FDA Grants Priority Review to Adagrasib Combo in KRAS G12C+ Advanced CRC

Supporting data for the sNDA came from the phase 1/2 KRYSTAL-1 study (NCT03785249) assessing adagrasib in those with advanced KRAS G12C–mutated solid tumors.

A supplemental new drug application (sNDA) for adagrasib (Krazati) in combination with cetuximab (Erbitux) for previously treated patients with KRAS G12C–mutated locally advanced or metastatic colorectal cancer (CRC) has earned priority review from the FDA, according to a press release from Bristol Myers Squibb.¹

The regulatory agency has set a Prescription Drug User Fee Act date of June 21, 2024 for its decision on approving the combination in this indication.

Supporting data for the sNDA came from the phase 1/2 KRYSTAL-1 study (NCT03785249) assessing adagrasib in those with advanced KRAS G12C–mutated solid tumors.

According to previously published data in The New England Journal of Medicine, adagrasib plus cetuximab yielded an objective response rate (ORR) of 46% (95% CI, 28%-66%) in a cohort of 28 evaluable patients with KRAS G12-mutated CRC.² Combination therapy also produced a median duration of response (DOR) of 7.6 months (95% CI, 5.7-not estimable [NE]) and a median time to response of 1.4 months (range, 1.2-19.2). Additionally, the median progression-free survival (PFS) and overall survival (OS) was 6.9 months (95% CI, 5.4-8.1) and 13.4 months (95% CI, 9.5-20.1), respectively.

The most common treatment-related adverse effects (TRAEs) in the adagrasib/cetuximab cohort included nausea (62%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (41%), and dry skin (41%). Investigators concluded that the safety profile of adagrasib plus cetuximab was manageable and comparable with prior reports of each individual agent.

“Pretreated KRAS G12C–mutated CRC is associated with poor outcomes and the current standard of care offers limited clinical benefit for patients,” Anne Kerber, MD, senior vice president and head of late clinical development of Hematology, Oncology, Cell Therapy at Bristol Myers Squibb, said in the press release.¹ “The acceptance of this filing for [adagrasib] 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.”

In the phase 1/2 KRYSTAL-1 trial, patients were assigned to receive oral adagrasib at 600 mg orally twice daily with or without intravenous cetuximab. Cetuximab was administered once weekly at an initial loading dose of 400 mg/m² followed by 250 mg/m² or every 2 weeks at 500 mg/m².

The trial’s primary end point was ORR in the phase 2 portion. Secondary end points included DOR, PFS, OS, and safety.

Patients 18 years and older with histologically confirmed advanced, unresectable, or metastatic CRC harboring a KRAS G12C mutation with no available treatment with curative intent were able to enroll on the trial. Additional eligibility criteria included having an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 guidelines. Those who had active central nervous system metastases, carcinomatous meningitis, and prior systemic or radiotherapy within 2 weeks of study entry were ineligible for enrollment.

The FDA granted breakthrough therapy designation to adagrasib/cetuximab as a treatment for patients with KRAS G12C-mutated CRC in December 2022.³ The designation was supported by findings from the KRYSTAL-1 study.

“With the [breakthrough therapy designation] status, we look forward to working together with the FDA to potentially bring this treatment option to [patients with] late-line KRAS G12C-mutant [CRC] through the accelerated approval pathway,” Alan Sandler, MD, executive vice president and chief medical officer at Mirati Therapeutics, said in a press release at the time of the breakthrough therapy designation.³

References

1. 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... News release. Bristol Myers Squibb. February 20, 2024. Accessed February 21, 2024. http://tinyurl.com/ybhkrph4
2. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419
3. Mirati announces adagrasib (KRAZATI) receives breakthrough therapy designation from FDA for patients with advanced, KRAS-mutated colorectal cancer and NEJM publishes phase 1b/2 data from adagrasib with or without cetuximab in colorectal cancer. News release. Mirati Therapeutics, Inc. December 21, 2022. Accessed February 21, 2024. https://prn.to/42OP7X1