biology, Revised,
2000, Oxford University Press, provide one of skill with a general
dictionary of many of the terms used in this disclosure.
[0025] Units, prefixes, and symbols are denoted in their Systeme
International de Unites (SI) accepted form. Numeric ranges are
inclusive of the numbers defining the range. The headings provided
herein are not limitations of the various aspects of the
disclosure, which can be had by reference to the specification as a
whole. Accordingly, the terms defined immediately below are more
fully defined by reference to the specification in its
entirety.
[0026] "Administering" refers to the physical introduction of a
composition comprising a therapeutic agent to a subject, using any
of the various methods and delivery systems known to those skilled
in the art. Routes of administration for the formulations disclosed
herein include intravenous, intramuscular, subcutaneous,
intraperitoneal, spinal or other parenteral routes of
administration, for example by injection or infusion. The phrase
"parenteral administration" as used herein means modes of
administration other than enteral and topical administration,
usually by injection, and includes, without limitation,
intravenous, intramuscular, intraarterial, intrathecal,
intralymphatic, intralesional, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal, epidural and intrasternal injection and
infusion, as well as in vivo electroporation. In some embodiments,
the formulation is administered via a non-parenteral route, in some
embodiments, orally. Other non-parenteral routes include a topical,
epidermal or mucosal route of administration, for example,
intranasally, vaginally, rectally, sublingually or topically.
Administering can also be performed, for example, once, a plurality
of times, and/or over one or more extended periods.
[0027] An "adverse event" (AE) as used herein is any unfavorable
and generally unintended or undesirable sign (including an abnormal
laboratory finding), symptom, or disease associated with the use of
a medical treatment. For example, an adverse event may be
associated with activation of the immune system or expansion of
immune system cells (e.g., T cells) in response to a treatment. A
medical treatment may have one or more associated AEs and each AE
may have the same or different level of severity. Reference to
methods capable of "altering adverse events" means a treatment
regime that decreases the incidence and/or severity of one or more
AEs associated with the use of a different treatment regime.
[0028] An "antibody" (Ab) shall include, without limitation, a
glycoprotein immunoglobulin which binds specifically to an antigen
and comprises at least two heavy (H) chains and two light (L)
chains interconnected by disulfide bonds, or an antigen-binding
portion thereof. Each H chain comprises a heavy chain variable
region (abbreviated herein as V.sub.H) and a heavy chain constant
region. The heavy chain constant region comprises three constant
domains, C.sub.H1, C.sub.H2 and C.sub.H3. Each light chain
comprises a light chain variable region (abbreviated herein as
V.sub.L) and a light chain constant region. The light chain
constant region is comprises one constant domain, C.sub.L. The
V.sub.H and V.sub.L regions can be further subdivided into regions
of hypervariability, termed complementarity determining regions
(CDRs), interspersed with regions that are more conserved, termed
framework regions (FR). Each V.sub.H and V.sub.L comprises three
CDRs and four FRs, arranged from amino-terminus to carboxy-terminus
in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The
variable regions of the heavy and light chains contain a binding
domain that interacts with an antigen. The constant regions of the
antibodies may mediate the binding of the immunoglobulin to host
tissues or factors, including various cells of the immune system
(e.g., effector cells) and the first component (C1q) of the
classical complement system.
[0029] An immunoglobulin may derive from any of the commonly known
isotypes, including but not limited to IgA, secretory IgA, IgG and
IgM. IgG subclasses are also well known to those in the art and
include but are not limited to human IgG1, IgG2, IgG3 and IgG4.
"Isotype" refers to the antibody class or subclass (e.g., IgM or
IgG1) that is encoded by the heavy chain constant region genes. The
term "antibody" includes, by way of example, both naturally
occurring and non-naturally occurring antibodies; monoclonal and
polyclonal antibodies; chimeric and humanized antibodies; human or
nonhuman antibodies; wholly synthetic antibodies; and single chain
antibodies. A nonhuman antibody may be humanized by recombinant
methods to reduce its immunogenicity in man. Where not expressly
stated, and unless the context indicates otherwise, the term
"antibody" also includes an antigen-binding fragment or an
antigen-binding portion of any of the aforementioned
immunoglobulins, and includes a monovalent and a divalent fragment
or portion, and a single chain antibody.
[0030] The term "monoclonal antibody" ("mAb") refers to a
non-naturally occurring preparation of antibody molecules of single
molecular composition, i.e., antibody molecules whose primary
sequences are essentially identical, and which exhibits a single
binding specificity and affinity for a particular epitope. A mAb is
an example of an isolated antibody. MAbs may be produced by
hybridoma, recombinant, transgenic or other techniques known to
those skilled in the art.
[0031] A "human" antibody (HuMAb) refers to an antibody having
variable regions in which both the framework and CDR regions are
derived from human germline immunoglobulin sequences. Furthermore,
if the antibody contains a constant region, the constant region is
also derived from human germline immunoglobulin sequences. The
human antibodies of the invention may include amino acid residues
not encoded by human germline immunoglobulin sequences (e.g.,
mutations introduced by random or site-specific mutagenesis in
vitro or by somatic mutation in vivo). However, the term "human
antibody," as used herein, is not intended to include antibodies in
which CDR sequences derived from the germline of another mammalian
species, such as a mouse, have been grafted onto human framework
sequences. The terms "human" antibodies and "fully human"
antibodies and are used synonymously.
[0032] A "humanized antibody" refers to an antibody in which some,
most or all of the amino acids outside the CDR domains of a
non-human antibody are replaced with corresponding amino acids
derived from human immunoglobulins. In one embodiment of a
humanized form of an antibody, some, most or all of the amino acids
outside the CDR domains have been replaced with amino acids from
human immunoglobulins, whereas some, most or all amino acids within
one or more CDR regions are unchanged. Small additions, deletions,
insertions, substitutions or modifications of amino acids are
permissible as long as they do not abrogate the ability of the
antibody to bind to a particular antigen. A "humanized" antibody
retains an antigenic specificity similar to that of the original
antibody.
[0033] A "chimeric antibody" refers to an antibody in which the
variable regions are derived from one species and the constant
regions are derived from another species, such as an antibody in
which the variable regions are derived from a mouse antibody and
the constant regions are derived from a human antibody.
[0034] An "anti-antigen" antibody refers to an antibody that binds
specifically to the antigen. For example, an anti-PD-1 antibody
binds specifically to PD-1 and an anti-CTLA-4 antibody binds
specifically to CTLA-4.
[0035] An "antigen-binding portion" of an antibody (also called an
"antigen-binding fragment") refers to one or more fragments of an
antibody that retain the ability to bind specifically to the
antigen bound by the whole antibody.
[0036] A "cancer" refers a broad group of various diseases
characterized by the uncontrolled growth of abnormal cells in the
body. Unregulated cell division and growth results in the formation
of malignant tumors that invade neighboring tissues and may also
metastasize to distant parts of the body through the lymphatic
system or bloodstream. A "cancer" or "cancer tissue" can include a
tumor.
[0037] "Cytotoxic T-Lymphocyte Antigen-4" (CTLA-4) refers to an
immunoinhibitory receptor belonging to the CD28 family. CTLA-4 is
expressed exclusively on T cells in vivo, and binds to two ligands,
CD80 and CD86 (also called B7-1 and B7-2, respectively). The term
"CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants,
isoforms, and species homologs of hCTLA-4, and analogs having at
least one common epitope with hCTLA-4. The complete hCTLA-4
sequence can be found under GenBank Accession No. AAB59385.
[0038] The term "progression-free survival," which can be
abbreviated as PFS, as used herein refers to the length of time
during and after the treatment of a solid tumor (i.e., melanoma)
that a patient lives with the disease but it does not get
worse.
[0039] "Dosing interval," as used herein, means the amount of time
that elapses between multiple doses of a formulation disclosed
herein being administered to a subject. Dosing interval can thus be
indicated as ranges.
[0040] The term "dosing frequency" as used herein refers to the
frequency of administering doses of a formulation disclosed herein
in a given time. Dosing frequency can be indicated as the number of
doses per a given time, e.g., once a week or once in two weeks.
[0041] The use of the term "fixed dose" with regard to a
composition of the invention means that two or more different
antibodies in a single composition are present in the composition
in particular (fixed) ratios with each other. In some embodiments,
the fixed dose is based on the weight (e.g., mg) of the antibodies.
In certain embodiments, the fixed dose is based on the
concentration (e.g., mg/ml) of the antibodies. In some embodiments,
the ratio is at least about 1:1, about 1:2, about 1:3, about 1:4,
about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10,
about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about
1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120,
about 1:140, about 1:160, about 1:180, about 1:200, about 200:1,
about 180:1, about 160:1, about 140:1, about 120:1, about 100:1,
about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about
40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1,
about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1,
or about 2:1 mg first antibody to mg second antibody. For example,
the 3:1 ratio of a first antibody and a second antibody can mean
that a vial can contain about 240 mg of the first antibody and 80
mg of the second antibody or about 3 mg/ml of the first antibody
and 1 mg/ml of the second antibody.
[0042] The use of the term "flat dose" with regard to the
composition of the invention means a dose that is administered to a
patient without regard for the weight or body surface area (BSA) of
the patient. The flat dose is therefore not provided as a mg/kg
dose, but rather as an absolute amount of the agent (e.g., the
anti-CTLA-4 antibody and/or anti-PD-1 antibody). For example, a 60
kg person and a 100 kg person would receive the same dose of the
composition (e.g., 240 mg of an anti-PD-1 antibody and 80 mg of an
anti-CTLA-4 antibody in a single fixed dosing formulation vial
containing both 240 mg of an anti-PD-1 antibody and 80 mg of an
anti-CTLA-4 antibody (or two fixed dosing formulation vials
containing 120 mg of an anti-PD-1 antibody and 40 mg of an
anti-CTLA-4 antibody, etc.)).
[0043] The term "weight based dose" as referred to herein means
that a dose that is administered to a patient is calculated based
on the weight of the patient. For example, when a patient with 60
kg body weight requires 3 mg/kg of an anti-PD-1 antibody in
combination with 1 mg/kg of an anti-CTLA-4 antibody, one can draw
the appropriate amounts of the anti-PD-1 antibody (i.e., 180 mg)
and the anti-CTLA-4 antibody (i.e., 60 mg) at once from a 3:1 ratio
fixed dosing formulation of an anti-PD1 antibody and an anti-CTLA-4
antibody.
[0044] The term "anti-PD-1 antibody monotherapy" as used herein
includes a therapy of an anti-PD-1 antibody without an anti-CTLA-4
antibody therapy. The anti-PD-1 antibody monotherapy comprises,
consists essentially of, or consists of administering one or more
doses of an anti-PD-1 antibody to a patient in need thereof, but
does not include administering an anti-CTLA-4 antibody. In one
embodiment, the anti-PD-1 antibody monotherapy comprises
administering one or more doses of an anti-PD-1 antibody to a
patient in need thereof, but does not include administering an
anti-CTLA-4 antibody. In another embodiment, the anti-PD-1 antibody
monotherapy comprises administering one or more doses of an
anti-PD-1 antibody to a patient in need thereof, but does not
include administering an antibody specifically targeting a protein
other than PD-1. In other embodiments, the anti-PD-1 antibody
monotherapy comprises administering one or more doses of an
anti-PD-1 antibody to a patient in need thereof, but does not
include administering another anti-cancer agent.
[0045] An "immune response" refers to the action of a cell of the
immune system (for example, T lymphocytes, B lymphocytes, natural
killer (NK) cells, macrophages, eosinophils, mast cells, dendritic
cells and neutrophils) and soluble macromolecules produced by any
of these cells or the liver (including antibodies, cytokines, and
complement) that results in selective targeting, binding to, damage
to, destruction of, and/or elimination from a vertebrate's body of
invading pathogens, cells or tissues infected with pathogens,
cancerous or other abnormal cells, or, in cases of autoimmunity or
pathological inflammation, normal human cells or tissues.
[0046] "PD-L1 negative" or "PD-L1 expression negative," relating to
cell surface PD-L1 expression, refers to the lack of a detectable
amount of cell surface PD-L1. For cell surface expression assayed
by IHC, e.g., with the mAb 28-8, a PD-L1 negative tumor or PD-L1
expression negative tumor means that less than 0.01% of cells
express a detectable level of PD-L1. In some embodiments, a PD-L1
negative tumor or PD-L1 expression negative tumor means that zero
(0) cells express a detectable level of PD-L1. In some embodiments,
a PD-L1 negative or a PD-L1 expression negative tumor is any tumor
other than a PD-L1 positive or a PD-L1 expression positive
tumor.
[0047] The term "PD-L1 positive" or "PD-L1 expression positive,"
relating to cell surface PD-L1 expression, refers to the proportion
of cells in a test tissue sample comprising tumor cells and
tumor-infiltrating inflammatory cells above which the sample is
scored as expressing cell surface PD-L1. For cell surface
expression assayed by immunohistochemistry (IHC), e.g., with the
mAb 28-8, the PD-L1 positive tumor or PD-L1 expression positive
tumor means that at least about 0.01%, at least about 0.5%, at
least about 1%, at least about 2%, at least about 3%, at least
about 4%, at least about 5%, at least about 6%, at least about 7%,
at least about 8%, at least about 9%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, or at least
about 30% of the total number of cells express PD-L1. PD-L1
positive tumor or PD-L1 expression positive tumor can also be
expressed herein as tumor expressing PD-L1. In other embodiments,
the PD-L1 positive tumor or PD-L1 expression positive tumor means
that at least about 0.1% to at least about 20% of the total number
of cells express PD-L1. In certain embodiments, the PD-L1 positive
tumor or PD-L1 expression positive tumor means that at least about
0.1% to at least about 10% of the total number of cells express
PD-L1. In some embodiments, the PD-L1 positive or PD-L1 expression
positive tumor means that at least about 1% of the total number of
cells express PD-L1 on the cell surface. In other embodiments, the
PD-L1 positive or PD-L1 expression positive tumor means that at
least about 5% of the total number of cells express PD-L1 on the
cell surface. In one particular embodiment, PD-L1 positive or PD-L1
expression positive tumor means that at least about 1%, or in the
range of 1-5% of the total number of cells express PD-L1 on the
cell surface.
[0048] "Programmed Death-1 (PD-1)" refers to an immunoinhibitory
receptor belonging to the CD28 family. PD-1 is expressed
predominantly on previously activated T cells in vivo, and binds to
two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein
includes human PD-1 (hPD-1), variants, isoforms, and species
homologs of hPD-1, and analogs having at least one common epitope
with hPD-1. The complete hPD-1 sequence can be found under GenBank
Accession No. U64863.
[0049] "Programmed Death Ligand-1 (PD-L1)" is one of two cell
surface glycoprotein ligands for PD-1 (the other being PD-L2) that
down-regulate T cell activation and cytokine secretion upon binding
to PD-1. The term "PD-L1" as used herein includes human PD-L1
(hPD-L1), variants, isoforms, and species homologs of hPD-L1, and
analogs having at least one common epitope with hPD-L1. The
complete hPD-L1 sequence can be found under GenBank Accession No.
Q9NZQ7.
[0050] A "patient" as used herein includes any patient who is
afflicted with a cancer (e.g., melanoma). The terms "subject" and
"patient" are used interchangeably herein.
[0051] A "therapeutically effective amount" or "therapeutically
effective dosage" of a drug or therapeutic agent is any amount of
the drug that, when used alone or in combination with another
therapeutic agent, protects a subject against the onset of a
disease or promotes disease regression evidenced by a decrease in
severity of disease symptoms, an increase in frequency and duration
of disease symptom-free periods, or a prevention of impairment or
disability due to the disease affliction. The ability of a
therapeutic agent to promote disease regression can be evaluated
using a variety of methods known to the skilled practitioner, such
as in human subjects during clinical trials, in animal model
systems predictive of efficacy in humans, or by assaying the
activity of the agent in in vitro assays.
[0052] "Treatment" or "therapy" of a subject refers to any type of
intervention or process performed on, or the administration of an
active agent to, the subject with the objective of reversing,
alleviating, ameliorating, inhibiting, slowing down or preventing
the onset, progression, development, severity or recurrence of a
symptom, complication or condition, or biochemical indicia
associated with a disease.
[0053] A "tumor-infiltrating inflammatory cell" is any type of cell
that typically participates in an inflammatory response in a
subject and which infiltrates tumor tissue. Such cells include
tumor-infiltrating lymphocytes (TILs), macrophages, monocytes,
eosinophils, histiocytes and dendritic cells.
[0054] The use of the alternative (e.g., "or") should be understood
to mean either one, both, or any combination thereof of the
alternatives. As used herein, the indefinite articles "a" or "an"
should be understood to refer to "one or more" of any recited or
enumerated component.
[0055] The terms "about" or "comprising essentially of" refer to a
value or composition that is within an acceptable error range for
the particular value or composition as determined by one of
ordinary skill in the art, which will depend in part on how the
value or composition is measured or determined, i.e., the
limitations of the measurement system. For example, "about" or
"comprising essentially of" can mean within 1 or more than 1
standard deviation per the practice in the art. Alternatively,
"about" or "comprising essentially of" can mean a range of up to
10% or 20% (i.e., .+-.10% or .+-.20%). For example, about 3 mg can
include any number between 2.7 mg and 3.3 mg (for 10%) or between
2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect
to biological systems or processes, the terms can mean up to an
order of magnitude or up to 5-fold of a value. When particular
values or compositions are provided in the application and claims,
unless otherwise stated, the meaning of "about" or "comprising
essentially of" should be assumed to be within an acceptable error
range for that particular value or composition.
[0056] The terms "about once a week," "once about every week,"
"once about every two weeks," or any other similar dosing interval
terms as used herein means approximate number, and "about once a
week" or "once about every week" can include every seven
days.+-.two days, i.e., every five days to every nine days. The
dosing frequency of "once a week" thus can be every five days,
every six days, every seven days, every eight days, or every nine
days. "Once about every two weeks" can include every fourteen
days.+-.three days, i.e., every eleven days to every seventeen
days. Similar approximations apply, for example, to once about
every three weeks, once about every four weeks, once about every
five weeks, once about every six weeks and once about every twelve
weeks. In some embodiments, a dosing interval of once about every
six weeks or once about every twelve weeks means that the first
dose can be administered any day in the first week, and then the
next dose can be administered any day in the sixth or twelfth week,
respectively. In other embodiments, a dosing interval of once about
every six weeks or once about every twelve weeks means that the
first dose is administered on a particular day of the first week
(e.g., Monday) and then the next dose is administered on the same
day of the sixth or twelfth weeks (i.e., Monday), respectively.
[0057] As described herein, any concentration range, percentage
range, ratio range or integer range is to be understood to include
the value of any integer within the recited range and, when
appropriate, fractions thereof (such as one-tenth and one-hundredth
of an integer), unless otherwise indicated.
[0058] Various aspects of the invention are described in further
detail in the following subsections.
Methods of the Invention
[0059] The present invention is directed to a method for treating a
PD-L1-negative melanoma in a subject in need thereof. The present
invention shows that for PD-L1 negative tumors, a combination
therapy of an anti-PD-1 antibody and an anti-CTLA-4 antibody is
more suitable than a monotherapy of either an anti-PD-1 antibody or
an anti-CTLA-4 antibody.
[0060] Not bound to any theory, the present invention identifies
that in patients having a PD-L1-negative tumor progression-free
survival and overall response rate are higher following treatment
with a combination therapy with an anti-PD-1 antibody and an
anti-CTLA-4 antibody than following treatment with either an
anti-PD-1 antibody or an anti-CTLA-4 antibody alone. Therefore, in
order to increase the response of a patient having a PD-L1-negative
tumor, the present invention provides identifying a patient
suitable for the combination therapy of an anti-PD-1 antibody and
an anti-CTLA-4 antibody.
[0061] In one embodiment, the invention includes a method of
treating a PD-L1 negative melanoma comprising administering to a
patient: (a) an anti-PD-1 antibody or an antigen-binding portion
thereof that binds specifically to a human PD-1; and (b) an
anti-CTLA-4 antibody or an antigen-binding portion thereof that
binds specifically to a human CTLA-4, wherein the patient is
identified as having a PD-L1-negative melanoma tumor prior to the
administration. In another embodiment, the invention includes a
method for treating a melanoma in a patient in need thereof
comprising: (i) identifying a patient having a PD-L1-negative
melanoma tumor; and (ii) administering to the patient: (a) an
anti-PD-1 antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4.
[0062] In certain embodiments, the invention includes a method for
extending a progression-free survival period for over 9 months in a
patient afflicted with a PD-L1 negative melanoma tumor comprising
administering to the patient: (a) an anti-PD-1 antibody or an
antigen-binding portion thereof that binds specifically to a human
PD-1; and (b) an anti-CTLA-4 antibody or an antigen-binding portion
thereof that binds specifically to a human CTLA-4, wherein the
patient is identified as having a PD-L1-negative melanoma tumor
prior to the administration and wherein the patient demonstrates
progression-free survival for over 9 months. In other embodiments,
the invention provides a method for extending a progression-free
survival period for over 9 months in a patient afflicted with a
melanoma tumor comprising: (i) identifying a patient having a
PD-L1-negative melanoma tumor; and (ii) administering to the
patient (a) an anti-PD-1 antibody or an antigen-binding portion
thereof that binds specifically to a human PD-1; and (b) an
anti-CTLA-4 antibody or an antigen-binding portion thereof that
binds specifically to a human CTLA-4, wherein the patient
demonstrates progression-free survival for over 9 months. According
to the invention, the progression-free survival of the patient can
be extended, after the administration, over about 10 months, over
about 11 months, over about 12 months, over about 13 months, about
14 months, about 15 months, about 16 months, about 17 months, about
18 months, about 2 years, about 3 years, about 4 years, about 5
years, about 6 years, about 7 years, about 8 years, about 9 years,
or about 10 years. In a particular embodiment, the progression-free
survival of the patient is extended for over 10 months.
[0063] In still other embodiments, the invention is directed to a
method for reducing a tumor size at least by 10% in a patient
afflicted with a PD-L1 negative melanoma tumor comprising
administering to the patient: (a) an anti-PD-1 antibody or an
antigen-binding portion thereof that binds specifically to a human
PD-1; and (b) an anti-CTLA-4 antibody or an antigen-binding portion
thereof that binds specifically to a human CTLA-4, wherein the
patient is identified as having a PD-L1-negative melanoma tumor
prior to the administration and wherein the administration reduces
the tumor size at least about 10%, about 20%, about 30%, about 40%,
or about 50% compared to the tumor size prior to the
administration. In yet other embodiments, the method comprises (i)
identifying a patient having a PD-L1-negative melanoma tumor; and
(ii) administering to the patient (a) an anti-PD-1 antibody or an
antigen-binding portion thereof that binds specifically to a human
PD-1; and (b) an anti-CTLA-4 antibody or an antigen-binding portion
thereof that binds specifically to a human CTLA-4, wherein the
administration reduces the tumor size at least about 10%, about
20%, about 30%, about 40%, or about 50% compared to the tumor size
prior to the administration. The tumor size, after the
administration, can be reduced at least about 60%, 70%, 80%, 90% or
100%. The tumor can be completely eliminated from the patient's
body after the administration.
[0064] The invention can also include a method of preventing a
relapse and/or induce a remission to a patient having a PD-L1
negative melanoma tumor comprising administering to the patient:
(a) an anti-PD-1 antibody or an antigen-binding portion thereof
that binds specifically to a human PD-1; and (b) an anti-CTLA-4
antibody or an antigen-binding portion thereof that binds
specifically to a human CTLA-4, wherein the patient is identified
as having a PD-L1-negative melanoma tumor prior to the
administration. In some embodiments, the method of the invention
comprises (i) identifying a patient having a PD-L1-negative
melanoma tumor; and (ii) administering to the patient (a) an
anti-PD-1 antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4.
[0065] In certain embodiments, the invention includes a method for
increasing an objective response rate to be higher than 40% in a
patient population, wherein each patient of the patient population
is afflicted with a melanoma tumor, in a cancer treatment
comprising administering to the patient: (a) an anti-PD-1 antibody
or an antigen-binding portion thereof that binds specifically to a
human PD-1; and (b) an anti-CTLA-4 antibody or an antigen-binding
portion thereof that binds specifically to a human CTLA-4, wherein
each patient is identified as having a PD-L1-negative melanoma
tumor prior to the administration and wherein the objective
response rate is higher than 40%, 45%, 50%, 55%, 60%, 65%, 70%, or
75%. The methods can further comprise identifying each patient as
having a PD-L1-negative melanoma tumor prior to the administration.
In other embodiments, each patient in the methods can further be
characterized by (i) extended progression-free survival for over 11
months, (ii) tumor size reduction at least about 10%, about 20%,
about 30%, about 40%, or about 50% compared to the tumor size prior
to the administration, or (iii) both. In some embodiments, the
patient population can be at least 100 patients having a
PD-L1-negative melanoma tumor. In some embodiments, the patient
population can be at least 200, 300, 400, 500, 600, 700, 800, 900,
or 1000 patients having a PD-L1-negative melanoma tumor.
[0066] In further embodiments, the invention provides a method for
selecting a suitable cancer therapy course in a patient having a
PD-L1 negative melanoma tumor comprising: (i) identifying a patient
having a PD-L1-negative melanoma tumor; and (ii) instructing a
healthcare provider to administer to the patient: (a) an anti-PD-1
antibody or an antigen-binding portion thereof that binds
specifically to a human PD-1; and (b) an anti-CTLA-4 antibody or an
antigen-binding portion thereof that binds specifically to a human
CTLA-4. The method further comprises administering the antibodies
to the patient.
[0067] The methods of the invention as a result of the combination
therapy can treat the melanoma tumor, reduce the tumor size,
prevent growth of the tumor, eliminate the tumor from the patient,
prevent a relapse of a tumor, induce a remission in a patient, or
any combination thereof. In certain embodiments, the combination
therapy induces a complete response. In other embodiments, the
combination therapy induces a partial response.
Melanoma
[0068] Melanoma (MEL) is a malignant tumor of melanocytes, the
melanin-producing cells found predominantly in skin. Though less
common than other skin cancers, it is the most dangerous of skin
cancers if not diagnosed early and causes the majority (75%) of
skin cancer deaths. The incidence of MEL is increasing worldwide in
Caucasian populations, especially where peoples with low amounts of
skin pigmentation receive excessive ultraviolet light exposure from
the sun. In Europe, the incidence rate is <10-20 per 100,000
population; in the USA 20-30 per 100,000; and in Australia, where
the highest incidence is observed, 50-60 per 100,000 (Garbe et al.,
Eur. J. Cancer. 48(15):2375-90 (2012)). MEL accounts for about 5%
of all new cases of cancer in the United States (U.S.), and the
incidence continues to rise by almost 3% per year. This translates
to an estimated 76,690 new cases in the U.S. in 2013 with 9,480
associated deaths (Siegel et al., CA Cancer J. Clin. 63(1):11-30
(2013)).
[0069] For in situ (stage 0) or early-stage MEL (Stages I-II),
surgical excision is the primary treatment. In general, the
prognosis is excellent for patients with localized disease and
tumors 1.0 mm or less in thickness, with 5-year survival rates of
more than 90% (NCCN GUIDELINES.RTM., 2013--Melanoma). Where
surgical excision is not feasible for in situ melanoma due to
comorbidity or cosmetically sensitive tumor location, topical
imiquimod (INN) and radiotherapy are emerging as treatments,
especially for lentigo maligna. Chemotherapeutic agents for
treating MEL include dacarbazine, temozolomide and imatinib for
melanoma with a c-KIT mutation, high-dose interleukin-2, and
paclitaxel with or without carboplatin. However, these treatments
have modest success, with response rates below 20% in first-line
(1L) and second-line (2L) settings.
[0070] For patients with localized melanomas more than 1.0 mm in
thickness, survival rates range from 50-90%. The likelihood of
regional nodal involvement increases with increasing tumor
thickness. With Stage III MEL (clinically positive nodes and/or
in-transit disease), 5-year survival rates range from 20-70%. By
far the most lethal is Stage IV MEL where long-term survival in
patients with distant metastatic melanoma is less than 10% (NCCN
GUIDELINES.RTM., 2013--melanoma).
[0071] The types of melanoma that can be treated with the present
methods include, but are not limited to, lentigo maligna, lentigo
maligna melanoma, superficial spreading melanoma, acral lentiginous
melanoma, nucosal melanoma, nodular melanoma, polypoid melanoma,
desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma,
melanoma with small nevus-like cells, melanoma with features of a
Spitz nevus, or uveal melanoma. The stages of melanoma that can be
treated with the present methods include, but are not limited to,
(i) Stage I/II (invasive melanoma): T1a characterized by less than
1.0 mm primary tumor thickness, without ulceration, and mitosis
<1/mm.sup.2; T1b characterized by less than 1.0 mm primary tumor
thickness, with ulceration or mitoses .gtoreq.1/mm.sup.2; T2a
characterized by 1.01-2.0 mm primary tumor thickness, without
ulceration; (ii) Stage II (high risk melanoma): T2b characterized
by 1.01-2.0 mm primary tumor thickness, with ulceration; T3a
characterized by 2.01-4.0 mm primary tumor thickness, without
ulceration; T3b characterized by 2.01-4.0 mm primary tumor
thickness, with ulceration; T4a characterized by greater than 4.0
mm primary tumor thickness, without ulceration; or T4b
characterized by greater than 4.0 mm primary tumor thickness, with
ulceration; (iii) Stage III (regional metastasis): N1 characterized
by single positive lymph node; N2 characterized by two to three
positive lymph nodes or regional skin/in-transit metastasis; or N3
characterized by four positive lymph nodes or one lymph node and
regional skin/in-transit metastases; and (iv) Stage IV (distant
metastasis): M1a characterized by distant skin metastasis, normal
LDH; M1b characterized by Lung metastasis, normal LDH; or M1c
characterized by other distant metastasis or any distant metastasis
with elevated LDH. PD-L1-negative tumors that are treatable by the
present methods can lack PD-L1 expression on the surface of tumor
cells and/or tumor infiltrating inflammatory cells.
Measurement of PD-L1 Expression
[0072] In certain embodiments, identifying a patient suitable for a
combination therapy for the present methods includes measuring or
assessing a PD-L1 expression on the surface of the melanoma tumor
cells or tumor infiltrating inflammatory cells. The phrases "tumors
expressing PD-L1," "PD-L1 expressing tumor," "PD-L1 positive
tumor," and "PD-L1 expression positive tumor" are used
interchangeably herein. The meaning of the phrases is provided
elsewhere herein. The methods of measuring or assessing the PD-L1
expression can be achieved by any methods applicable.
[0073] In order to assess the PD-L1 expression, in one embodiment,
a test tissue sample is obtained from the patient who is in need of
the therapy. In another embodiment, the assessment of PD-L1
expression can be achieved without obtaining a test tissue sample.
In some embodiments, selecting a suitable patient includes (i)
optionally providing a test tissue sample obtained from a patient
with cancer of the tissue, the test tissue sample comprising tumor
cells and/or tumor-infiltrating inflammatory cells; and (ii)
assessing the proportion of cells in the test tissue sample that
express PD-L1 on the surface of the cells based on an assessment
that the proportion of cells in the test tissue sample that express
PD-L1 on the cell surface is lower than a predetermined threshold
level. A test tissue sample can be considered to be PD-L1-negative
if less than about 5% of the cells in the test tissue express PD-L1
on the cell surface. In other embodiments, a test tissue sample is
considered to be PD-L1-negative if less than about 4%, less than
about 3%, less than about 2%, less than about 1%, less than about
0.5%, less than about 0.1%, less than about 0.01% or 0% of the
cells in the test tissue express PD-L1 on the cell surface. In one
particular example, the test tissue sample can be considered to be
PD-L1-negative if less than about 5% of the cells in the test
tissue express PD-L1 on the cell surface.
[0074] In any of the methods comprising the measurement of PD-L1
expression in a test tissue sample, however, it should be
understood that the step comprising the provision of a test tissue
sample obtained from a patient is an optional step. That is, in
certain embodiments the method includes this step, and in other
embodiments, this step is not included in the method. It should
also be understood that in certain embodiments the "measuring" or
"assessing" step to identify, or determine the number or proportion
of, cells in the test tissue sample that express PD-L1 on the cell
surface is performed by a transformative method of assaying for
PD-L1 expression, for example by performing a reverse
transcriptase-polymerase chain reaction (RT-PCR) assay or an IHC
assay. In certain other embodiments, no transformative step is
involved and PD-L1 expression is assessed by, for example,
reviewing a report of test results from a laboratory. In certain
embodiments, the steps of the methods up to, and including,
assessing PD-L1 expression provides an intermediate result that may
be provided to a physician or other healthcare provider for use in
selecting a suitable candidate for the combination therapy of an
anti-PD-1 antibody and an anti-CTLA-4 antibody. In certain
embodiments, the steps that provide the intermediate result is
performed by a medical practitioner or someone acting under the
direction of a medical practitioner. In other embodiments, these
steps are performed by an independent laboratory or by an
independent person such as a laboratory technician.
[0075] In certain embodiments of any of the present methods, the
proportion of cells that express PD-L1 is assessed by performing an
assay to determine the presence of PD-L1 RNA. In further
embodiments, the presence of PD-L1 RNA is determined by RT-PCR, in
situ hybridization or RNase protection. In other embodiments, the
proportion of cells that express PD-L1 is assessed by performing an
assay to determine the presence of PD-L1 polypeptide. In further
embodiments, the presence of PD-L1 polypeptide is determined by
immunohistochemistry (IHC), enzyme-linked immunosorbent assay
(ELISA), in vivo imaging, or flow cytometry. In some embodiments,
PD-L1 expression is assayed by IHC. In other embodiments of all of
these methods, cell surface expression of PD-L1 is assayed using,
e.g., IHC or in vivo imaging.
[0076] Imaging techniques have provided important tools in cancer
research and treatment. Recent developments in molecular imaging
systems, including positron emission tomography (PET),
single-photon emission computed tomography (SPECT), fluorescence
reflectance imaging (FRI), fluorescence-mediated tomography (FMT),
bioluminescence imaging (BLI), laser-scanning confocal microscopy
(LSCM) and multiphoton microscopy (MPM), will likely herald even
greater use of these techniques in cancer research. Some of these
molecular imaging systems allow clinicians to not only see where a
tumor is located in the body, but also to visualize the expression
and activity of specific molecules, cells, and biological processes
that influence tumor behavior and/or responsiveness to therapeutic
drugs (Condeelis and Weissleder, Cold Spring Harb. Perspect. Biol.
2(12):a003848 (2010)). Antibody specificity, coupled with the
sensitivity and resolution of PET, makes immunoPET imaging
particularly attractive for monitoring and assaying expression of
antigens in tissue samples (McCabe and Wu, Cancer Biother.
Radiopharm. 25(3):253-61 (2010); Olafsen et al., Protein Eng. Des.
Sel. 23(4):243-9 (2010)). In certain embodiments of any of the
present methods, PD-L1 expression is assayed by immunoPET imaging.
In certain embodiments of any of the present methods, the
proportion of cells in a test tissue sample that express PD-L1 is
assessed by performing an assay to determine the presence of PD-L1
polypeptide on the surface of cells in the test tissue sample. In
certain embodiments, the test tissue sample is a FFPE tissue
sample. In other embodiments, the presence of PD-L1 polypeptide is
determined by IHC assay. In further embodiments, the IHC assay is
performed using an automated process. In some embodiments, the IHC
assay is performed using an anti-PD-L1 mAb to bind to the PD-L1
polypeptide, if present.
Assaying Cell-Surface PD-L1 Expression by Automated IHC
[0077] In one embodiment of the present methods, an automated IHC
method is used to assay the expression of PD-L1 on the surface of
cells in FFPE tissue specimens. This disclosure provides methods
for detecting the presence of human PD-L1 antigen in a test tissue
sample, or quantifying the level of human PD-L1 antigen or the
proportion of cells in the sample that express the antigen, which
methods comprise contacting the test sample, and a negative control
sample, with a mAb that specifically binds to human PD-L1, under
conditions that allow for formation of a complex between the
antibody or portion thereof and human PD-L1. In certain
embodiments, the test and control tissue samples are FFPE samples.
The formation of a complex can then be detected, wherein a
difference in complex formation between the test sample and the
negative control sample is indicative of the presence of human
PD-L1 antigen in the sample. Various methods are used to quantify
PD-L1 expression.
[0078] In a particular embodiment, the automated IHC method
comprises: (a) deparaffinizing and rehydrating mounted tissue
sections in an autostainer; (b) retrieving antigen using a
decloaking chamber and pH 6 buffer, heated to 110.degree. C. for 10
min; (c) setting up reagents on an autostainer; and (d) running the
autostainer to include steps of neutralizing endogenous peroxidase
in the tissue specimen; blocking non-specific protein-binding sites
on the slides; incubating the slides with primary Ab; incubating
with a postprimary blocking agent; incubating with NovoLink
Polymer; adding a chromogen substrate and developing; and
counterstaining with hematoxylin.
[0079] For assessing PD-L1 expression in tumor tissue samples, a
pathologist examines the number of membrane PD-L1.sup.+ tumor cells
in each field under a microscope and mentally estimates the
percentage of cells that are positive, then averages them to come
to the final percentage. The different staining intensities are
defined as 0/negative, 1+/weak, 2+/moderate, and 3+/strong.
Typically, percentage values are first assigned to the 0 and 3+
buckets, and then the intermediate 1+ and 2+ intensities are
considered. For highly heterogeneous tissues, the specimen is
divided into zones, and each zone is scored separately and then
combined into a single set of percentage values. The percentages of
negative and positive cells for the different staining intensities
are determined from each area and a median value is given to each
zone. A final percentage value is given to the tissue for each
staining intensity category: negative, 1+, 2+, and 3+. The sum of
all staining intensities needs to be 100%.
[0080] Staining is also assessed in tumor-infiltrating inflammatory
cells such as macrophages and lymphocytes. In most cases
macrophages serve as an internal positive control since staining is
observed in a large proportion of macrophages. While not required
to stain with 3+ intensity, an absence of staining of macrophages
should be taken into account to rule out any technical failure.
Macrophages and lymphocytes are assessed for plasma membrane
staining and only recorded for all samples as being positive or
negative for each cell category. Staining is also characterized
according to an outside/inside tumor immune cell designation.
"Inside" means the immune cell is within the tumor tissue and/or on
the boundaries of the tumor region without being physically
intercalated among the tumor cells. "Outside" means that there is
no physical association with the tumor, the immune cells being
found in the periphery associated with connective or any associated
adjacent tissue.
[0081] In certain embodiments of these scoring methods, the samples
are scored by two pathologists operating independently, and the
scores are subsequently consolidated. In certain other embodiments,
the identification of positive and negative cells is scored using
appropriate software.
[0082] A histoscore is used as a more quantitative measure of the
IHC data. The histoscore is calculated as follows:
Histoscore=[(% tumor.times.1 (low intensity))+(% tumor.times.2
(medium intensity))+(% tumor.times.3 (high intensity)]
[0083] To determine the histoscore, the pathologist estimates the
percentage of stained cells in each intensity category within a
specimen. Because expression of most biomarkers is heterogeneous
the histoscore is a truer representation of the overall expression.
The final histoscore range is 0 (no expression) to 300 (maximum
expression). A test sample can be designated as PD-L1-negative even
though some level of PD-L1 expression is detected. For example, a
designation of PD-L1-negative can be assigned to a specimen having
a final histoscore of about 15 or less, of about 10 or less, about
9 or less, about 8 or less, about 7 or less, about 6 or less, about
5 or less, about 4 or less, about 3 or less, about 2 or less, about
1 or less, or of 0.
[0084] An alternative means of quantifying PD-L1 expression in a
test tissue sample IHC is to determine the adjusted inflammation
score (AIS) score defined as the density of inflammation multiplied
by the percent PD-L1 expression by tumor-infiltrating inflammatory
cells (Taube et al., Sci. Transl. Med. 4(127):127ra37 (2012)).
Anti-PD-1 Antibodies
[0085] PD-1 is a key immune checkpoint receptor expressed by
activated T and B cells and mediates immunosuppression. PD-1 is a
member of the CD28 family of receptors, which includes CD28,
CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands
for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1)
and Programmed Death Ligand-2 (PD-L2), that are expressed on
antigen-presenting cells as well as many human cancers and have
been shown to down regulate T cell activation and cytokine
secretion upon binding to PD-1. Inhibition of the PD-1/PD-L1
interaction mediates potent antitumor activity in preclinical
models.
[0086] HuMAbs that bind specifically to PD-1 with high affinity
have been disclosed in U.S. Pat. Nos. 8,008,449 and 8,779,105.
Other anti-PD-1 mAbs have been described in, for example, U.S. Pat.
Nos. 6,808,710, 7,488,802, 8,168,757 and 8,354,509, and PCT
Publication No. WO 2012/145493. Each of the anti-PD-1 HuMAbs
disclosed in U.S. Pat. No. 8,008,449 has been demonstrated to
exhibit one or more of the following characteristics: (a) binds to
human PD-1 with a K.sub.D of 1.times.10.sup.-7 M or less, as
determined by surface plasmon resonance using a Biacore biosensor
system; (b) does not substantially bind to human CD28, CTLA-4 or
ICOS; (c) increases T-cell proliferation in a Mixed Lymphocyte
Reaction (MLR) assay; (d) increases interferon-.gamma. production
in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f)
binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibits the
binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates
antigen-specific memory responses; (i) stimulates antibody
responses; and (j) inhibits tumor cell growth in vivo. Anti-PD-1
antibodies useful for the present invention include mAbs that bind
specifically to human PD-1 and exhibit at least one, at least two,
at least three, at least four, or at least five, of the preceding
characteristics.
[0087] In one embodiment, the anti-PD-1 antibody is nivolumab.
Nivolumab (also known as "OPDIVO.RTM."; formerly designated 5C4,
BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P)
PD-1 immune checkpoint inhibitor antibody that selectively prevents
interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking
the down-regulation of antitumor T-cell functions (U.S. Pat. No.
8,008,449; Wang et al., Cancer Immunol Res. 2(9):846-56 (2014)). In
another embodiment, the anti-PD-1 antibody or fragment thereof
cross-competes with nivolumab. In other embodiments, the anti-PD-1
antibody or fragment thereof binds to the same epitope as
nivolumab. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as nivolumab.
[0088] In another embodiment, the anti-PD-1 antibody or fragment
thereof cross-competes with pembrolizumab. In some embodiments, the
anti-PD-1 antibody or fragment thereof binds to the same epitope as
pembrolizumab. In certain embodiments, the anti-PD-1 antibody has
the same CDRs as pembrolizumab. In another embodiment, the
anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also known as
"KEYTRUDA.RTM.", lambrolizumab, and MK-3475) is a humanized
monoclonal IgG4 antibody directed against human cell surface
receptor PD-1 (programmed death-1 or programmed cell death-1).
Pembrolizumab is described, for example, in U.S. Pat. Nos.
8,354,509 and 8,900,587; see also
http://www.cancer.gov/drugdictionary?cdrid=695789 (last accessed:
Dec. 14, 2014). Pembrolizumab has been approved by the FDA for the
treatment of relapsed or refractory melanoma.
[0089] In other embodiments, the anti-PD-1 antibody or fragment
thereof cross-competes with MEDI0608. In still other embodiments,
the anti-PD-1 antibody or fragment thereof binds to the same
epitope as MEDI0608. In certain embodiments, the anti-PD-1 antibody
has the same CDRs as MEDI0608. In other embodiments, the anti-PD-1
antibody is MEDI0608 (formerly AMP-514), which is a monoclonal
antibody. MEDI0608 is described, for example, in U.S. Pat. No.
8,609,089B2 or in http://www.cancer.gov/drugdictionary?cdrid=756047
(last accessed Dec. 14, 2014).
[0090] In certain embodiments, the first antibody is an anti-PD-1
antagonist. One example of the anti-PD-1 antagonist is AMP-224,
which is a B7-DC Fc fusion protein. AMP-224 is discussed in U.S.
Publ. No. 2013/0017199 or in
http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=700595
(last accessed Jul. 8, 2015).
[0091] In other embodiments, the anti-PD-1 antibody or fragment
thereof cross-competes with BGB-A317. In some embodiments, the
anti-PD-1 antibody or fragment thereof binds the same epitope as
BGB-A317. In certain embodiments, the anti-PD-1 antibody has the
same CDRs as BGB-A317. In certain embodiments, the anti-PD-1
antibody is BGB-A317, which is a humanized monoclonal antibody.
BGB-A317 is described in U.S. Publ. No. 2015/0079109.
[0092] In some embodiments, the antibody is Pidilizumab (CT-011),
which is an antibody previously reported to bind to PD-1 but which
is believed to bind to a different target. Pidilizumab is described
in U.S. Pat. No. 8,686,119 B2 or WO 2013/014668 A1.
[0093] Anti-PD-1 antibodies useful for the disclosed compositions
also include isolated antibodies that bind specifically to human
PD-1 and cross-compete for binding to human PD-1 with nivolumab
(see, e.g., U.S. Pat. Nos. 8,008,449 and 8,779,105; WO
2013/173223). The ability of antibodies to cross-compete for
binding to an antigen indicates that these antibodies bind to the
same epitope region of the antigen and sterically hinder the
binding of other cross-competing antibodies to that particular
epitope region. These cross-competing antibodies are expected to
have functional properties very similar to those of nivolumab by
virtue of their binding to the same epitope region of PD-1.
Cross-competing antibodies can be readily identified based on their
ability to cross-compete with nivolumab in standard PD-1 binding
assays such as Biacore analysis, ELISA assays or flow cytometry
(see, e.g., WO 2013/173223).
[0094] In certain embodiments, the antibodies that cross-compete
for binding to human PD-1 with, or bind to the same epitope region
of human PD-1 as, nivolumab are mAbs. For administration to human
subjects, these cross-competing antibodies can be chimeric
antibodies, or humanized or human antibodies. Such chimeric,
humanized or human mAbs can be prepared and isolated by methods
well known in the art.
[0095] Anti-PD-1 antibodies useful for the compositions of the
disclosed invention also include antigen-binding portions of the
above antibodies. It has been amply demonstrated that the
antigen-binding function of an antibody can be performed by
fragments of a full-length antibody. Examples of binding fragments
encompassed within the term "antigen-binding portion" of an
antibody include (i) a Fab fragment, a monovalent fragment
consisting of the V.sub.L, V.sub.H, C.sub.L and C.sub.H1 domains;
(ii) a F(ab').sub.2 fragment, a bivalent fragment comprising two
Fab fragments linked by a disulfide bridge at the hinge region;
(iii) a Fd fragment consisting of the V.sub.H and C.sub.H1 domains;
and (iv) a Fv fragment consisting of the V.sub.L and V.sub.H
domains of a single arm of an antibody.
[0096] Anti-PD-1 antibodies suitable for use in the disclosed
compositions are antibodies that bind to PD-1 with high specificity
and affinity, block the binding of PD-L1 and or PD-L2, and inhibit
the immunosuppressive effect of the PD-1 signaling pathway. In any
of the compositions or methods disclosed herein, an anti-PD-1
"antibody" includes an antigen-binding portion or fragment that
binds to the PD-1 receptor and exhibits the functional properties
similar to those of whole antibodies in inhibiting ligand binding
and upregulating the immune system. In certain embodiments, the
anti-PD-1 antibody or antigen-binding portion thereof
cross-competes with nivolumab for binding to human PD-1. In other
embodiments, the anti-PD-1 antibody or antigen-binding portion
thereof is a chimeric, humanized or human monoclonal antibody or a
portion thereof. In certain embodiments, the antibody is a
humanized antibody. In other embodiments, the antibody is a human
antibody. Antibodies of an IgG1, IgG2, IgG3 or IgG4 isotype can be
used.
[0097] In certain embodiments, the anti-PD-1 antibody or
antigen-binding portion thereof comprises a heavy chain constant
region which is of a human IgG1 or IgG4 isotype. In certain other
embodiments, the sequence of the IgG4 heavy chain constant region
of the anti-PD-1 antibody or antigen-binding portion thereof
contains an S228P mutation which replaces a serine residue in the
hinge region with the proline residue normally found at the
corresponding position in IgG1 isotype antibodies. This mutation,
which is present in nivolumab, prevents Fab arm exchange with
endogenous IgG4 antibodies, while retaining the low affinity for
activating Fc receptors associated with wild-type IgG4 antibodies
(Wang et al., Cancer Immunol Res. 2(9):846-56 (2014)). In yet other
embodiments, the antibody comprises a light chain constant region
which is a human kappa or lambda constant region. In other
embodiments, the anti-PD-1 antibody or antigen-binding portion
thereof is a mAb or an antigen-binding portion thereof. In certain
embodiments of any of the therapeutic methods described herein
comprising administration of an anti-PD-1 antibody, the anti-PD-1
antibody is nivolumab. In other embodiments, the anti-PD-1 antibody
is pembrolizumab. In other embodiments, the anti-PD-1 antibody is
chosen from the human antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4
described in U.S. Pat. No. 8,008,449. In still other embodiments,
the anti-PD-1 antibody is MEDI0608 (formerly AMP-514), AMP-224, or
BGB-A317.
[0098] Because anti-PD-1 and anti-PD-L1 target the same signaling
pathway and have been shown in clinical trials to exhibit similar
levels of efficacy in a variety of cancers, including RCC (see
Brahmer et al. (2012) N Engl J Med 366:2455-65; Topalian et al.
(2012a) N Engl J Med 366:2443-54; WO 2013/173223), an anti-PD-L1
antibody may be substituted for the anti-PD-1 Ab in any of the
therapeutic methods disclosed herein. In certain embodiments, the
anti-PD-L1 antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see,
e.g., U.S. Pat. No. 7,943,743; WO 2013/173223). In other
embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as
RG7446) (see, e.g., Herbst et al. (2013) J Clin Oncol
31(suppl):3000. Abstract; U.S. Pat. No. 8,217,149) or MEDI4736
(Khleif (2013) in: Proceedings from the European Cancer Congress
2013; Sep. 27-Oct. 1, 2013; Amsterdam, The Netherlands. Abstract
802). In certain embodiments, the antibodies that cross-compete for
binding to human PD-L1 with, or bind to the same epitope region of
human PD-L1 as the above-references PD-L1 antibodies are mAbs. For
administration to human subjects, these cross-competing antibodies
can be chimeric antibodies, or can be humanized or human
antibodies. Such chimeric, humanized or human mAbs can be prepared
and isolated by methods well known in the art.
Anti-PD-L1 Antibodies
[0099] In certain embodiments, the present application encompasses
use of an anti-PD-L1 antibody in lieu of anti-PD-1 antibody. In one
embodiment, the anti-PD-L1 antibody inhibits the binding of PD-L1
receptor, i.e., PD-1, with its ligand PD-L1.
[0100] Anti-PD-L1 antibodies useful for the invention include
antibodies engineered starting from antibodies having one or more
of the V.sub.H and/or V.sub.L sequences disclosed herein, which
engineered antibodies can have altered properties from the starting
antibodies. An anti-PD-L1 antibody can be engineered by a variety
of modifications as described above for the engineering of modified
anti-PD-1 antibodies of the invention.
[0101] Anti-PD-L1 antibodies of the invention also include isolated
antibodies selected for their ability to bind to PD-L1 in
formalin-fixed, paraffin-embedded (FFPE) tissue specimens. The use
of FFPE samples is essential for the long-term follow-up analysis
of the correlation between PD-L1 expression in tumors and disease
prognosis or progression. The use of different antibodies to stain
PD-L1 in frozen versus FFPE tissues, and the ability of certain
antibodies to distinguish membranous and/or cytoplasmic forms of
PD-L1, may account for some of the disparate data reported in the
literature correlating PD-L1 expression with disease prognosis
(Hamanishi et al., Proc. Natl. Acad. Sci. USA 104(9):3360-3365
(2007); Gadiot et al., Cancer 117(10):2192-2201 (2011)). This
disclosure provides several rabbit mAbs that bind with high
affinity specifically to membranous human PD-L1 in FFPE tissue
samples comprising tumor cells and tumor-infiltrating inflammatory
cells.
[0102] In some embodiments, an anti-PD-L1 antibody useful for the
present methods includes mAb 28-8 set forth in SEQ ID NOs. 1 and 2,
respectively. The sequences of the heavy and light chain CDR
domains of mAb 28-8, as delineated using the Kabat system, are set
forth in SEQ ID NOs. 3-8. In other embodiments, an anti-PD-L1
antibody useful for the invention comprises mAbs 28-1, 28-12, 29-8
and 20-12 or an antigen-binding portion thereof, for example,
including Fab, F(ab').sub.2 Fd, Fv, and scFv, di-scFv or bi-scFv,
and scFv-Fc fragments, diabodies, triabodies, tetrabodies, and
isolated CDRs.
Anti-CTLA-4 Antibodies
[0103] Anti-CTLA-4 antibodies of the instant invention bind to
human CTLA-4 so as to disrupt the interaction of CTLA-4 with a
human B7 receptor. Because the interaction of CTLA-4 with B7
transduces a signal leading to inactivation of T-cells bearing the
CTLA-4 receptor, disruption of the interaction effectively induces,
enhances or prolongs the activation of such T cells, thereby
inducing, enhancing or prolonging an immune response.
[0104] HuMAbs that bind specifically to CTLA-4 with high affinity
have been disclosed in U.S. Pat. Nos. 6,984,720 and 7,605,238.
Other anti-PD-1 mAbs have been described in, for example, U.S. Pat.
Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121. The anti-PD-1
HuMAbs disclosed in U.S. Pat. Nos. 6,984,720 and 7,605,238 have
been demonstrated to exhibit one or more of the following
characteristics: (a) binds specifically to human CTLA-4 with a
binding affinity reflected by an equilibrium association constant
(K.sub.a) of at least about 10.sup.7 M.sup.-1, or about 10.sup.9
M.sup.-1, or about 10.sup.10 M.sup.-1 to 10.sup.11 M.sup.-1 or
higher, as determined by Biacore analysis; (b) a kinetic
association constant (k.sub.a) of at least about 10.sup.3, about
10.sup.4, or about 10.sup.5 m.sup.-1 s.sup.-1; (c) a kinetic
disassociation constant (k.sub.d) of at least about 10.sup.3, about
10.sup.4, or about 10.sup.5 m.sup.-1 s.sup.-1; and (d) inhibits the
binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4
antibodies useful for the present invention include mAbs that bind
specifically to human CTLA-4 and exhibit at least one, at least
two, or at least three of the preceding characteristics.
[0105] An exemplary clinical anti-CTLA-4 antibody is the human mAb
10D1 (now known as ipilimumab and marketed as YERVOY.RTM.) as
disclosed in U.S. Pat. No. 6,984,720. Ipilimumab is an anti-CTLA-4
antibody for use in the methods disclosed herein. Ipilimumab is a
fully human, IgG1 monoclonal antibody that blocks the binding of
CTLA-4 to its B7 ligands, thereby stimulating T cell activation and
improving overall survival (OS) in patients with advanced
melanoma.
[0106] Another anti-CTLA-4 antibody useful for the present methods
is tremelimumab (also known as CP-675,206). Tremelimumab is human
IgG2 monoclonal anti-CTLA-4 antibody. Tremelimumab is described in
WO/2012/122444, U.S. Publ. No. 2012/263677, or WO Publ. No.
2007/113648 A2.
[0107] Anti-CTLA-4 antibodies useful for the disclosed composition
also include isolated antibodies that bind specifically to human
CTLA-4 and cross-compete for binding to human CTLA-4 with
ipilimumab or tremelimumab or bind to the same epitope region of
human CTLA-4 as ipilimumab or tremelimumab. In certain embodiments,
the antibodies that cross-compete for binding to human CTLA-4 with,
or bind to the same epitope region of human CTLA-4 as does
ipilimumab or tremelimumab, are antibodies comprising a heavy chain
of the human IgG1 isotype. For administration to human subjects,
these cross-competing antibodies are chimeric antibodies, or
humanized or human antibodies. Useful anti-CTLA-4 antibodies also
include antigen-binding portions of the above antibodies such as
Fab, F(ab').sub.2, Fd or Fv fragments.
Dosages
[0108] The combination of an anti-PD-1 antibody and an anti-CTLA-4
antibody can be administered to a suitable patient in
therapeutically effective amounts. For example, each antibody can
be administered at a dosage ranging from at least about 0.1 to at
least about 20.0 mg/kg body weight. In certain embodiments, each of
the anti-PD-1 and anti-CTLA-4 antibodies is individually
administered at a dosage of at least about 0.1, at least about 0.3,
at least about 0.5, at least about 1, at least about 3, at least
about 5, at least about 10 or at least about 20 mg/kg, e.g., at
least about 1 to at least about 10 mg/kg, e.g., at least about 1 to
at least about 3 mg/kg, e.g., at least about 3 mg/kg, e.g., at
least about 1 mg/kg. Each of the anti-PD-1 antibody and anti-CTLA-4
antibody can be administered at a dosing frequency of at least
about once every week, at least about once every 2 weeks, at least
about once every 3 weeks, or at least about once every 4 weeks, or
at least about once a month, for up to 6 to up to 72 doses, or for
as long as clinical benefit is observed, or until unmanageable
toxicity or disease progression occurs. In some embodiments, the
anti-PD-1 antibody is administered at a dosage of about 1 or about
3 mg/kg. In certain embodiments, the sequenced regimen comprises
administering the anti-PD-1 antibody to the subject at a dosing
frequency of once about every week, once about every 2 weeks, once
about every 3 weeks, or once about every 4 weeks, or once a month
for 6 to 72 doses, or for as long as clinical benefit is observed,
or until unmanageable toxicity or disease progression occurs. In
other embodiments, the anti-PD-1 is administered at a dosage of
about 1 mg/kg at a dosing frequency of once about every 3 weeks for
up to 48 doses. In some embodiments, the anti-CTLA-4 antibody is
administered at a dosage of about 1 or about 3 mg/kg. In certain
embodiments, the sequenced regimen comprises administering the
anti-CTLA-4 antibody to the subject at a dosing frequency of once
about every week, at least about once every 2 weeks, at least about
once every 3 weeks, or at least about once every 4 weeks, or about
once a month for 6 to 72 doses, or for as long as clinical benefit
is observed, or until unmanageable toxicity or disease progression
occurs. In other embodiments, the anti-CTLA-4 antibody is
administered at a dosage of about 3 mg/kg at a dosing frequency of
once about every 3 weeks for up to 48 doses.
[0109] In other embodiments, the anti-PD-1 and anti-CTLA-4
antibodies are administered at the following dosages: (a) 0.1 mg/kg
anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (b) 0.3
mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (c) 1
mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (d) 3
mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (e) 5
mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (f)
10 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody;
(g) 0.1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4
antibody; (h) 0.3 mg/kg anti-PD-1 antibody and 1 mg/kg of
anti-CTLA-4 antibody; (i) 1 mg/kg anti-PD-1 antibody and 1 mg/kg of
anti-CTLA-4 antibody; (j) 3 mg/kg anti-PD-1 antibody and 1 mg/kg of
anti-CTLA-4 antibody; (k) 5 mg/kg anti-PD-1 antibody and 1 mg/kg of
anti-CTLA-4 antibody; or (1) 10 mg/kg anti-PD-1 antibody and 1
mg/kg of anti-CTLA-4 antibody. In a particular embodiment, the
methods include administration of 1 mg/kg of an anti-PD-1 antibody
and 3 mg/kg of an anti-CTLA-4 antibody.
[0110] In some embodiments, the dosage of each of the anti-PD-1 and
anti-CTLA-4 antibodies is kept constant during the induction dosing
schedule and the maintenance dosing schedule. In certain
embodiments, a regimen comprises: (i) an induction dosing schedule
comprising combined administration of the anti-PD-1 and anti-CTLA-4
antibodies at a dosing frequency of at least once about every 2
weeks, at least once about every 3 weeks, or at least once about
every 4 weeks, or at least about once a month, for at least 2, 4,
6, 8 or 10 doses, followed by administration of the anti-PD-1
antibody alone at a dosing frequency of at least once every 2, 3 or
4 weeks, or at least once a month, for at least 2, 4, 6, 8 or 12
doses; followed by (ii) a maintenance dosing schedule comprising
combined administration of the anti-PD-1 and anti-CTLA-4 antibodies
at a dosing frequency of at least about once every 8 weeks, once
about every 12 weeks, or once about every 16 weeks, or at least
once a quarter, for at least 4, 6, 8, 10, 12 or 16 doses, or for as
long as clinical benefit is observed, or until unmanageable
toxicity or disease progression occurs. In another embodiment, the
dosing schedule comprises administering about 3 mg/kg of an
anti-PD-1 antibody every 2 weeks, or about 1 mg/kg of an anti-PD-1
antibody every 3 weeks plus about 3 mg/kg of an anti-CTLA-4
antibody every 3 weeks for 4 doses, followed by about 3 mg/kg of an
anti-PD-1 antibody every 2 weeks for cycle 3 and beyond, or 3 mg/kg
of an anti-CTLA-4 antibody every 3 weeks for 4 doses. In one
particular embodiment, the dosing schedule comprises administering
about 1 mg/kg of an anti-PD-1 antibody followed by an anti-CTLA-4
antibody (e.g., about 3 mg/kg anti-CTLA-4 antibody) on the same day
every 3 weeks for 4 doses, followed by about 3 mg/kg of an
anti-PD-1 antibody every 2 weeks.
[0111] In certain embodiments of this method, the maintenance
dosing schedule comprises combined administration of up to 4, 6, 8,
10, 12 or 16 doses of the anti-PD-1 and anti-CTLA-4 antibodies. In
other embodiments, the concurrent regimen comprises: (i) an
induction dosing schedule comprising combined administration of the
anti-PD-1 and anti-CTLA-4 antibodies at a dosing frequency of once
about every 2 weeks, at least once about every 3 weeks, or at least
once about every 4 weeks, or about once a month, for 2, 4, 6 or 8
doses, followed by administration of the anti-PD-1 antibody alone
at a dosing frequency of once about every 2 weeks, at least once
about every 3 weeks, or at least once about every 4 weeks, or about
once a month, for 2, 4, 6, 8 or 12 doses; followed by (ii) a
maintenance dosing schedule comprising combined administration of
the anti-PD-1 and anti-CTLA-4 antibodies at a dosing frequency of
once every once about every 8, once about every 12 or once about
every 16 weeks, or once a quarter, for 4, 6, 8, 10, 12 or 16 doses,
or for as long as clinical benefit is observed, or until
unmanageable toxicity or disease progression occurs.
[0112] In a particular embodiment, the anti-PD-1 and anti-CTLA-4
antibodies are administered at dosages of about 1 mg/kg anti-PD-1
antibody every three weeks and about 3 mg/kg of anti-CTLA-4
antibody every three weeks. In another embodiment, the patient is
administered at a dose of about 1 mg/kg of an anti-PD-1 antibody,
followed by an anti-CTLA-4 antibody on the same day, every 3 weeks
for 4 doses, then 3 mg/kg of an anti-PD-1 antibody every 2
weeks.
[0113] In certain embodiments of the present methods, the anti-PD-1
and anti-CTLA-4 antibodies are formulated for parenteral
administration, e.g., intravenous administration. In certain other
embodiments, when the anti-PD-1 and anti-CTLA-4 antibodies are
administered in combination, they are administered within about 30
minutes of each other. Either antibody may be administered first,
that is, in certain embodiments, the anti-PD-1 antibody is
administered before the anti-CTLA-4 antibody, whereas in other
embodiments, the anti-CTLA-4 antibody is administered before the
anti-PD-1 antibody. Typically, each antibody is administered
intravenously over a period of about 60 minutes. In further
embodiments, the anti-PD-1 and anti-CTLA-4 antibodies are
administered concurrently, either admixed as a single composition
in a pharmaceutically acceptable formulation for concurrent
administration, or concurrently as separate compositions with each
antibody in a pharmaceutically acceptable formulation.
[0114] In some embodiments, the anti-PD-1 antibody and the
anti-CTLA-4 antibody are formulated in a single composition. The
ratio of the amount of the anti-PD-1 antibody and the amount of the
anti-CTLA-4 antibody in the single composition can be 10:1 to 1:10.
In other embodiments, the ratio of the amount of the anti-PD-1
antibody and the amount of the anti-CTLA-4 antibody in the single
composition is 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5. In a
particular embodiment, the ratio of the amount of the anti-PD-1
antibody and the amount of the anti-CTLA-4 antibody in the single
composition is 1:3.
[0115] In some embodiments, the composition is administered at a
flat dose regardless of the weight of the patient. For example,
each of the anti-PD-1 antibody with the anti-CTLA-4 antibody may be
administered at a flat dose of 20, 50, 75, 80, 160, 200, 240, 300,
360, 400, 480, 500, 750 or 1500 mg, without regard to the patient's
weight. In some embodiments the composition is administered at a
weight-based dose at any dose disclosed herein. In some
embodiments, the amount of the anti-PD-1 antibody and the amount of
the anti-CTLA-4 antibody administered to the patient at a single
dose are identical.
[0116] In certain embodiments of the present methods, the
therapeutically effective dosage of the anti-PD-1 antibody or
antigen-binding portion thereof is a flat dosing (not a bodyweight
based dosing) and comprises about 60 mg, about 80 mg, about 100 mg,
about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200
mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or
about 300 mg. In other embodiments, the therapeutically effective
dosage of the anti-PD-1 antibody or antigen-binding portion thereof
comprises about 320 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540
mg, 550 mg, 600 mg, 620 mg, 650 mg, 680 mg, 700 mg, 720 mg, 780 mg,
800 mg, 840 mg, or 900 mg. In some embodiments, the dose of the
anti-PD-1 antibody in the composition is between about 60 mg and
about 300 mg, between about 60 mg and about 100 mg, between about
100 mg and about 200 mg, or between about 200 mg and about 300 mg.
In some embodiments, the amount of the anti-PD-1 antibody in the
composition is at least about 80 mg, about 160 mg, or about 240 mg.
In some embodiments, the dose of the anti-PD-1 antibody in the
composition is at least about 240 mg or at least about 80 mg.
[0117] In other embodiments, the dosages are given every week,
every two weeks, every three weeks, every four weeks, every five
weeks, every six weeks, every seven weeks, every eight weeks, every
nine weeks, or every 10 weeks.
[0118] In some embodiments, the anti-PD-1 antibody or
antigen-binding portion thereof is administered at a dose of about
240 mg. In embodiments, the anti-PD-1 antibody or antigen-binding
portion thereof is administered at a dose of about 360 mg. In
embodiments, the anti-PD-1 antibody or antigen-binding portion
thereof is administered at a dose of about 480 mg. In one
embodiment, 360 mg of the anti-PD-1 antibody or antigen binding
fragment is administered once every 3 weeks. In another embodiment,
480 mg of the anti-PD-1 antibody or antigen binding fragment is
administered once every 4 weeks.
[0119] In other embodiments, the therapeutically effective dosage
of the anti-CTLA-4 antibody or antigen-binding portion thereof is a
flat dosing (not a bodyweight based dosing) and comprises about 60
mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about
160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg,
about 260 mg, about 280 mg, or about 300 mg. In other embodiments,
the therapeutically effective dosage of the anti-CTLA-4 antibody or
antigen-binding portion thereof comprises about 320 mg, 360 mg, 400
mg, 420 mg, 480 mg, 500 mg, 540 mg, 550 mg, 600 mg, 620 mg, 650 mg,
680 mg, 700 mg, 720 mg, 780 mg, 800 mg, 840 mg, or 900 mg. In some
embodiments, the dose of the anti-CTLA-4 antibody in the
composition is between about 60 mg and about 300 mg, between about
60 mg and about 100 mg, between about 100 mg and about 200 mg, or
between about 200 mg and about 300 mg. In some embodiments, the
amount of the anti-CTLA-4 antibody in the composition is at least
about 80 mg, about 160 mg, or about 240 mg. In some embodiments,
the dose of the anti-CTLA-4 antibody in the composition is at least
about 240 mg or at least about 80 mg.
[0120] In some embodiments, a flat dose of an anti-PD-1 antibody is
80 mg, and a flat dose of an anti-CTLA-4 antibody is 240 mg.
[0121] In some embodiments, the anti-PD-1 antibody is administered
at a subtherapeutic dose, i.e., a dose of the therapeutic agent
that is significantly lower than the usual or FDA-approved dose
when administered as monotherapy for the treatment of the cancer.
The quantity of the second antibody in the composition is
calculated based on the desired ratio.
[0122] In some embodiments, the composition is administered by
intravenous infusion about once per week, about once every 2 weeks,
about once every 3 weeks, or about once a month. In certain
embodiments, the composition is administered once every 3 weeks. In
some embodiments, the infusion occurs over at least about 10
minutes, about 20 minutes, about 30 minutes, about 45 minutes,
about 60 minutes, about 90 minutes, about 2 hours, about 3 hours,
about 4 hours or about 5 hours.
[0123] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of the present invention can be flat or
varied so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration,
without being unduly toxic to the patient. The selected dosage
level will depend upon a variety of pharmacokinetic factors
including the activity of the particular compositions of the
present invention employed, the route of administration, the time
of administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compositions employed, the age, sex, weight, condition, general
health and prior medical history of the patient being treated, and
like factors well known in the medical arts. A composition of the
present invention can be administered via one or more routes of
administration using one or more of a variety of methods well known
in the art. As will be appreciated by the skilled artisan, the
route and/or mode of administration will vary depending upon the
desired results.
Kits
[0124] Also within the scope of the present invention are kits,
including pharmaceutical kits, comprising a combination of an
anti-PD-1 antibody and an anti-CTLA-4 antibody, for therapeutic
uses, and diagnostic kits comprising an anti-PD-L1 antibody for
assaying membranous PD-L1 expression as a biomarker for screening
patients for the combination therapy or for predicting the efficacy
of the combination therapy. Kits typically include a label
indicating the intended use of the contents of the kit and
instructions for use. The term "label" includes any writing, or
recorded material supplied on or with the kit, or which otherwise
accompanies the kit. In certain embodiments of a pharmaceutical
kit, the anti-PD-1 antibody is co-packaged with an anti-CTLA-4
antibody in unit dosage form. In certain embodiments of a
diagnostic kit, the anti-PD-L1 antibody is co-packaged with an
anti-PD-1 antibody and an anti-CTLA-4 antibody for performing an
assay to detect and/or quantify PD-L1 expression.
[0125] In certain embodiments, the pharmaceutical kit comprises the
anti-human PD-1 HuMAb, nivolumab. In other embodiments, the
pharmaceutical kit comprises the anti-human PD-L1 HuMAb,
BMS-936559. In yet other embodiments, the pharmaceutical kit
comprises the anti-human CTLA-4 HuMAb, ipilimumab. In certain
embodiments, the diagnostic kit comprises the rabbit anti-human
PD-L1 mAb, 28-8, comprising the V.sub.H and V.sub.L regions whose
amino acid sequences are set forth in SEQ ID NOs. 1 and 2,
respectively. In other embodiments, the diagnostic kit comprises
the murine anti-human PD-L1 mAb, 5H1 (Dong et al., Nature Med.
8(8):793-800 (2002)).
[0126] In some embodiments, the invention provides a kit for
treating a patient afflicted with a melanoma tumor, the kit
comprising: [0127] (a) a dosage ranging from at least about 0.1 to
at least about 10 mg/kg body weight of an anti-PD-1 antibody or an
antigen-binding portion thereof; [0128] (b) a dosage ranging from
at least about 0.1 to at least about 10 mg/kg body weight of an
anti-CTLA-4 antibody or an antigen-binding portion thereof; and
[0129] (c) instructions for using the anti-PD-1 antibody or the
antigen-binding portion thereof and the anti-CTLA-4 antibody or the
antigen-binding portion thereof in the methods disclosed
herein.
[0130] The present invention is further illustrated by the
following examples which should not be construed as further
limiting. The contents of all references cited throughout this
application are expressly incorporated herein by reference.
EXAMPLES
Example 1
[0131] A randomized, double-blind, multicenter, phase 3 trial was
conducted to evaluate the safety and efficacy of nivolumab alone or
nivolumab combined with ipilimumab in comparison with ipilimumab
alone in previously untreated metastatic melanoma.
Patients
[0132] Eligible patients had histologically confirmed stage III
(unresectable) or stage IV melanoma, and no prior systemic
treatment for unresectable or metastatic melanoma. Other
eligibility criteria included an age of at least 18 years, an
Eastern Cooperative Oncology Group (ECOG) performance status score
of 0 (indicating no symptoms) or 1 (indicating mild symptoms),
measurable disease by computed tomography or magnetic resonance
imaging per RECIST v1.1, availability of tissue collected from
metastatic or unresectable tumors for the assessment of PD-L1
status, and known BRAF V600 mutation status (or consent to BRAF
V600 mutation testing per local standards). Key exclusion criteria
were presence of active brain metastases, ocular melanoma, or
autoimmune disease, and any prior treatment with an anti-PD-1,
anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody. Patients who
required systemic corticosteroid treatment or other
immunosuppressive medications within 14 days of study drug
administration were excluded.
Study Design and Treatment
[0133] In the double-blind, phase 3 study, enrolled patients were
randomly assigned in a 1:1:1 ratio to receive 3 mg of nivolumab per
kilogram of body weight every 2 weeks (plus ipilimumab-matched
placebo), or 1 mg of nivolumab per kilogram every 3 weeks plus 3 mg
of ipilimumab per kilogram every 3 weeks for 4 doses (plus
nivolumab-matched placebo), followed by 3 mg of nivolumab per
kilogram every 2 weeks for cycle 3 and beyond, or 3 mg of
ipilimumab per kilogram every 3 weeks for 4 doses (plus
nivolumab-matched placebo).
[0134] Both nivolumab and ipilimumab were administered by
intravenous infusion. Randomization was stratified according to
tumor PD-L1 status (positive vs. negative or indeterminate), BRAF
mutation status (V600 mutation positive vs. wild-type), and
American Joint Committee on Cancer metastasis stage (M0, M1a, or
M1b vs. M1c). Treatment continued until RECIST v1.1-defined disease
progression, unacceptable toxicity, or withdrawal of consent.
Patients could be treated beyond progression provided they had a
clinical benefit without clinical deterioration, and did not have
substantial adverse effects, as assessed by the investigator.
[0135] Progression-free survival and overall survival were
co-primary end points. Secondary end points included objective
response rate, tumor PD-L1 expression as a predictive biomarker for
progression-free and overall survival, and health-related quality
of life. Exploratory end points include duration of objective
response and safety/tolerability of study drug therapy.
Assessments
[0136] Patients were assessed for tumor response, according to
RECIST v1.1 at 12 weeks after randomization and continuing every 6
weeks for 49 weeks, and then every 12 weeks until progression or
treatment discontinuation, whichever occurred later.
Progression-free survival was defined as the time between the date
of randomization and the first date of documented progression or
death, whichever occurred first. Patients treated beyond
progression were considered to have progressive disease at the time
of the initial progression event, as assessed by the investigator,
regardless of subsequent tumor responses. Expression of PD-L1 on
the surface of the tumor cells was assessed in a central laboratory
by immunohistochemistry in formalin-fixed, paraffin-embedded tumor
specimens using a rabbit monoclonal anti-human PD-L1 antibody
(clone 28-8) and an analytically validated automated assay
developed by Dako (Carpinteria, Calif.). PD-L1 positivity was
defined as at least 5% of tumor cells showing cell surface PD-L1
staining of any intensity in a section containing at least 100
tumor cells that could be evaluated. Indeterminate status was
attributed to samples for which tumor cell-surface expression could
not be discerned because of melanin content or strong cytoplasmic
staining.
[0137] Any patient who received at least one dose of study drug in
each of the 3 treatment groups was included in the assessment of
safety. The severity of adverse events was graded according to the
National Cancer Institute Common Terminology Criteria for Adverse
Events, version 4.0.18. Safety assessments were made continuously
during the treatment phase, and up to 100 days after the last dose
of study drug.
Statistical Analysis
[0138] A study sample size of approximately 915 patients,
randomized to the 3 treatment arms in a 1:1:1 ratio, was planned.
For the comparison of progression-free survival, the number of
events projected to be observed at a follow-up of at least 9 months
provided approximately 83% power to detect an average hazard ratio
of 0.71 with a type I error of 0.005 (two-sided). Progression-free
survival was compared between nivolumab plus ipilimumab and
ipilimumab alone, and between nivolumab alone and ipilimumab alone
with the use of a two-sided log-rank test stratified according to
PD-L1 status, BRAF mutation status, and metastasis stage (as
described above). The study was not designed for a formal
statistical comparison between the nivolumab alone and nivolumab
plus ipilimumab groups. Hazard ratios and corresponding two-sided
99.5% confidence intervals (CIs) were estimated using a Cox
proportional hazards model, with treatment group as a single
covariate, stratified by the above factors. Progression-free
survival curves, medians with 95% CIs, and progression-free
survival rates at 6, 12, and 18 months with 95% CIs were estimated
using Kaplan-Meier methodology. Overall survival will be analyzed
when all patients have a minimum follow-up of 22 months.
Results
Patients and Treatment
[0139] From July 2013 through March 2014, a total of 1296 patients
were enrolled at 137 centers in Australia, Europe, Israel, New
Zealand, and North America. A total of 945 patients underwent
randomization: 316 patients were assigned to the nivolumab group,
314 to the nivolumab plus ipilimumab group, and 315 to the
ipilimumab group (FIG. 1). Baseline characteristics were balanced
across the three groups. A total of 58.0% had stage M1c disease,
36.1% had an elevated lactate dehydrogenase level, 31.5% had a BRAF
mutation, and 73.5% had negative PD-L1 status (Table 1).
[0140] All randomized patients had been followed for a minimum of 9
months at the time of database lock (Feb. 17, 2015); 117 of 313
patients (37.4%) in the nivolumab group, 93 of 313 patients (29.7%)
in the nivolumab plus ipilimumab group, and 50 of 311 patients
(16.1%) in the ipilimumab group were continuing study treatment
(Table 2). The most frequent reason for discontinuation was disease
progression in the nivolumab and ipilimumab monotherapy groups (154
of 313 patients [49.2%] and 202 of 311 patients [65.0%],
respectively), versus study drug toxicity in the nivolumab plus
ipilimumab group (120 of 313 patients [38.3%]). The number of
patients who had died was 85 (27.2%) in the nivolumab group, 86
(27.5%) in the nivolumab plus ipilimumab group, and 114 (36.7%) in
the ipilimumab group.
[0141] The median number of doses in patients who received
nivolumab alone or ipilimumab alone was 15 (range 1-38) and 4
(1-4), respectively. In the combination group, the median number of
doses was 4 (range 1-39) for nivolumab and 4 (range 1-4) for
ipilimumab; 147 of 313 patients (47%) received four or more doses
of nivolumab monotherapy after combination treatment.
TABLE-US-00001 TABLE 1 Baseline Characteristics of the Patients.
Nivolumab alone Nivolumab plus Ipilimumab alone Total
Characteristic (N = 316) Ipilimumab (N = 314) (N = 315) (N = 945)
Age - yr Mean 58.7 59.3 60.8 59.6 Range 25-90 18-88 18-89 18-90 Age
groups - no. (%) <65 yr 198 (62.7) 185 (58.9) 182 (57.8) 565
(59.8) .gtoreq.65, <75 yr 79 (25.0) 94 (29.9) 89 (28.3) 262
(27.7) .gtoreq.75 yr 39 (12.3) 35 (11.1) 44 (14.0) 118 (12.5) Sex -
no. (%) Male 202 (63.9) 206 (65.6) 202 (64.1) 610 (64.6) Female 114
(36.1) 108 (34.4) 113 (35.9) 335 (35.4) ECOG performance status -
no. (%) 0 238 (75.3) 230 (73.2) 224 (71.1) 692 (73.2) 1 77 (24.4)
83 (26.4) 91 (28.9) 251 (26.6) 2 1 (0.3) 0 0 1 (0.1) Not reported 0
1 (0.3) 0 1 (0.1) M stage - no. (%) M1c 184 (58.2) 181 (57.6) 183
(58.1) 548 (58.0) M0, M1a, or M1b 132 (41.8) 133 (42.4) 132 (41.9)
397 (42.0) Lactate dehydrogenase - no. (%)* .ltoreq. ULN 196 (62.0)
199 (63.4) 194 (61.6) 589 (62.3) >ULN 112 (35.4) 114 (36.3) 115
(36.5) 341 (36.1) .ltoreq.2x ULN 271 (85.8) 276 (87.9) 279 (88.6)
826 (87.4) >2x ULN 37 (11.7) 37 (11.8) 30 (9.5) 104 (11.0)
Unknown 8 (2.5) 1 (0.3) 6 (1.9) 15 (1.6) Brain metastases at
baseline - no. (%) Yes 8 (2.5) 11 (3.5) 15 (4.8) 34 (3.6) No 308
(37.5) 303 (96.5) 300 (95.2) 911 (96.4) PD-L1 status - no. (%)
Positive 80 (27.8) 68 (24.5) 75 (27.1) 223 (26.4) Negative 208
(72.2) 210 (75.5) 202 (72.9) 620 (73.5) BRAF status - no. (%)
Mutation 100 (31.6) 101 (32.2) 97 (30.8) 298 (31.5) No mutation 216
(68.4) 213 (67.8) 218 (69.2) 647 (68.5) *ULN denotes upper limit of
normal.
Efficacy
[0142] The median progression-free survival was 6.5 months (95%
confidence interval [CI], 4.3 to 9.5) in the nivolumab group, 11.5
months (95% CI, 8.9 to 16.5) in the nivolumab plus ipilimumab
group, and 2.9 months (95% CI, 2.8 to 3.4) in the ipilimumab group
(FIG. 2A). A significant improvement in progression-free survival
was observed in the nivolumab plus ipilimumab group as compared
with the ipilimumab group (hazard ratio, 0.42; 95% CI, 0.31 to
0.57; P<0.0001) (FIG. 2A). A significant improvement in
progression-free survival was also observed in the nivolumab group
as compared with the ipilimumab group (hazard ratio, 0.57; 95% CI,
0.43 to 0.76; P<0.00001) (FIG. 2A). The hazard ratio for the
comparison between nivolumab plus ipilimumab and nivolumab groups
was 0.74 (95% CI, 0.60 to 0.92).
[0143] Analyses of progression-free survival among prespecified
patient subgroups showed a consistent improvement with nivolumab or
nivolumab plus ipilimumab as compared with ipilimumab, including
subgroups defined by PD-L1 status, BRAF mutation status, and
metastasis stage (FIGS. 3A and 3B). In the combination group,
median PFS was 11.7 months (95% CI, 8.0 to not reached) among
patients with a BRAF mutation and was 11.2 months (95% CI, 8.3 to
not reached) in patients with wild-type BRAF (FIG. 3B). For
patients with a positive PD-L1 tumor status, median
progression-free survival in the nivolumab, nivolumab plus
ipilimumab, and ipilimumab groups was 14.0 months (95% CI, 9.1 to
not reached), 14.0 months (95% CI, 9.7 to not reached), and 3.9
months (95% CI, 2.8 to 4.2), respectively (FIG. 2B). For patients
with a negative PD-L1 tumor status, median progression-free
survival in the nivolumab, nivolumab plus ipilimumab, and
ipilimumab groups was 5.3 months (95% CI, 2.8 to 7.1 months), 11.2
months (95% CI, 8.0 to not reached) and 2.8 months (95% CI, 2.8 to
3.1), respectively (FIG. 2C).
[0144] Investigator-assessed objective response rates were 43.7%
(95% CI, 38.1 to 49.3%), 57.6% (95% CI, 52.0 to 63.2), and 19.0%
(95% CI, 14.9 to 23.8) in the nivolumab, nivolumab plus ipilimumab,
and ipilimumab groups, respectively (Table 3). The percentage of
patients with a complete response was higher in the nivolumab plus
ipilimumab group than in either the nivolumab or ipilimumab alone
groups (11.5% vs. 8.9% and 2.2%) (Table 3). Time to objective
response was similar in each group (Table 3), and the median
duration of response was not reached in any of the groups.
[0145] Median reduction in the sum of the longest diameters of
tumor target lesions was -34.5% (interquartile range: -75.4 to
15.4), -51.1% (-75.8 to -10.2), and 5.8% (-28.0 to 33.3) in the
nivolumab, nivolumab plus ipilimumab, and ipilimumab groups,
respectively (FIGS. 4A-4C). Among patients with PD-L1-positive
tumors, the objective response rates were 57.5% (95% CI, 45.9 to
68.5), 72.1% (95% CI, 59.9 to 82.3), and 21.3% (95% CI, 12.7 to
32.3) for the nivolumab, nivolumab plus ipilimumab, and ipilimumab
groups, respectively; in patients with PD-L1-negative tumors, the
objective response rates were 41.3% (95% CI, 34.6 to 48.4), 54.8%
(95% CI, 47.8 to 61.6), and 17.8% (95% CI, 12.8 to 23.8) (Table
4).
Adverse Events
[0146] Treatment-related adverse events of any grade occurred in
82.1%, 95.5%, and 86.2% of patients in the nivolumab, nivolumab
plus ipilimumab groups, and ipilimumab groups, respectively (Table
5). The most common adverse events in the nivolumab group were
fatigue (in 34.2% of patients), rash (in 21.7%), and diarrhea (in
19.2%). In the nivolumab plus ipilimumab and ipilimumab groups,
diarrhea (in 44.1% and 33.1% of patients, respectively), fatigue
(in 35.1% and 28.0%), and pruritus (in 33.2% and 35.4%) were most
common (Table 5). The incidence of treatment-related adverse events
of grade 3 or 4 was also higher in the nivolumab plus ipilimumab
group than in either the nivolumab or ipilimumab groups (55.0% vs.
16.3% and 27.3%), with diarrhea being the most common (2.2%, 9.3%,
and 6.1% in the nivolumab, nivolumab plus ipilimumab, and
ipilimumab groups, respectively) (Table 5). Treatment-related
adverse events of any grade leading to discontinuation occurred in
7.7%, 36.4%, and 14.8% of patients in the nivolumab, nivolumab plus
ipilimumab, and ipilimumab groups, respectively, with the most
common being diarrhea (in 1.9%, 8.3%, and 4.5%, respectively) and
colitis (in 0.6%, 8.3%, and 7.7%, respectively) (Table 5). One
death due to study-drug toxicity was reported in the nivolumab
group (neutropenia) and one in the ipilimumab group (cardiac
arrest), although such adverse events have not been associated with
these drugs in prior studies. No treatment-related deaths were
reported in the combination group.
TABLE-US-00002 TABLE 2 Patient Disposition.* Nivolumab alone
Nivolumab plus Ipilimumab alone (N = 313) Ipilimumab (N = 313) (N =
311) Patients in the treatment period - no. (%) Continuing 117
(37.4) 93 (29.7) 50 (16.1) Not continuing 196 (62.6) 220 (70.3) 261
(83.9) Reason for not continuing the treatment - no. (%) Disease
progression 154 (49.2) 69 (22.0) 202 (65.0) Study drug toxicity 27
(8.6) 120 (38.3) 47 (15.1) Adverse event unrelated to study drug 5
(1.6) 12 (3.8) 4 (1.3) Patient request to discontinue treatment 5
(1.6) 5 (1.6) 4 (1.3) Death 5 (1.6) 5 (1.6) 4 (1.3) Maximum
clinical benefit 2 (0.6) 2 (0.6) 0 Poor/non-compliance 1 (0.3) 1
(0.3) 1 (0.3) Patient withdrew consent 0 3 (1.0) 0 Lost to
follow-up 1 (0.3) 0 0 Patient no longer meets study criteria 0 1
(0.3) 0 Other 0 3 (1.0) 2 (0.6) Patients in the study - no. (%)
Continuing 223 (71.2) 221 (70.6) 189 (60.8) Died 85 (27.2) 86
(27.5) 114 (36.7) Not continuing 5 (1.6) 6 (1.9) 8 (2.6) *At the
time of database lock on Feb. 17, 2015.
TABLE-US-00003 TABLE 3 Response to Treatment. Nivolumab alone
Nivolumab plus Ipilimumab alone Response (N = 316) Ipilimumab (N =
314) (N = 315) Best overall response - no. (%).sup..dagger.
Complete response 28 (8.9) 36 (11.5) 7 (2.2) Partial response 110
(34.8) 145 (46.2) 53 (16.8) Stable disease 34 (10.8) 41 (13.1) 69
(21.9) Progressive disease 119 (37.7) 71 (22.6) 154 (48.9) Could
not be determined 25 (7.9) 21 (6.7) 32 (10.2) Objective
response.sup..dagger-dbl. No. of patients (% [95% CI]) 138 (43.7
[38.1-49.3]) 181 (57.6 [52.0-63.2]) 60 (19.0 [14.9-23.8]) Estimated
odds ratio (95% CI).sup..sctn. 3.40 (2.02-5.72) 6.11 (3.59-10.38)
-- Two-sided P value <0.00001 <0.00001 -- Time to objective
response - mo No. of responders 138 181 60 Median 2.78 2.76 2.79
Range 2.3-12.5 1.1-11.6 2.5-12.4 .sup..dagger.Best overall response
were assessed by the investigators with the use of RECIST v1.1.
.sup..dagger-dbl.Data include patients with a complete response and
those with a partial response. .sup..sctn.Relative to ipilimumab
alone.
TABLE-US-00004 TABLE 4 Objective Response Rate by PD-L1 Status.
PD-L1 Positive Nivolumab alone Nivolumab plus Ipilimumab alone
Objective response.sup..dagger. (N = 80) Ipilimumab (N = 68) (N =
75) No. of patients (% [95% CI]) 46 (57.5 [45.9-68.5]) 49 (72.1
[59.9-82.3]) 16 (21.3 [12.7-32.3]) Estimated odds ratio (95%
CI).sup..sctn. 5.03 (2.44-10.37) 10.41 (4.63-23.40) -- PD-L1
Negative Nivolumab alone Nivolumab plus Ipilimumab alone Objective
response.sup..dagger. (N = 208) Ipilimumab (N = 210) (N = 202) No.
of patients (% [95% CI]) 86 (41.3 [34.6-48.4]) 115 (54.8
[47.8-61.6]) 36 (17.8 [12.8-23.8]) Estimated odds ratio (95%
CI).sup..sctn. 3.25 (2.05-5.13) 5.90 (3.71-9.38) --
.sup..dagger.Best overall response was assessed by the
investigators with the use of RECIST v1.1. .sup..sctn.Relative to
ipilimumab alone.
[0147] The most frequent grade 3 or 4 treatment-related select
adverse events were diarrhea (2.2%, 9.3%, and 6.1% of patients in
the nivolumab, nivolumab plus ipilimumab, and ipilimumab groups,
respectively), colitis (in 0.6%, 7.7%, and 8.7%, respectively),
increased alanine aminotransferase (in 1.3%, 8.3%, and 1.6%,
respectively), and increased aspartate aminotransferase (in 1.0%,
6.1%, and 0.6%, respectively) (Table 6). With the use of immune
modulatory agents, resolution rates for grade 3 or 4 select adverse
events were generally similar across treatment groups, and were
between 85-100% across organ categories in the nivolumab plus
ipilimumab group. As observed in prior studies, most endocrine
events in all treatment groups did not resolve (Table 7).
DISCUSSION
[0148] In this randomized, double-blind, phase 3 study, both
nivolumab alone and the combination of nivolumab and ipilimumab
significantly increased progression-free survival and objective
response rates, as compared with ipilimumab alone, in previously
untreated advanced melanoma. These results were observed
independently of PD-L1 tumor status, BRAF mutation status, or
metastasis stage. Baseline characteristics of study participants
were typical of patients with advanced melanoma, although the BRAF
mutation rate (31.5%) was lower than the 40-50% generally reported
for advanced disease. While not a primary end point of the study,
the combination of nivolumab and ipilimumab resulted in numerically
longer progression-free survival and a higher response rate as
compared with nivolumab alone in the overall study population.
While time to response was similar between groups, the first tumor
assessment was done at week 12 and thus the possibility that
responses may have occurred earlier with the combination remains
unknown.
TABLE-US-00005 TABLE 5 Adverse Events (Safety Population).*
Nivolumab Nivolumab alone plus Ipilimumab Ipilimumab alone (N =
313) (N = 313) (N = 311) Total Grade 3 or 4 Total Grade 3 or 4
Total Grade 3 or 4 Event no. of patients with event (%) Any adverse
event 311 (99.4) 136 (43.5) 312 (99.7) 215 (68.7) 308 (99.0) 173
(55.6) Treatment-related adverse event.sup..dagger. 257 (82.1) 51
(16.3) 299 (95.5) 172 (55.0) 268 (86.2) 85 (27.3) Diarrhea 60
(19.2) 7 (2.2) 138 (44.1) 29 (9.3) 103 (33.1) 19 (6.1) Fatigue 107
(34.2) 4 (1.3) 110 (35.1) 13 (4.2) 87 (28.0) 3 (1.0) Pruritus 59
(18.8) 0 104 (33.2) 6 (1.9) 110 (35.4) 1 (0.3) Rash 81 (25.9) 2
(0.6) 126 (40.3) 15 (4.8) 102 (32.8) 6 (1.9) Nausea 41 (13.1) 0 81
(25.9) 7 (2.2) 50 (16.1) 2 (0.6) Pyrexia 18 (5.8) 0 58 (18.5) 2
(0.6) 21 (6.8) 1 (0.3) Decreased appetite 34 (10.9) 0 56 (17.9) 4
(1.3) 39 (12.5) 1 (0.3) Increase in alanine 12 (3.8) 4 (1.3) 55
(17.6) 26 (8.3) 12 (3.9) 5 (1.6) aminotransferase Vomiting 20 (6.4)
1 (0.3) 48 (15.3) 8 (2.6) 23 (7.4) 1 (0.3) Increase in aspartate 12
(3.8) 3 (1.0) 48 (15.3) 19 (6.1) 11 (3.5) 2 (0.6) aminotransferase
Hypothyroidism 27 (8.6) 0 47 (15.0) 1 (0.3) 13 (4.2) 0 Colitis 4
(1.3) 2 (0.6) 37 (11.8) 24 (7.7) 36 (11.6) 27 (8.7) Arthralgia 24
(7.7) 0 33 (10.5) 1 (0.3) 19 (6.1) 0 Headache 23 (7.3) 0 32 (10.2)
1 (0.3) 24 (7.7) 1 (0.3) Dyspnea 14 (4.5) 1 (0.3) 32 (10.2) 2 (0.6)
13 (4.2) 0 Treatment-related adverse event 24 (7.7) 16 (5.1) 114
(36.4) 92 (29.4) 46 (14.8) 41 (13.2) leading to discontinuation
*The severity of adverse events was graded according to the
National Cancer Institute Common Terminology Criteria for Adverse
Events, version 4.0. .sup..dagger.The treatment-related adverse
events listed here were reported in at least 10% of the patients in
any of the three study groups.
TABLE-US-00006 TABLE 6 Treatment-related Select Adverse Events
(Safety Population).* Nivolumab Nivolumab alone plus Ipilimumab
Ipilimumab alone (N = 313) (N = 313) (N = 311) Total Grade 3 or 4
Total Grade 3 or 4 Total Grade 3 or 4 Event no. of patients with
event (%) Any select adverse event 194 (62.0) 24 (7.7) 275 (87.9)
124 (39.6) 229 (73.6) 58 (18.6) Treatment-related select adverse
event.sup..dagger. Skin 131 (41.9) 5 (1.6) 185 (59.1) 18 (5.8) 168
(54.0) 9 (2.9) Pruritus 59 (18.8) 0 104 (33.2) 6 (1.9) 110 (35.4) 1
(0.3) Rash 68 (21.7) 1 (0.3) 89 (28.4) 9 (2.9) 65 (20.9) 5 (1.6)
Rash maculo-papular 13 (4.2) 1 (0.3) 37 (11.8) 6 (1.9) 37 (11.9) 1
(0.3) Vitiligo 23 (7.3) 1 (0.3) 21 (6.7) 0 12 (3.9) 0
Gastrointestinal 61 (19.5) 7 (2.2) 145 (46.3) 46 (14.7) 114 (36.7)
36 (11.6) Diarrhea 60 (19.2) 7 (2.2) 138 (44.1) 29 (9.3) 103 (33.1)
19 (6.1) Colitis 4 (1.3) 2 (0.6) 37 (11.8) 24 (7.7) 36 (11.6) 27
(8.7) Hepatic 20 (6.4) 8 (2.6) 94 (30.0) 59 (18.8) 22 (7.1) 5 (1.6)
Increase in alanine aminotransferase 12 (3.8) 4 (1.3) 55 (17.6) 26
(8.3) 12 (3.9) 5 (1.6) Increase in aspartate aminotransferase 12
(3.8) 3 (1.0) 48 (15.3) 19 (6.1) 11 (3.5) 2 (0.6) Endocrine 45
(14.4) 2 (0.6) 94 (30.0) 15 (4.8) 34 (10.9) 7 (2.3) Hypothyroidism
27 (8.6) 0 47 (15.0) 1 (0.3) 13 (4.2) 0 Hyperthyroidism 13 (4.2) 0
31 (9.9) 3 (1.0) 3 (1.0) 0 Hypophysitis 2 (0.6) 1 (0.3) 24 (7.7) 5
(1.6) 12 (3.9) 6 (1.9) Pulmonary 5 (1.6) 1 (0.3) 22 (7.0) 3 (1.0) 6
(1.9) 1 (0.3) Pneumonitis 4 (1.3) 1 (0.3) 20 (6.4) 3 (1.0) 5 (1.6)
1 (0.3) *The severity of adverse events was graded according to the
National Cancer Institute Common Terminology Criteria for Adverse
Events, version 4.0. .sup..dagger.The treatment-related select
adverse events listed here were reported in at least 5% of the
patients in any of the three study groups.
TABLE-US-00007 TABLE 7 Management of Treatment-related Select
Adverse Events With Immune Modulatory Medication (IMM). Nivolumab
Nivolumab plus Ipilimumab Patients with Patients with Select
Adverse Patients resolution of AE Median time to Patients
resolution of AE Event Organ managed with after treatment
resolution, managed with after treatment Category IMM, n (%) with
IMM, n (%) weeks (95% CI) IMM, n (%) with IMM, n (%) Skin 33/131
(25.2) 17 (54.8) 34.9 (18.0, NE) 80/185 (43.2) 55 (75.3) Grade 3-4
3/5 (60.0) 3 (75.0) 2.1 (0.9, NE) 12/18 (66.7) 12 (85.7)
Gastrointestinal 9/61 (14.8) 5 (71.4) 4.0 (0.8, NE) 71/145 (49.0)
62 (93.9) Grade 3-4 5/7 (71.4) 3 (50.0) NE (0.8, NE) 41/46 (89.1)
41 (97.6) Endocrine 5/45 (11.1) 2 (40.0) 24.3 (7.1, NE) 36/94
(38.3) 14 (41.2) Grade 3-4 2/2 (100) 0 NE (NE, NE) 10/15 (66.7) 5
(45.5) Hepatic 8/22 (36.4) 6 (100.0) 7.0 (2.0, 27.1) 46/95 (48.4)
43 (95.6) Grade 3-4 7/8 (87.5) 6 (100.0) 7.0 (2.0, 27.1) 37/60
(61.7) 38 (100.0) Pulmonary 4/5 (80.0) 4 (100.0) 3.3 (2.3, 9.1)
17/22 (77.3) 16 (94.1) Grade 3-4 1/1 (100) 1 (100.0) 2.3 (NE, NE)
2/3 (66.7) 2 (100.0) Renal 1/3 (33.3) 1 (100.0) 0.3 (NE, NE) 4/17
(23.5) 3 (100.0) Grade 3-4 0/1 0 -- 3/6 (50.0) 3 (100.0) Nivolumab
plus Ipilimumab Ipilimumab Patients with Select Adverse Median time
to Patients resolution of AE Median time to Event Organ resolution,
managed with after treatment resolution, Category weeks (95% CI)
IMM, n (%) with IMM, n (%) weeks (95% CI) Skin 8.6 (7.0, 12.6)
58/168 (34.5) 41 (74.5) 12.4 (8.9, 19.1) Grade 3-4 3.4 (1.1, 12.4)
5/9 (55.6) 5 (83.3) 6.1 (4.4, NE) Gastrointestinal 4.5 (3.5, 5.7)
54/114 (47.4) 44 (88.0) 4.9 (2.9, 7.6) Grade 3-4 3.0 (1.9, 4.3)
33/36 (91.7) 31 (88.6) 4.7 (1.9, 6.1) Endocrine NE (10.4, NE) 15/34
(44.1) 4 (28.6) NE (0.71, NE) Grade 3-4 NE (4.5, NE) 7/7 (100.0) 3
(42.9) NE (0.43, NE) Hepatic 5.9 (3.3, 6.6) 3/22 (13.6) 3 (100.0)
4.1 (4.0, 7.7) Grade 3-4 4.1 (3.0, 6.1) 2/5 (40.0) 2 (100.0) 5.9
(4.0, 7.7) Pulmonary 6.1 (1.1, 8.3) 3/6 (50.0) 2 (66.7) 6.1 (6.0,
6.3) Grade 3-4 4.2 (1.1, 7.3) 1/1 (100) 1 (100.0) 4.7 (NE, NE)
Renal 1.7 (0.4, 3.7) 3/8 (37.5) 3 (100.0) 4.6 (0.6, 16.1) Grade 3-4
1.7 (0.4, 3.6) 1/1 (100) 1 (100.0) 4.6 (NE, NE)
[0149] The median progression-free survival reported for the
combination of nivolumab and ipilimumab in this study (11.7 months
in BRAF-mutant patients) is similar to that recently reported for
the combination of BRAF and MEK inhibition in BRAF-mutant
metastatic melanoma (9.9 months for vemurafenib and cobimetinib;
9.3 to 11.4 months for dabrafenib and trametinib). Resistance to
such targeted therapies is almost inevitable when used as
monotherapy and in many cases is very rapid. The confirmed rate of
objective response for combined nivolumab and ipilimumab (57.6%) is
numerically higher than observed with PD-1 blockade alone in
advanced melanoma (nivolumab [40%] in treatment-naive patients with
wild-type BRAF or pembrolizumab [37%] in ipilimumab-naive
patients).
[0150] The results of subgroup analyses suggest that the greatest
benefit for the combination of nivolumab and ipilimumab versus
nivolumab alone may occur in the setting of negative PD-L1 tumor
expression. In the PD-L1-positive group, both nivolumab alone and
nivolumab plus ipilimumab resulted in a similar prolongation of
progression-free survival as compared with ipilimumab alone,
although objective response rates were numerically higher in the
combination group versus either nivolumab or ipilimumab alone.
Thus, the use of PD-L1 as a biomarker may allow clinicians to make
more informed decisions about the risk-benefit of combination
therapy versus monotherapy. Nonetheless, the observation of at
least additive activity of the combination of ipilimumab and
nivolumab in the setting of negative PD-L1 expression is of
interest in melanoma as well as in other tumor types in which PD-1
checkpoint inhibitors are under evaluation.
[0151] The incidence of adverse events in this study was, in
general, lowest in the nivolumab group and highest in the
combination group. The overall incidence of grade 3 or 4
drug-related adverse events was higher in the combination group as
compared with ipilimumab alone (39.6% versus 18.6%), as a result of
a slightly higher incidence in most adverse events, particularly
hepatic toxicity, where the rates of grade 3 or 4 ALT/AST
elevations were 6-8% for the combination and approximately 1% for
ipilimumab alone. One drug-related death was reported in each of
the nivolumab and ipilimumab groups but none in the combination
group. Overall, the safety profile of the combination of nivolumab
and ipilimumab was consistent with previous experience with
nivolumab or ipilimumab alone. No new safety signals were
identified, and adverse events were manageable with established
treatment guidelines as most select adverse events resolved with
immune modulatory agents. These data suggest that the combination
of nivolumab and ipilimumab can be used safely in a broad range of
clinical settings.
[0152] In summary, the report shows increased progression-free
survival and objective response rates for nivolumab alone and the
combination of nivolumab and ipilimumab, as compared with
ipilimumab alone, in previously untreated advanced melanoma.
Adverse events with the combination were managed with established
algorithms, with no study drug-related deaths. The combination of
nivolumab and ipilimumab may represent a means to improve outcomes
with either agent as monotherapy, particularly for patients having
PD-L1-negative tumors. Overall, nivolumab alone and the combination
of nivolumab and ipilimumab are promising treatment options for
previously untreated advanced melanoma.
TABLE-US-00008 SEQUENCES V.sub.H amino acid sequence of 28-8
(Oryctolagus cuniculus) (SEQ ID NO: 1) Met Glu Thr Gly Leu Arg Trp
Leu Leu Leu Val Ala Val Leu Lys Gly Val Gln Cys Leu Ser Val Glu Glu
Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro Leu Thr Leu Thr Cys Thr
Ala Ser Gly Phe Thr Ile Thr Asn Tyr His Met Phe Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Thr Ser Ser Gly Ile Gly
Ser Ser Ser Thr Thr Tyr Tyr Ala Thr Trp Ala Lys Gly Arg Phe Thr Ile
Ser Lys Thr Ser Thr Thr Val Asn Leu Arg Ile Thr Ser Pro Thr Thr Glu
Asp Thr Ala Thr Tyr Phe Cys Ala Arg Asp Tyr Phe Thr Asn Thr Tyr Tyr
Ala Leu Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser V.sub.L
amino acid sequence of 28-8 (Oryctolagus cuniculus) (SEQ ID NO: 2)
Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu
Pro Gly Ala Arg Cys Ala Leu Val Met Thr Gln Thr Pro Ser Ser Thr Ser
Thr Ala Val Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile
Ser Val Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
Leu Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys
Gly Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Gly Val Gln Arg
Glu Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Ala Gly Ser Heavy Chain
CDR1 sequence of 28-8 (Oryctolagus cuniculus) (SEQ ID NO: 3) Asn
Tyr His Met Phe Heavy Chain CDR2 sequence of 28-8 (Oryctolagus
cuniculus) (SEQ ID NO: 4) Val Ile Thr Ser Ser Gly Ile Gly Ser Ser
Ser Thr Thr Tyr Tyr Ala Thr Trp Ala Lys Gly Heavy Chain CDR3
sequence of 28-8 (Oryctolagus cuniculus) (SEQ ID NO: 5) Asp Tyr Phe
Thr Asn Thr Tyr Tyr Ala Leu Asp Ile Light Chain CDR1 sequence of
28-8 (Oryctolagus cuniculus) (SEQ ID NO: 6) Gln Ala Ser Gln Ser Ile
Ser Val Tyr Leu Ala Light Chain CDR2 sequence of 28-8 (Oryctolagus
cuniculus) (SEQ ID NO: 7) Ser Ala Ser Thr Leu Ala Ser Light Chain
CDR3 sequence of 28-8 (Oryctolagus cuniculus) (SEQ ID NO: 8) Leu
Gly Ser Ala Gly Ser Asp Asp Ala Ala
Sequence CWU 1
1
81141PRTOryctolagus cuniculus 1Met Glu Thr Gly Leu Arg Trp Leu Leu
Leu Val Ala Val Leu Lys Gly1 5 10 15Val Gln Cys Leu Ser Val Glu Glu
Ser Gly Gly Arg Leu Val Thr Pro 20 25 30Gly Thr Pro Leu Thr Leu Thr
Cys Thr Ala Ser Gly Phe Thr Ile Thr 35 40 45Asn Tyr His Met Phe Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 50 55 60Trp Ile Gly Val Ile
Thr Ser Ser Gly Ile Gly Ser Ser Ser Thr Thr65 70 75 80Tyr Tyr Ala
Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser 85 90 95Thr Thr
Val Asn Leu Arg Ile Thr Ser Pro Thr Thr Glu Asp Thr Ala 100 105
110Thr Tyr Phe Cys Ala Arg Asp Tyr Phe Thr Asn Thr Tyr Tyr Ala Leu
115 120 125Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 130
135 1402116PRTOryctolagus cuniculus 2Met Asp Thr Arg Ala Pro Thr
Gln Leu Leu Gly Leu Leu Leu Leu Trp1 5 10 15Leu Pro Gly Ala Arg Cys
Ala Leu Val Met Thr Gln Thr Pro Ser Ser 20 25 30Thr Ser Thr Ala Val
Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser 35 40 45Gln Ser Ile Ser
Val Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 50 55 60Pro Pro Lys
Leu Leu Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val65 70 75 80Pro
Ser Arg Phe Lys Gly Ser Arg Ser Gly Thr Glu Tyr Thr Leu Thr 85 90
95Ile Ser Gly Val Gln Arg Glu Asp Ala Ala Thr Tyr Tyr Cys Leu Gly
100 105 110Ser Ala Gly Ser 11535PRTOryctolagus cuniculus 3Asn Tyr
His Met Phe1 5421PRTOryctolagus cuniculus 4Val Ile Thr Ser Ser Gly
Ile Gly Ser Ser Ser Thr Thr Tyr Tyr Ala1 5 10 15Thr Trp Ala Lys Gly
20512PRTOryctolagus cuniculus 5Asp Tyr Phe Thr Asn Thr Tyr Tyr Ala
Leu Asp Ile1 5 10611PRTOryctolagus cuniculus 6Gln Ala Ser Gln Ser
Ile Ser Val Tyr Leu Ala1 5 1077PRTOryctolagus cuniculus 7Ser Ala
Ser Thr Leu Ala Ser1 5810PRTOryctolagus cuniculus 8Leu Gly Ser Ala
Gly Ser Asp Asp Ala Ala1 5 10
* * * * *
References