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...
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Insights
The FDA's priority review of KRAZATI® (adagrasib) in combination with cetuximab for KRAS G12C-mutated colorectal cancer (CRC) represents a significant development in the field of oncology. KRAS mutations are known to be drivers of cancer progression and poor prognosis, particularly in CRC. The KRAS G12C mutation, in particular, has been challenging to target effectively with existing therapies. The combination therapy's advancement to priority review suggests that it could potentially fill an unmet medical need for patients with this specific mutation who have exhausted other treatment options.
Moreover, the safety profile being consistent with individual drug profiles is encouraging, as it suggests a manageable risk for patients. The emphasis on objective response rate and secondary endpoints like progression-free survival and overall survival indicates a comprehensive assessment of the drug's efficacy. If approved, this combination therapy could become a pivotal treatment, potentially improving outcomes for patients with limited options.
From a financial perspective, the FDA's acceptance of the supplemental new drug application (sNDA) for KRAZATI® may have a positive impact on Bristol Myers Squibb's stock performance. The company's focus on developing treatments for hard-to-treat cancers could strengthen its market position and possibly lead to revenue growth if the drug is approved. The priority review designation implies a faster review process, which could accelerate the time to market and thus the potential revenue stream for Bristol Myers Squibb.
Investors should note that the oncology market is highly competitive and the success of this drug will depend on its comparative efficacy and safety, as well as pricing and insurance coverage. Still, given the high unmet need in KRAS G12C-mutated CRC, a successful launch could capture significant market share and support long-term growth for the company.
As a medical research analyst, the KRYSTAL-1 study's results are of particular interest. The study's primary endpoint, the objective response rate, is a direct measure of the drug's effect on tumor size, a critical factor in assessing the drug's clinical significance. The secondary endpoints, including duration of response, progression-free survival and overall survival, are equally important as they provide a more holistic view of the drug's potential impact on patient outcomes.
The fact that the study showed promising clinical activity and a manageable safety profile in a difficult-to-treat population is noteworthy. If the FDA approves this combination therapy, it could set a precedent for future therapies targeting specific genetic mutations in cancer, underscoring the importance of personalized medicine in oncology.
Application based on results from the Phase 1/2 KRYSTAL-1 study
Bristol Myers Squibb (NYSE: BMY) today announced that the
“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
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
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In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in
1.6% , including1.4% grade 3 or 4, gastrointestinal bleeding in0.5% of patients, including0.5% grade 3, and colitis in0.3% , including0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in89% of 366 patients, including9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in29% of patients and permanent discontinuation of KRAZATI in0.3% - 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
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In the pooled safety population,
6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and11% 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
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In the pooled safety population, hepatotoxicity occurred in
37% , and7% were grade 3 or 4. A total of32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate -
aminotransferase (AST);
5% were grade 3 and0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in11% of patients. KRAZATI was discontinued due to increased ALT/AST in0.5% 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
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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 in0.8% 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
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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
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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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FAQ
When is the target action date set by the FDA for KRAZATI in combination with cetuximab?
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What were the findings of the KRYSTAL-1 study regarding KRAZATI in combination with cetuximab?
