LUMAKRAS ® (sotorasib)
Demonstrated Delayed Time to CNS Progression, Longer CNS PFS and
Higher Intracranial ORR vs Docetaxel in Post-Hoc Analysis of Phase
3 CodeBreaK 200 Trial
LUMAKRAS Shows Improved PFS vs Docetaxel
Across Key Co-Alteration Subgroups in the Phase 3 CodeBreaK 200
Study
LUMAKRAS Plus
Vectibix® (panitumumab) and FOLFIRI
Combination Show ORR of 55% in Previously Treated KRAS
G12C-Mutated Metastatic CRC
THOUSAND
OAKS, Calif., June 4, 2023
/PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced the
presentation of new data from the CodeBreaK clinical trial program,
the most comprehensive global development program in patients with
KRAS G12C-mutated cancers, at the American Society of
Clinical Oncology (ASCO) Annual Meeting taking place June 2-6 in Chicago. The research presented reinforces the
efficacy of
LUMAKRAS®/LUMYKRAS® (sotorasib) in
advanced non-small cell lung cancer (NSCLC) and metastatic
colorectal cancer (mCRC). Additionally, data from SCARLET, an Amgen
funded investigator study sponsored by the West Japan Oncology
Group, will be presented on June 6
and is the first study to highlight the safety and efficacy of
sotorasib in combination with platinum-based chemotherapy for
frontline treatment of patients with advanced NSCLC harboring a
KRAS G12C mutation.
"As the leader in KRAS inhibition, Amgen continues to
advance the CodeBreaK program by evaluating LUMAKRAS across
different indications and combinations to potentially help more
people living with KRAS G12C-mutated cancers," said
David M. Reese, M.D., executive vice president of Research and
Development at Amgen. "These data presented at ASCO underscore
the clinical importance of LUMAKRAS, including the only randomized
trial of a KRASG12C inhibitor to show higher
intracranial activity compared to chemotherapy, along with data
validating our combination treatment approach in metastatic
colorectal cancer, where new precision medicine strategies are
desperately needed."
Improved CNS Activity in Advanced NSCLC
In the first
and only randomized study for any KRASG12C inhibitor,
data from a post-hoc analysis of the global Phase 3 CodeBreaK 200
trial included patients with advanced NSCLC and treated/stable
central nervous system (CNS) lesions at baseline, as assessed by a
blinded independent central review (BICR). In this analysis using a
modified exploratory response assessment in neuro-oncology brain
metastases (RANO-BM), LUMAKRAS demonstrated delayed time to CNS
progression and longer CNS progression-free survival (PFS) compared
with docetaxel.
Additionally, the CNS objective response rate (ORR),* an
assessment of CNS tumor shrinkage following treatment, was more
than double (33.3% vs 15.4%) in patients treated with LUMAKRAS (n=
18) compared to docetaxel (n= 13). The safety profile in this
analysis was similar to the CodeBreaK 200 overall population.
"CNS metastases are an unfortunately common complication of
KRAS G12C-mutated advanced NSCLC, occurring in about 30–40%
of patients," said Melissa L.
Johnson, M.D., director of Lung Cancer Research, Sarah
Cannon Research Institute at Tennessee Oncology. "In this post-hoc
analysis from CodeBreaK 200, sotorasib delayed CNS progression-free
survival by more than five months and is a potential clinically
meaningful benefit for second-line NSCLC patients with KRAS G12C
mutations."
These results will be presented on Sunday, June 4, as a late-breaking abstract in a
poster discussion session: Lung Cancer—Non-Small Cell Metastatic,
beginning at 4:30 p.m. CDT.
(#LBA9016).
*Exploratory post-hoc analysis in patients with
stable/treated CNS lesions at baseline, in which measurable lesions
were defined per study as CNS lesions ≥10 mm in diameter by BICR
using modified RANO-BM Criteria
New NSCLC Biomarker Data from CodeBreaK 200 Show Consistent
Clinical Benefit Across Subgroups
In the first randomized,
molecularly-defined analysis of a KRASG12C inhibitor
versus chemotherapy, LUMAKRAS showed improved PFS over docetaxel,
irrespective of PD-L1 expression level, and retained PFS benefit
versus docetaxel across key co-alteration subgroups (including
STK11, KEAP1, TP53). Collectively, the
biomarker data help inform treatment decision making and the
ongoing CodeBreaK clinical development program, which explores
LUMAKRAS in novel combinations.
These data will be presented on Tuesday, June 6 during an oral abstract session:
Lung Cancer–Non-Small Cell Metastatic, from 9:45 a.m.- 12:45 p.m. CDT (Abstract
#9008).
Encouraging Safety and Efficacy in Metastatic CRC
Data
from the CodeBreaK 101 Phase 1B
study, the first reported results for the combination of LUMAKRAS
with Vectibix® (panitumumab) and FOLFIRI, showed
encouraging safety and efficacy in previously-treated KRAS
G12C-mutated metastatic CRC.
Among 42 patients evaluable for response, confirmed ORR was 55%
(95% CI: 38.7, 70.2), and disease control rate (DCR) was 93% (95%
CI: 80.5, 98.5), with responses observed regardless of the number
of prior lines of therapy and regardless of progression on prior
irinotecan-based therapy. LUMAKRAS plus Vectibix and FOLFIRI
combination reported adverse events consistent with those expected
for the therapies under study.
"A priority in KRAS G12C-mutated colorectal cancer
research is exploring new treatment combinations that can
drastically improve response rates attained with current
treatments, which can be as low as 2%," said lead investigator,
David S. Hong, M.D., professor of
Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center,
Houston. "These results showed
encouraging efficacy with sotorasib in combination with panitumumab
and FOLFIRI, and importantly showed consistent safety for each
product."
These data will be presented on Monday, June 5 during a poster discussion
session: Gastrointestinal Cancer—Colorectal and Anal, from
1:15-2:45 p.m. CDT (Abstract
#3513.)
More information on Amgen's abstracts is available on the ASCO
website.
About
LUMAKRAS®/LUMYKRAS® (sotorasib)
Amgen took on one of the toughest challenges of the last 40
years in cancer research by developing LUMAKRAS/LUMYKRAS, a
KRASG12C inhibitor.i LUMAKRAS/LUMYKRAS
has demonstrated a positive benefit-risk profile with rapid, deep,
and durable anticancer activity in patients with locally advanced
or metastatic non-small cell lung cancer (NSCLC) harboring
the KRAS G12C mutation with a once daily oral
formulation.ii
Amgen is progressing the largest and broadest global
KRASG12C inhibitor development program with unparalleled
speed and exploring more than 10 sotorasib combination regimens,
with clinical trial sites spanning five continents. To date, over
6,500 patients around the world have received LUMAKRAS/LUMYKRAS
through the clinical development program and commercial
use.
In May 2021, LUMAKRAS was the first
KRASG12C inhibitor to receive regulatory approval
with its approval in the U.S., under accelerated approval.
LUMAKRAS/LUMYKRAS is also approved in the European
Union, Japan, United Arab Emirates, South
Korea, Hong Kong, Switzerland, Taiwan, Qatar,
and in Australia, Brazil, Canada, Great
Britain, Singapore, and
Israel under the FDA's Project
Orbis. Additionally, Amgen has submitted MAAs in Argentina, Colombia, Kuwait, Macao, Malaysia, Mexico, Russia, Saudi
Arabia, Thailand and
Turkey.
LUMAKRAS/LUMYKRAS is also being studied in multiple other solid
tumors.iii
About Non-Small Cell Lung Cancer and
the KRAS G12C Mutation
Lung cancer is the leading cause of cancer-related deaths
worldwide, and it accounts for more deaths worldwide than colon
cancer, breast cancer and prostate cancer
combined.iv Overall survival rates for NSCLC are
improving but remain poor for patients with advanced disease, and
5-year survival is only 9% for those with metastatic
disease.v
KRAS G12C is the most common KRAS mutation in
NSCLC.vi About 13% of patients with NSCLC harbor
the KRAS G12C mutation.[vii] Unmet medical need remains
high and treatment options are limited for NSCLC patients with
the KRAS G12C mutation whose first-line treatment has
failed to work or has stopped working. The outcomes with other
approved therapies are suboptimal, with a median progression-free
survival of approximately four months following second-line
treatment of KRAS G12C-mutated
NSCLC.viii
About Advanced Colorectal Cancer and
the KRAS G12C Mutation
Colorectal cancer (CRC) is the second leading cause of
cancer deaths worldwide, comprising 10% of all cancer
diagnoses.ix It is also the third most commonly
diagnosed cancer globally.x
Patients with previously treated metastatic CRC need more
effective treatment options. For patients in the third-line
setting, standard therapies yield median PFS times of about two
months and patients' response rates are less than
2%.xi,xii
KRAS mutations are among the most common genetic
alterations in colorectal cancers, with the KRAS G12C
mutation present in approximately 3-5% of colorectal
cancers.xiii,xiv,xv
About CodeBreaK
The CodeBreaK clinical development program for Amgen's drug
sotorasib is designed to study patients with an advanced solid
tumor with the KRAS G12C mutation and address the
longstanding unmet medical need for these cancers.
CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label
multicenter study, enrolled patients
with KRAS G12C-mutant solid
tumors.xvi Eligible patients must have received a
prior line of systemic anticancer therapy, consistent with their
tumor type and stage of disease. The primary endpoint for the Phase
2 study was centrally assessed objective response rate. The Phase 2
trial in NSCLC enrolled 126 patients, 124 of whom had centrally
evaluable lesions by RECIST at baseline.ii The Phase 2
trial in metastatic colorectal cancer (mCRC) is fully enrolled and
results have been published.xvii
CodeBreaK 200, the global Phase 3 randomized active-controlled
study comparing sotorasib to docetaxel
in KRAS G12C-mutated NSCLC completed enrollment of 345
patients. Eligible patients had previously treated, locally
advanced and unresectable or metastatic KRAS G12C-mutated
NSCLC. The primary endpoint is progression-free survival and key
secondary endpoints include overall survival, objective response
rate, and patient-reported outcomes.xviii
Amgen also has several Phase 1b
studies investigating sotorasib monotherapy and sotorasib
combination therapy across various advanced solid tumors (CodeBreaK
101) open for enrollment.xix A Phase 2 randomized study
will evaluate sotorasib in patients with stage
IV KRAS G12C-mutated NSCLC in need of first-line treatment
(CodeBreaK 201).xx
LUMAKRAS® (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients
with KRAS G12C-mutated locally advanced or metastatic
non-small cell lung cancer (NSCLC), as determined by an
FDA-approved test, who have received at least one prior systemic
therapy.
This indication is approved under accelerated approval based on
overall response rate (ORR) and duration of response (DOR).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial(s).
LUMAKRAS® (sotorasib)
Important U.S. Safety Information
Hepatotoxicity
- LUMAKRAS can cause hepatotoxicity, which may lead to
drug-induced liver injury and hepatitis.
- Among 357 patients who received LUMAKRAS in CodeBreaK 100,
hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A
total of 18% of patients who received LUMAKRAS had increased
alanine aminotransferase (ALT)/increased aspartate aminotransferase
(AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose
interruption or reduction, 5% of patients received corticosteroids
for the treatment of hepatotoxicity.
- Monitor liver function tests (ALT, AST and total bilirubin)
prior to the start of LUMAKRAS every 3 weeks for the first 3 months
of treatment, then once a month or as clinically indicated, with
more frequent testing in patients who develop transaminase and/or
bilirubin elevations.
- Withhold, dose reduce or permanently discontinue LUMAKRAS based
on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis
- LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357
patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis
occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset,
and 1 case was fatal. LUMAKRAS was discontinued due to
ILD/pneumonitis in 0.6% of patients.
- Monitor patients for new or worsening pulmonary symptoms
indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).
Immediately withhold LUMAKRAS in patients with suspected
ILD/pneumonitis and permanently discontinue LUMAKRAS if no other
potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions
- The most common adverse reactions occurring in ≥ 20% were
diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and
cough.
Drug Interactions
- Advise patients to inform their healthcare provider of all
concomitant medications, including prescription medicines,
over-the-counter drugs, vitamins, dietary and herbal products.
- Inform patients to avoid proton pump inhibitors and
H2 receptor antagonists while taking LUMAKRAS.
- If coadministration with an acid-reducing agent cannot be
avoided, inform patients to take LUMAKRAS 4 hours before or 10
hours after a locally acting antacid.
Please see LUMAKRAS full Prescribing Information.
About
Vectibix® (panitumumab)
Vectibix is the first fully human monoclonal anti-EGFR antibody
approved by the FDA for the treatment of mCRC. Vectibix was
approved in the U.S. in September 2006 as a monotherapy for the
treatment of patients with EGFR-expressing mCRC after disease
progression after prior treatment with fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing chemotherapy.
In May 2014, the FDA approved Vectibix for use in combination
with FOLFOX, as first-line treatment in patients with
wild-type KRAS (exon 2) mCRC. With this approval, Vectibix
became the first-and-only biologic therapy indicated for use with
FOLFOX, one of the most commonly used chemotherapy regimens, in the
first-line treatment of mCRC for patients with
wild-type KRAS mCRC.
In June 2017, the FDA approved a refined indication for Vectibix
for use in patients with wild-type RAS (defined as wild-type
in both KRAS and NRAS as determined by
an FDA-approved test for this use) mCRC.
INDICATION AND LIMITATION OF USE
Vectibix® is indicated for the treatment of patients
with wild-type RAS (defined as wild-type in
both KRAS and NRAS as determined by
an FDA-approved test for this use) metastatic colorectal cancer
(mCRC): as first-line therapy in combination with FOLFOX, and as
monotherapy following disease progression after prior treatment
with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing
chemotherapy.
Limitation of Use: Vectibix® is not indicated for the
treatment of patients with RAS mutant mCRC or for
whom RAS mutation status is unknown.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity: Dermatologic toxicities
occurred in 90% of patients and were severe (NCI-CTC grade 3 and
higher) in 15% of patients receiving Vectibix
monotherapy [see Dosage and Administration (2.3),
Warnings and Precautions (5.1), and Adverse Reactions
(6.1)].
- In Study 20020408, dermatologic toxicities occurred in 90% of
patients and were severe (NCI-CTC grade 3 and higher) in 15% of
patients with mCRC receiving Vectibix®. The clinical
manifestations included, but were not limited to, acneiform
dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia,
dry skin, and skin fissures.
- Monitor patients who develop dermatologic or soft tissue
toxicities while on Vectibix® for the development of
inflammatory or infectious sequelae. Life-threatening and fatal
infectious complications including necrotizing fasciitis,
abscesses, and sepsis have been observed in patients treated with
Vectibix®. Life-threatening and fatal bullous
mucocutaneous disease with blisters, erosions, and skin sloughing
has also been observed in patients treated with
Vectibix®. It could not be determined whether these
mucocutaneous adverse reactions were directly related to EGFR
inhibition or to idiosyncratic immune- related effects
(e.g., Stevens Johnson syndrome or toxic epidermal necrolysis).
Withhold or discontinue Vectibix® for dermatologic or
soft tissue toxicity associated with severe or life-threatening
inflammatory or infectious complications. Dose modifications for
Vectibix® concerning dermatologic toxicity are provided
in the product labeling.
- Vectibix® is not indicated for the treatment of
patients with colorectal cancer that harbor
somatic RAS mutations in exon 2 (codons 12 and 13),
exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of
either KRAS or NRAS and hereafter is
referred to as "RAS."
- Retrospective subset analyses across several randomized
clinical trials were conducted to investigate the role
of RAS mutations on the clinical effects of
anti-EGFR-directed monoclonal antibodies (panitumumab or
cetuximab). Anti-EGFR antibodies in patients with tumors
containing RAS mutations resulted in exposing those
patients to anti-EGFR related adverse reactions without clinical
benefit from these agents. Additionally, in Study 20050203, 272
patients with RAS-mutant mCRC tumors received
Vectibix® in combination with FOLFOX and 276 patients
received FOLFOX alone. In an exploratory subgroup
analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45)
in patients with RAS-mutant mCRC who received
Vectibix® and FOLFOX versus FOLFOX alone.
- Progressively decreasing serum magnesium levels leading to
severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study
20080763) of patients across clinical trials. Monitor patients for
hypomagnesemia and hypocalcemia prior to initiating
Vectibix® treatment, periodically during
Vectibix® treatment, and for up to 8 weeks after the
completion of treatment. Other electrolyte disturbances, including
hypokalemia, have also been observed. Replete magnesium and other
electrolytes as appropriate.
- In Study 20020408, 4% of patients experienced infusion
reactions and 1% of patients experienced severe infusion reactions
(NCI-CTC grade 3-4). Infusion reactions, manifesting as fever,
chills, dyspnea, bronchospasm, and hypotension, can occur following
Vectibix® administration. Fatal infusion reactions
occurred in postmarketing experience. Terminate the infusion for
severe infusion reactions.
- Severe diarrhea and dehydration, leading to acute renal failure
and other complications, have been observed in patients treated
with Vectibix® in combination with chemotherapy.
- Fatal and nonfatal cases of interstitial lung disease (ILD)
(1%) and pulmonary fibrosis have been observed in patients treated
with Vectibix®. Pulmonary fibrosis occurred in less than
1% (2/1467) of patients enrolled in clinical studies of
Vectibix®. In the event of acute onset or worsening of
pulmonary symptoms interrupt Vectibix® therapy.
Discontinue Vectibix® therapy if ILD is confirmed.
- In patients with a history of interstitial pneumonitis or
pulmonary fibrosis, or evidence of interstitial pneumonitis or
pulmonary fibrosis, the benefits of therapy with
Vectibix® versus the risk of pulmonary complications
must be carefully considered.
- Exposure to sunlight can exacerbate dermatologic toxicity.
Advise patients to wear sunscreen and hats and limit sun exposure
while receiving Vectibix®.
- Keratitis and ulcerative keratitis, known risk factors for
corneal perforation, have been reported with
Vectibix® use. Monitor for evidence of keratitis or
ulcerative keratitis. Interrupt or discontinue
Vectibix® for acute or worsening keratitis.
- In an interim analysis of an open-label, multicenter,
randomized clinical trial in the first-line setting in patients
with mCRC, the addition of Vectibix® to the combination
of bevacizumab and chemotherapy resulted in decreased OS and
increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse
reactions. NCI-CTC grade 3-4 adverse reactions occurring at a
higher rate in Vectibix®-treated patients included
rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%),
dehydration (16% vs 5%), primarily occurring in patients with
diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs <
1%), and hypomagnesemia (4% vs 0).
- NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate
in Vectibix®-treated patients (7% vs 3%) and included
fatal events in three (< 1%) Vectibix®-treated
patients. As a result of the toxicities experienced, patients
randomized to Vectibix®, bevacizumab, and chemotherapy
received a lower mean relative dose intensity of each
chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or
infusional 5-FU) over the first 24 weeks on study compared with
those randomized to bevacizumab and chemotherapy.
- Vectibix® can cause fetal harm when administered to
a pregnant woman. Advise pregnant women and females of reproductive
potential of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment, and for at least 2 months after the last dose of
Vectibix®.
- In monotherapy, the most commonly reported adverse reactions (≥
20%) in patients with Vectibix® were skin rash with
variable presentations, paronychia, fatigue, nausea, and
diarrhea.
- The most commonly reported adverse reactions (≥ 20%) with
Vectibix® + FOLFOX were diarrhea, stomatitis, mucosal
inflammation, asthenia, paronychia, anorexia, hypomagnesemia,
hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin.
The most common serious adverse reactions (≥ 2% difference between
treatment arms) were diarrhea and dehydration.
To see the Vectibix® Prescribing Information, including
Boxed Warning, visit www.vectibix.com.
About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that
we do. That's why we're relentlessly focused on accelerating the
delivery of medicines that have the potential to empower all angles
of care and transform lives of people with cancer.
For the last four decades, we have been dedicated to discovering
the firsts that matter in oncology and to finding ways to reduce
the burden of cancer. Building on our heritage, Amgen continues to
advance the largest pipeline in the Company's history, moving with
great speed to advance those innovations for the patients who need
them.
For more information, follow us
on www.twitter.com/amgenoncology.
About Amgen
Amgen is committed to unlocking the potential of biology for
patients suffering from serious illnesses by discovering,
developing, manufacturing and delivering innovative human
therapeutics. This approach begins by using tools like advanced
human genetics to unravel the complexities of disease and
understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and
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and is not part of the labeling approved by the U.S. Food and Drug
Administration for the products. The products are not approved for
the investigational use(s) discussed in this news release, and no
conclusions can or should be drawn regarding the safety or
effectiveness of the products for these uses.
CONTACT: Amgen, Thousand
Oaks
Michael Strapazon, 805-313-5553
(media)
Jessica Akopyan, 805-440-5721
(media)
Arvind Sood, 805-447-1060
(investors)
_______________________________
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