U.S. FDA has assigned a target action date
of June 21, 2024
Application based on results from the Phase
1/2 KRYSTAL-1 study
U.S. Food and Drug Administration (FDA)
Accepts Supplemental New Drug Application for KRAZATI® (adagrasib)
in Combination with Cetuximab as a Targeted Treatment Option for
Patients with Previously Treated KRAS G12C-Mutated Locally Advanced
or Metastatic Colorectal Cancer (CRC) for Priority Review
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S.
Food and Drug Administration (FDA) has accepted for priority review
the supplemental new drug application (sNDA) for KRAZATI®
(adagrasib) in combination with cetuximab for the treatment of
patients with previously treated KRASG12C-mutated locally advanced
or metastatic colorectal cancer (CRC). The FDA assigned a
Prescription Drug User Fee Act (PDUFA) goal date of June 21,
2024.
“Pretreated KRASG12C-mutated CRC is associated with poor
outcomes and the current standard of care offers limited clinical
benefit for patients,” said Anne Kerber, senior vice president,
head of late clinical development, Hematology, Oncology, Cell
Therapy (HOCT) at Bristol Myers Squibb. “The acceptance of this
filing for KRAZATI in combination with cetuximab is a positive step
toward providing a potential new option for patients and their
physicians. It reinforces our commitment to developing potentially
transformative targeted cancer therapies for patients for whom few
treatment options exist.”
The submission is based on the results of KRYSTAL-1 study, a
multicohort trial which evaluated KRAZATI alone or in combination
with other anticancer therapies in patients with advanced solid
tumors harboring a KRASG12C mutation. The primary endpoint for the
registrational cohort was objective response rate. The secondary
endpoints for the pooled cohorts included duration of response,
progression-free survival, overall survival and safety.
Results of the KRYSTAL-1 study showed that KRAZATI was well
tolerated and provided promising clinical activity in pretreated
patients with locally advanced or metastatic CRC harboring a
KRASG12C mutation. The safety profile for KRAZATI plus cetuximab
was manageable and consistent with previous reports, and with the
known safety profile of each drug individually.
ABOUT KRAZATI®
(adagrasib)
KRAZATI (adagrasib) is highly selective and potent oral
small-molecule inhibitor of KRASG12C that is optimized to sustain
target inhibition, an attribute that could be important to treat
KRASG12C-mutated cancers, as the KRASG12C protein regenerates every
24-48 hours. KRASG12C mutations act as oncogenic drivers and occur
in approximately 14% of NSCLC (adenocarcinoma), 3-4% of colorectal
cancer, and 1-2% of several other cancers.
In 2022, KRAZATI was granted accelerated approval for treatment
of adult patients with KRASG12C-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 objective response rate (ORR) and duration of response
(DOR). Continued approval for this indication may be contingent
upon verification and description of a clinical benefit in a
confirmatory trial(s).
In 2024, the European Commission (EC) granted conditional
marketing authorization for KRAZATI as a targeted treatment option
for adult patients with KRASG12C-mutated advanced NSCLC and disease
progression after at least one prior systemic therapy.
KRAZATI continues to be evaluated as monotherapy and in
combination with other anti-cancer therapies in patients with
advanced KRASG12C-mutated solid tumors, including NSCLC and
colorectal cancer.
In 2022, the FDA granted breakthrough therapy designation for
KRAZATI in combination with cetuximab in patients with
KRASG12C-mutated advanced colorectal cancer (CRC) whose cancer has
progressed following prior treatment with chemotherapy and an
anti-VEGF therapy.
For Prescribing Information, visit KRAZATI.
ABOUT KRYSTAL-1
KRYSTAL-1 is an open-label, multicenter, multiple expansion
cohort Phase 1/2 trial to determine the safety and efficacy of
KRAZATI in patients with advanced solid tumors that harbor a
KRASG12C mutation. The primary endpoint for the Phase 2 cohort of
the KRYSTAL-1 study was objective response rate. Secondary
endpoints included duration of response, progression-free survival,
overall survival and safety.
INDICATION
KRAZATI is indicated for the treatment of adult patients with
KRASG12C-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
objective response rate (ORR) and duration of response (DOR).
Continued approval for this indication may be contingent upon
verification and description of a clinical benefit in a
confirmatory trial(s).
IMPORTANT SAFETY
INFORMATION
GASTROINTESTINAL ADVERSE REACTIONS
- In the pooled safety population, serious gastrointestinal
adverse reactions observed were gastrointestinal obstruction in
1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in
0.5% of patients, including 0.5% grade 3, and colitis in 0.3%,
including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting
occurred in 89% of 366 patients, including 9% grade 3. Nausea,
diarrhea, or vomiting led to dosage interruption or dose reduction
in 29% of patients and permanent discontinuation of KRAZATI in
0.3%
- Monitor and manage patients using supportive care, including
antidiarrheals, antiemetics, or fluid replacement, as indicated.
Withhold, reduce the dose, or permanently discontinue KRAZATI based
on severity
QTC INTERVAL PROLONGATION
- KRAZATI can cause QTc interval prolongation, which can increase
the risk for ventricular tachyarrhythmias (eg, torsades de pointes)
or sudden death
- In the pooled safety population, 6% of 366 patients with at
least one post-baseline electrocardiogram (ECG) assessment had an
average QTc ≥501 ms, and 11% of patients had an increase from
baseline of QTc >60 msec. KRAZATI causes concentration-dependent
increases in the QTc interval
- Avoid concomitant use of KRAZATI with other products with a
known potential to prolong the QTc interval. Avoid use of KRAZATI
in patients with congenital long QT syndrome and in patients with
concurrent QTc prolongation
- Monitor ECGs and electrolytes prior to starting KRAZATI, during
concomitant use, and as clinically indicated in patients with
congestive heart failure, bradyarrhythmias, electrolyte
abnormalities, and in patients who are taking medications that are
known to prolong the QT interval. Withhold, reduce the dose, or
permanently discontinue KRAZATI, depending on severity
HEPATOTOXICITY
- KRAZATI can cause hepatotoxicity
- In the pooled safety population, hepatotoxicity occurred in
37%, and 7% were grade 3 or 4. A total of 32% of patients who
received KRAZATI had increased alanine aminotransferase
(ALT)/increased aspartate
- aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4.
Increased ALT/AST leading to dose interruption or reduction
occurred in 11% of patients. KRAZATI was discontinued due to
increased ALT/AST in 0.5% of patients
- Monitor liver laboratory tests (AST, ALT, alkaline phosphatase,
and total bilirubin) prior to the start of KRAZATI, and monthly for
3 months or as clinically indicated, with more frequent testing in
patients who develop transaminase elevations. Reduce the dose,
withhold, or permanently discontinue KRAZATI based on severity
INTERSTITIAL LUNG DISEASE /PNEUMONITIS
- KRAZATI can cause interstitial lung disease (ILD)/pneumonitis,
which can be fatal. In the pooled safety population,
ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or
4, and 1 case was fatal. The median time to first onset for
ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was
discontinued due to ILD/pneumonitis in 0.8% of patients
- Monitor patients for new or worsening respiratory symptoms
indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold
KRAZATI in patients with suspected ILD/pneumonitis and permanently
discontinue KRAZATI if no other potential causes of ILD/pneumonitis
are identified
ADVERSE REACTIONS
- The most common adverse reactions (≥25%) are nausea, diarrhea,
vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal
impairment, edema, dyspnea, decreased appetite
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL
- Infertility: Based on findings from animal studies, KRAZATI may
impair fertility in females and males of reproductive
potential
Please see U.S. Full Prescribing Information for
KRAZATI.
About Colorectal Cancer
Colorectal cancer (CRC) is cancer that develops in the colon or
the rectum, which are part of the body’s digestive or
gastrointestinal system. CRC is the third most commonly diagnosed
cancer in the world. In 2020, it is estimated that there were
approximately 1,931,000 new cases of the disease; it is the second
leading cause of cancer-related deaths among men and women
combined.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming patients’ lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine
and, through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep understanding of causal
human biology, cutting-edge capabilities and differentiated
research platforms uniquely position the company to approach cancer
from every angle.
Cancer can have a relentless grasp on many parts of a patient’s
life, and Bristol Myers Squibb is committed to taking actions to
address all aspects of care, from diagnosis to survivorship. As a
leader in cancer care, Bristol Myers Squibb is working to empower
all people with cancer to have a better future.
About Bristol Myers
Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube, Facebook and
Instagram.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on current expectations and projections about our future
financial results, goals, plans and objectives and involve inherent
risks, assumptions and uncertainties, including internal or
external factors that could delay, divert or change any of them in
the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
that Krazati (adagrasib) in combination with cetuximab may not
receive regulatory approval for the additional indication described
in this release in the currently anticipated timeline or at all,
that any marketing approvals, if granted, may have significant
limitations on their use, and, if approved, whether such
combination treatment for such additional indication described in
this release will be commercially successful. No forward-looking
statement can be guaranteed. It should be noted that acceptance of
the application does not change the standards for FDA approval.
Forward-looking statements in this press release should be
evaluated together with the many risks and uncertainties that
affect Bristol Myers Squibb’s business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for
the year ended December 31, 2023, as updated by our subsequent
Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and
other filings with the Securities and Exchange Commission. The
forward-looking statements included in this document are made only
as of the date of this document and except as otherwise required by
applicable law, Bristol Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
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