Pharma Focus Asia

Bristol Myers Squibb Announces FDA Accelerated Approval of KRAZATI® (adagrasib) Combined with Cetuximab for KRAS G12C-Mutated Colorectal Cancer

Saturday, June 22, 2024

Bristol Myers Squibb (NYSE: BMY) has received accelerated approval from the U.S. Food and Drug Administration (FDA) for KRAZATI® (adagrasib) in combination with cetuximab. This new treatment targets adult patients with locally advanced or metastatic colorectal cancer (CRC) who have the KRASG12C mutation and have previously undergone fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval is based on objective response rate (ORR) and duration of response (DOR) data, with continued approval contingent on confirmatory trials.

“KRASG12C mutations are found in approximately 3-4% of colorectal cancer cases and have proven difficult to treat,” said Dr. Rona Yaeger, Gastrointestinal Oncologist & Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. “The combination of KRAZATI and cetuximab offers a new option for patients who do not respond well to prior therapies.”

This approval stems from the Phase 1/2 KRYSTAL-1 study, which included 94 CRC patients with KRASG12C mutations who had undergone extensive prior treatment. The study reported a confirmed ORR of 34% (95% CI: 25-45), all of which were partial responses, and a median DOR of 5.8 months (95% CI: 4.2-7.6). Current treatment options for late-stage patients show limited response rates of 1-6% after progression on chemotherapy with or without VEGF/VEGFR inhibitors.

Warnings and precautions associated with KRAZATI include gastrointestinal adverse reactions, QTc interval prolongation, hepatotoxicity, and interstitial lung disease/pneumonitis. Serious adverse reactions occurred in 30% of patients, with common reactions including rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, and others.

“Today’s approval is a significant milestone for Bristol Myers Squibb and reflects our commitment to providing innovative cancer treatments,” said Wendy Short Bartie, Senior Vice President, U.S. Oncology and Hematology at Bristol Myers Squibb. “We are proud to offer KRAZATI to CRC patients and look forward to further research through our ongoing development program.”

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab for KRASG12C-mutated advanced CRC patients whose cancer had progressed following certain chemotherapy and anti-VEGF therapy.

KRAZATI is an irreversible KRASG12C inhibitor with a long half-life (23 hours) and dose-dependent pharmacokinetics. It can penetrate the central nervous system, and when combined with cetuximab, may improve inhibition of KRAS-dependent signaling or overcome adaptive feedback. The company collaborated with QIAGEN to develop a companion diagnostic test for KRAZATI, which is now available.

KRYSTAL-1 is a Phase 1/2 open-label, multicenter trial evaluating the safety and efficacy of KRAZATI in advanced CRC patients with KRASG12C mutations. The primary endpoint was ORR, with secondary endpoints including DOR. The study was funded by Mirati Therapeutics, Inc., now part of Bristol Myers Squibb.

Colorectal cancer (CRC) affects the colon or rectum, part of the digestive system. It is the third most commonly diagnosed cancer globally, with an estimated 106,590 new cases expected in the U.S. in 2024. CRC is the second leading cause of cancer-related deaths in the U.S. KRAS mutations occur in up to 50% of CRC cases, with KRASG12C mutations in approximately 3-4%.

KRAZATI is a potent oral small-molecule inhibitor of KRASG12C, designed to maintain target inhibition. KRASG12C mutations are key oncogenic drivers in 14% of non-small cell lung cancer (NSCLC) cases and 3% of other cancers. In 2022, KRAZATI received accelerated approval for KRASG12C-mutated locally advanced or metastatic NSCLC patients who had undergone prior systemic therapy, with continued approval contingent on further trials.

Bristol Myers Squibb is dedicated to transforming patients’ lives through innovative cancer treatments. Their research focuses on personalized medicine, leveraging digital platforms and a deep understanding of biology to enhance patient outcomes from diagnosis to survivorship. The company is committed to providing better futures for cancer patients.



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