KRAZATI (adagrasib) in Combination with Cetuximab Demonstrates Clinically Meaningful Activity as a Targeted Treatment Option for Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer (CRC)
Late-breaking data to be featured in an oral presentation at the
These late breaking data (abstract #CT013) will be featured in an oral presentation at the 2024
With a median follow up of 11.9 months in 94 patients, KRAZATI plus cetuximab demonstrated an objective response rate, the primary endpoint, of 34%, median progression-free survival of 6.9 months (95% CI, 5.7-7.4), and median overall survival of 15.9 months (95% CI, 11.8-18.8) in pre-treated patients with KRASG12C-mutated locally advanced or metastatic CRC. The median duration of response was 5.8 months. Disease control was observed in 85% of patients. The safety profile for KRAZATI plus cetuximab was manageable and consistent with previous reports, and with the known safety profile of each drug individually.
KRASG12C mutations act as oncogenic drivers and occur in approximately 3-4% of colorectal cancers. In previous studies, treatment with cetuximab as a single agent did not offer a clinical benefit in patients with KRAS-mutated colorectal cancer.
“Patients with KRASG12C-mutated colorectal cancer have historically faced poor prognoses and remain in need of additional treatment options,” said
“While there has been progress in the treatment of colorectal cancer, there remain groups of patients, such as those with KRAS-mutated cancers, who continue to need new, targeted treatment options,” said
The company announced in
This study was funded by Mirati Therapeutics, Inc., a
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 cancers, 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
KRAZATIcontinues 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 https://mirati.com/KRAZATI_USPI/.
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 (e.g., 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
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.
Cancer can have a relentless grasp on many parts of a patient’s life, and
About
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 future study results may not be consistent with the results to date, and that KRAZATI (adagrasib) in combination with cetuximab may not achieve its primary study endpoint or
KRAZATI (adagrasib) in combination with cetuximabmay not achieve its primary study endpoint or receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and,if approved, whethersuch combination treatment for such additional indication described in this releasewill be commercially successful. No forward-looking statement can be guaranteed. 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
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