Today, Bristol Myers Squibb announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for KRAZATI® (adagrasib) in combination with cetuximab. This targeted treatment is for adult patients with KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC), as identified by an FDA-approved test, who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval is based on objective response rate (ORR) and duration of response (DOR) results, with continued approval contingent upon confirmatory trials demonstrating clinical benefit.
“Approximately 3-4% of CRC patients have the KRASG12C mutation, which has been difficult to treat,” said Dr. Rona Yaeger, a gastrointestinal oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center. “The FDA’s approval of KRAZATI with cetuximab offers a new treatment option for these patients when their tumors do not respond well to previous therapies.”
The approval is based on results from the Phase 1/2 KRYSTAL-1 open-label study, which evaluated KRAZATI (600 mg tablets taken orally twice daily) with cetuximab in 94 heavily pretreated CRC patients with the KRASG12C mutation. The study met its primary endpoint, with a confirmed ORR of 34%, all of which were partial responses. The median DOR was 5.8 months. Current late-line standard care options show limited response rates (ORR 1-6%) after progression on chemotherapy with or without VEGF/VEGFR inhibitors.
KRAZATI carries warnings and precautions for gastrointestinal adverse reactions (including diarrhea, nausea, and vomiting), QTc interval prolongation, hepatotoxicity, and interstitial lung disease (ILD)/pneumonitis.
“This approval of KRAZATI for CRC is a significant milestone for Bristol Myers Squibb and the patients we serve, as it demonstrates our commitment to providing innovative cancer treatments,” said Wendy Short Bartie, senior vice president of U.S. Oncology and Hematology at Bristol Myers Squibb. “We are proud to offer KRAZATI, the first KRASG12C inhibitor approved beyond non-small cell lung cancer, to CRC patients and look forward to further evaluations in our ongoing development program.”
In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab for patients with KRASG12C-mutated advanced CRC that progressed after prior chemotherapy and anti-VEGF therapy.
KRAZATI is an irreversible KRASG12C inhibitor with a long half-life (23 hours), dose-dependent pharmacokinetics (PK), and central nervous system (CNS) penetration. When combined with cetuximab, it may enhance inhibition of KRAS-dependent signaling or overcome adaptive feedback.
The company partnered with QIAGEN to develop a tissue-based companion diagnostic (CDx) for KRAZATI, which is now available.
KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company.
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 colorectal cancer (CRC) harboring a KRASG12C mutation. The primary endpoint for the Phase 2 cohort was the objective response rate (ORR), with secondary endpoints including duration of response (DOR). The study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company.
Select Safety Profile from KRYSTAL-1
The safety profile of KRAZATI plus cetuximab was evaluated in patients with KRASG12C-mutated, locally advanced or metastatic CRC and aligns with known safety profiles of each drug individually. Serious adverse reactions occurred in 30% of 94 patients receiving the combination. Common adverse reactions (≥20%) included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.
