INDIANAPOLIS, Oct. 9, 2016 /PRNewswire/ -- Important
clinical study results from one of Eli Lilly and Company's (NYSE:
LLY) ongoing immuno-oncology collaborations with Merck (known as
MSD outside the U.S. and Canada)
were announced today at the ESMO 2016 Congress, the annual meeting
of the European Society for Medical Oncology. Specifically, data
released from KEYNOTE-021, Cohort G, which evaluated
ALIMTA® (pemetrexed) plus carboplatin in combination
with Merck's KEYTRUDA® (pembrolizumab) in the first-line
treatment of patients with metastatic non-small cell lung cancer
(NSCLC), showed that the combination of ALIMTA, KEYTRUDA and
carboplatin demonstrated superior efficacy compared to ALIMTA and
carboplatin – standard of care – alone.
In KEYNOTE-021, Cohort G, which included patients with advanced
nonsquamous NSCLC regardless of PD-L1 expression level, the
combination of pemetrexed, pembrolizumab and carboplatin achieved a
55 percent objective response rate (ORR) compared to 29 percent for
pemetrexed-plus-carboplatin alone, and reduced the risk of disease
progression or death by 47 percent. Median progression-free
survival (PFS) was 13.0 months with the
pemetrexed-pembrolizumab-carboplatin combination. To date, this
combination of pemetrexed-pembrolizumab-carboplatin is the only
anti-PD-1-containing regimen to demonstrate superior efficacy
compared to chemotherapy alone in NSCLC patients receiving
first-line treatment.
"These randomized study data of ALIMTA and KEYTRUDA in
first-line nonsquamous non-small cell lung cancer build on the
early results we've seen in this combination and are very
encouraging," said Richard Gaynor,
M.D., senior vice president, product development and medical
affairs for Lilly Oncology. "To see a near-doubling in the number
of patients responding to this combination gives us hope for what
may be able to be achieved above and beyond what is seen with the
ALIMTA-containing standard-of-care regimen. These types of clinical
advancements are truly exciting as we continue our pursuit to bring
meaningful benefits to patients facing cancer."
Dr. Gaynor added, "These data also reflect the progress that
Lilly is making in its oncology R&D strategy to develop cancer
treatments across three key areas of disease modification: tumor
cell signaling, tumor microenvironment and immuno-oncology. This
approach allows for testing of combinations of internally derived
agents to address tumor heterogeneity and drug resistance, through
our own efforts and research collaborations."
KEYNOTE-021, Cohort G, included 123 previously untreated
patients with advanced nonsquamous NSCLC regardless of PD-L1
expression and whose tumors did not have EGFR mutations or ALK
translocations. Patients were randomized to receive the
pemetrexed-pembrolizumab-carboplatin combination (n=60) or
pemetrexed-plus-carboplatin (n=63). Patients randomized to the
pemetrexed-plus-carboplatin control arm had the option of crossing
over to pembrolizumab monotherapy upon disease progression. The
median follow-up was 10.6 months (range, 0.8-19.3).
The findings demonstrated that ORR nearly doubled with the
pemetrexed-pembrolizumab-carboplatin combination, with an ORR of 55
percent (n=33/60), compared to 29 percent (n=18/63) for the control
arm alone (treatment difference 26%, 95% CI, 9-42% p=0.0016); all
responses were partial. Median duration of response was not reached
in either group (range, 1.4+-13.0+ for the
pemetrexed-pembrolizumab-carboplatin combination; 1.4+-15.2+ for
the control arm). Responses in both groups were durable, with 88
percent (n=29/33) of responders in the
pemetrexed-pembrolizumab-carboplatin combination group and 78
percent (n=14/18) of responders in the control arm group
experiencing ongoing response at the time of data cut-off.
Additionally, the pemetrexed-pembrolizumab-carboplatin
combination significantly reduced the risk of disease progression
or death compared to the control arm (hazard ratio 0.53, 95% CI,
0.31-0.91, p=0.0102). Median PFS was 13.0 months with the
pemetrexed-pembrolizumab-carboplatin combination compared to 8.9
months in the control arm. Overall survival (OS) was similar
between the two arms, with 92 percent survival at six months in
both, and 75 percent and 72 percent survival at 12 months in the
pemetrexed-pembrolizumab-carboplatin combination and control arm,
respectively.
Of treated patients on the pemetrexed-pembrolizumab-carboplatin
combination arm, 47 percent remained on treatment as of the cut-off
date, compared to 31 percent on the control arm. Of the treated
patients who discontinued treatment on the control arm, 52 percent
(n=32/62) subsequently received anti-PD-L1 therapy, with 32 percent
crossing over to pembrolizumab monotherapy as allowed by the study
protocol and 19 percent receiving it outside of study
crossover.
Additional Safety Information from KEYNOTE-021, Cohort
G
The most common treatment-related adverse events
(occurring in at least 15% of patients) for the
pemetrexed-pembrolizumab-carboplatin combination were fatigue,
nausea, anemia, rash, vomiting, diarrhea, increased AST,
constipation, decreased appetite, increased ALT, dysgeusia, and
decreased neutrophils. Grade 3-4 treatment-related adverse events
in this arm included fatigue, nausea, anemia, rash, vomiting,
increased AST, increased ALT, and decreased neutrophils. The most
common immune-mediated adverse events in patients receiving the
pemetrexed-pembrolizumab-carboplatin combination were
hypothyroidism and hyperthyroidism. Additionally, pneumonitis,
infusion reactions, and severe skin toxicity were noted. These
immune-mediated adverse events occurred at similar rates to
patients receiving pembrolizumab as a single agent. There was one
treatment-related death from sepsis in a patient receiving the
pemetrexed-pembrolizumab-carboplatin combination, and two (one from
sepsis and one from pancytopenia) in patients on the control
arm.
About KEYNOTE-021, Cohort G
Cohort G of the
multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study
evaluated the efficacy and safety of pembrolizumab in combination
with pemetrexed and carboplatin compared with pemetrexed and
carboplatin in patients with advanced, nonsquamous, EGFR- and
ALK-negative NSCLC in the first-line treatment setting. Patients
were randomized 1:1 to four cycles of pembrolizumab (200 mg) plus
pemetrexed (500 mg/m2 every three weeks) plus
carboplatin AUC 5 (5 mg/mL/min), or pemetrexed plus carboplatin
alone, followed by maintenance pemetrexed with or without
pembrolizumab. Randomization was stratified by PD-L1 expression
(positive expression defined as TPS of one percent or more;
negative expression defined as TPS of less than one percent).
Patients randomized to the control arm were allowed to cross over
to pembrolizumab monotherapy if they experienced disease
progression. Response was assessed by blinded, independent central
review using RECIST 1.1 every six weeks for the first 18 weeks,
every nine weeks through the first year, and every 12 weeks in the
second year. The primary endpoint was ORR; secondary endpoints
included PFS, duration of response, and OS.
About KEYNOTE-189, a Phase 3 Trial of
Pemetrexed-Pembrolizumab-Platinum Combination
KEYNOTE-189,
a randomized Phase 3 study evaluating pemetrexed-plus-platinum
chemotherapy (carboplatin or cisplatin) with and without
pembrolizumab as initial therapy in NSCLC patients, is currently
enrolling. The first results from this study could be available
before the end of 2017.
Pemetrexed (marketed under the brand name ALIMTA®) is
a folate analog metabolic inhibitor that exerts its action by
disrupting folate-dependent metabolic processes essential for cell
replication. In vitro studies have shown that
pemetrexed inhibits thymidylate synthase (TS), dihydrofolate
reductase (DHFR), and glycinamide ribonucleotide
formyltransferase (GARFT), which are folate-dependent enzymes
involved in the de novo biosynthesis of thymidine and purine
nucleotides.
Pembrolizumab (marketed under the brand name
KEYTRUDA®) is a humanized monoclonal antibody that works
by increasing the ability of the body's immune system to help
detect and fight tumor cells. Pembrolizumab blocks the interaction
between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T
lymphocytes, which may affect both tumor cells and healthy
cells.
NOTES TO EDITORS
About ALIMTA® (pemetrexed)
In 2004, ALIMTA
received consecutive approvals: it was the first agent to be
approved in combination with cisplatin as a treatment for patients
with malignant pleural mesothelioma, whose disease is unresectable
or who are otherwise not candidates for curative surgery, and then
as a single agent for the treatment of patients with locally
advanced or metastatic NSCLC after prior treatment.
In 2008, ALIMTA, in combination with cisplatin, was approved as
an initial chemotherapy treatment for locally advanced or
metastatic NSCLC for patients with nonsquamous histology. At the
time of this initial treatment approval, the FDA also
approved a change to the indication for subsequent treatment.
ALIMTA is now indicated as a single agent for the treatment of
patients with locally advanced or metastatic, nonsquamous NSCLC
after prior therapy.
In 2009, ALIMTA was approved as a maintenance therapy for
locally advanced or metastatic NSCLC, specifically for patients
with a nonsquamous histology whose disease has not progressed after
four cycles of platinum-based initial chemotherapy.
In 2012, ALIMTA was approved by the FDA as maintenance
therapy for locally-advanced or metastatic NSCLC, following initial
ALIMTA-plus-cisplatin treatment for locally advanced or metastatic
nonsquamous NSCLC.
ALIMTA is not indicated for treatment of patients with squamous
cell NSCLC. Myelosuppression is usually the dose-limiting toxicity
with ALIMTA therapy.
Indications and Important Safety Information for
ALIMTA® (pemetrexed for
injection)
Indications
ALIMTA is indicated in combination with
cisplatin therapy for the initial treatment of patients with
locally advanced or metastatic nonsquamous non-small cell lung
cancer.
ALIMTA is indicated for the maintenance treatment of patients
with locally advanced or metastatic nonsquamous non-small cell lung
cancer whose disease has not progressed after four cycles of
platinum-based first-line chemotherapy.
ALIMTA is indicated as a single agent for the treatment of
patients with locally advanced or metastatic nonsquamous non-small
cell lung cancer after prior chemotherapy.
Limitations of Use: ALIMTA is not indicated for the
treatment of patients with squamous cell non-small cell lung
cancer.
ALIMTA in combination with cisplatin is indicated for the
treatment of patients with malignant pleural mesothelioma whose
disease is unresectable or who are otherwise not candidates for
curative surgery.
Important Safety Information
Myelosuppression is usually the dose-limiting toxicity with
ALIMTA therapy.
Contraindication
ALIMTA is contraindicated in patients
who have a history of severe hypersensitivity reaction to
pemetrexed.
Warnings and Precautions
Prior to treatment with
ALIMTA, patients must be instructed to initiate supplementation
with oral folic acid. Additionally, intramuscular injections
of vitamin B12 are also required prior to ALIMTA
treatment. Folic acid and vitamin B12 supplementation
should be continued throughout treatment as they may reduce the
severity of treatment-related hematologic and GI toxicities.
Dexamethasone or its equivalent should be administered the day
before, the day of, and the day after ALIMTA treatment.
ALIMTA can suppress bone marrow function, as manifested by
neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce
doses for subsequent cycles based on hematologic and nonhematologic
toxicities.
ALIMTA should not be administered to patients with a creatinine
clearance <45 mL/min. One patient with severe renal impairment
(creatinine clearance 19 mL/min) who did not receive folic acid and
vitamin B12 died of drug-related toxicity following
administration of ALIMTA alone.
Caution should be used when administering NSAIDs concurrently
with ALIMTA to patients with mild to moderate renal insufficiency
(creatinine clearance from 45 to 79 mL/min). Patients with mild to
moderate renal insufficiency should avoid taking NSAIDs with short
elimination half-lives for a period of 2 days before, the day of,
and 2 days following administration of ALIMTA. In the absence of
data regarding potential interaction between ALIMTA and NSAIDs with
longer half-lives, all patients taking these NSAIDs should
interrupt dosing for at least 5 days before, the day of, and 2 days
following ALIMTA administration. If concomitant administration of
NSAIDs is necessary, patients should be monitored closely for
toxicity, especially myelosuppression, renal, and gastrointestinal
toxicity. No dose adjustment of ALIMTA is needed with concomitant
NSAIDs in patients with normal renal function.
Do not initiate a cycle of treatment in patients unless the ANC
is ≥1500 cells/mm3, the platelet count is ≥100,000
cells/mm3, and creatinine clearance is ≥45 mL/min.
Pregnancy Category D—ALIMTA may cause fetal harm when
administered to a pregnant woman. Women should be apprised of the
potential hazard to the fetus and should be advised to use
effective contraceptive measures to prevent pregnancy during
treatment with ALIMTA.
Drug Interactions
See Warnings and Precautions for
specific information regarding NSAID administration in patients
with renal insufficiency.
Concomitant administration of nephrotoxic drugs or substances
that are tubularly secreted could result in delayed clearance of
ALIMTA.
Use in Specific Patient Populations
It is recommended
that nursing be discontinued if the mother is being treated with
ALIMTA or discontinue the drug, taking into account the importance
of the drug for the mother.
Efficacy of ALIMTA in pediatric patients has not been
demonstrated. The most common toxicities reported in the studied
pediatric patients were hematological (leukopenia,
neutropenia/granulocytopenia, anemia, thrombocytopenia, and
lymphopenia), liver function abnormalities (increased ALT/AST),
fatigue, and nausea.
Dosage and Administration Guidelines
Complete blood
cell counts, including platelet counts and periodic chemistry
tests, which include renal and hepatic function tests, should be
performed on all patients receiving ALIMTA.
Dose adjustments at the start of a subsequent cycle should be
based on nadir hematologic counts or maximum nonhematologic
toxicity from the preceding cycle of therapy. Modify or suspend
therapy according to the Dosage Reduction Guidelines in the full
Prescribing Information.
Abbreviated Adverse Reactions (% incidence) – 1st-line
advanced nonsquamous non-small cell lung cancer (NS
NSCLC)
The most severe adverse reactions (grades 3-4) with
ALIMTA in combination with cisplatin versus gemcitabine in
combination with cisplatin, respectively, for the 1st-line
treatment of patients with advanced nonsquamous non-small cell lung
cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs
8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7%
vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs
1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).
Common adverse reactions (all grades) with ALIMTA in combination
with cisplatin versus gemcitabine in combination with cisplatin,
respectively, were nausea (56% vs 53%); fatigue (43% vs 45%);
vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs
38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia
(18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs
21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%);
neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%);
rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and
creatinine elevation (10% vs 7%).
Abbreviated Adverse Reactions (% incidence) – Maintenance in
advanced NS NSCLC following non-ALIMTA containing, platinum-based
induction therapy
The most severe adverse reactions
(grades 3-4) with ALIMTA as a single agent versus placebo,
respectively, for the maintenance treatment of patients with
locally advanced nonsquamous non-small cell lung cancer (NS NSCLC)
following non-ALIMTA containing platinum-based induction therapy
were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs
1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%);
mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2%
vs 0%); and neuropathy-sensory (1% vs 0%).
Common adverse reactions (all grades) with ALIMTA as a single
agent versus placebo, respectively, after non-ALIMTA containing
platinum-based induction therapy were anemia (15% vs 6%);
neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10%
vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19%
vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%);
mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5%
vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10%
vs 3%).
Abbreviated Adverse Reactions (% incidence) – Maintenance in
advanced NS NSCLC following ALIMTA plus cisplatin induction
therapy
The most severe adverse reactions (grades 3-4) with
ALIMTA as a single agent versus placebo, respectively, for the
maintenance treatment of patients with locally advanced nonsquamous
non-small cell lung cancer (NS NSCLC) following ALIMTA plus
cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia
(3.9% vs 0%); and fatigue (4.5% vs 0.6%).
Common adverse reactions (all grades) with ALIMTA as a single
agent versus placebo, respectively, following ALIMTA plus cisplatin
induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs
0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs
1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs
3.6%).
Abbreviated Adverse Reactions (% incidence) – 2nd-line
advanced NS NSCLC
The most severe adverse reactions (grades
3-4) with ALIMTA as a single agent versus docetaxel, respectively,
for the 2nd-line treatment of patients with advanced non-small cell
lung cancer (NSCLC) were neutropenia (5% vs 40%); leukopenia (4% vs
27%); thrombocytopenia (2% vs 0%); anemia (4% vs 4%); fatigue (5%
vs 5%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs
1%); increased ALT (2% vs 0%); increased AST (1% vs 0%); and
stomatitis/pharyngitis (1% vs 1%).
Common adverse reactions (all grades) with ALIMTA as a single
agent versus docetaxel, respectively, were fatigue (34% vs 36%);
nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%);
vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash
(14% vs 6%); diarrhea (13% vs 24%); leukopenia (12% vs 34%);
thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); increased
AST (7% vs 1%); constipation (6% vs 4%); fever (8% vs 8%); pruritus
(7% vs 2%); alopecia (6% vs 38%); and neutropenia (11% vs 45%).
Abbreviated Adverse Reactions (% incidence) – MPM
The
most severe adverse reactions (grades 3-4) with ALIMTA in
combination with cisplatin versus cisplatin alone, respectively,
for the treatment of patients with malignant pleural mesothelioma
(MPM) were neutropenia (23% vs 3%); leukopenia (15% vs 1%);
thrombocytopenia (5% vs 0%); anemia (4% vs 0%); nausea (12% vs 6%);
vomiting (11% vs 4%); fatigue (10% vs 9%); creatinine elevation (1%
vs 1%); stomatitis/pharyngitis (3% vs 0%); anorexia (1% vs 1%);
diarrhea (4% vs 0%); constipation (1% vs 1%); dyspepsia (1% vs 0%);
dehydration (4% vs 1%); neuropathy-sensory (0% vs 1%); rash (1% vs
0%); and creatinine clearance decrease (1% vs 2%).
Common adverse reactions (all grades) with ALIMTA in combination
with cisplatin versus cisplatin alone, respectively, were
neutropenia (56% vs 13%); leukopenia (53% vs 17%); anemia (26% vs
10%); thrombocytopenia (23% vs 9%); nausea (82% vs 77%); vomiting
(57% vs 50%); fatigue (48% vs 42%); creatinine elevation (11% vs
10%); creatinine clearance decreased (16% vs 18%); conjunctivitis
(5% vs 1%); anorexia (20% vs 14%); diarrhea (17% vs 8%);
constipation (12% vs 7%); dyspepsia (5% vs 1%); dehydration (7% vs
1%); neuropathy-sensory (10% vs 10%); taste disturbance (8% vs 6%);
rash (16% vs 5%); alopecia (11% vs 6%); and stomatitis/pharyngitis
(23% vs 6%).
PM_HCP_ISI_All_17OCT2012
For more complete information for Alimta, please see full
Prescribing Information and Patient Information.
About Lilly Oncology
For more than 50 years, Lilly has
been dedicated to delivering life-changing medicines and support to
people living with cancer and those who care for them. Lilly is
determined to build on this heritage and continue making life
better for all those affected by cancer around the world. To learn
more about Lilly's commitment to people with cancer, please
visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global
healthcare leader that unites caring with discovery to make life
better for people around the world. We were founded more than a
century ago by a man committed to creating high-quality medicines
that meet real needs, and today we remain true to that mission in
all our work. Across the globe, Lilly employees work to discover
and bring life-changing medicines to those who need them, improve
the understanding and management of disease, and give back to
communities through philanthropy and volunteerism. To learn more
about Lilly, please visit us at www.lilly.com and
newsroom.lilly.com/social-channels. (P-LLY)
© Lilly USA, LLC 2016. ALL
RIGHTS RESERVED.
ALIMTA® is a trademark owned by or licensed to Eli
Lilly and Company, its subsidiaries, or affiliates.
KEYTRUDA® is a registered trademark of Merck Sharp
& Dohme Corp., a subsidiary of Merck & Co., Inc.
Lilly Forward-Looking Statement
This press release
contains "forward-looking statements" (as that term is defined
in the United States Private Securities Litigation Reform
Act of 1995) regarding ALIMTA and Lilly's oncology research
program, and reflects Lilly's current beliefs. However, there are
substantial risks and uncertainties in the process of drug
research, development and commercialization. Among other risks,
there can be no guarantee that these investigational combination
regimens will receive regulatory approval, or, if approved, will
achieve intended benefits or become commercially successful. For
further discussion of these and other risks and uncertainties that
could cause actual results to differ materially from Lilly's
expectations, please see the company's latest Forms 10-K and 10-Q
filed with the U.S. Securities and Exchange Commission. Except
as required by law, Lilly undertakes no duty to update
forward-looking statements for events occurring after the date of
this release.
Refer to:
|
Tracy Henrikson;
tracy.henrikson@lilly.com; (609) 240-3902 (media)
|
|
Philip L. Johnson;
philip_johnson_l@lilly.com; (317) 655-6874 (investors)
|
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