FDA Grants Priority Review to Adagrasib/Cetuximab Combination Therapy in KRAS G12C–Mutant CRC

FDA

The FDA has accepted a supplemental new drug application (sNDA) for priority review seeking the approval of adagrasib (Krazati) in combination with cetuximab (Erbitux) for patients with previously treated, locally advanced or metastatic KRAS G12C–mutated colorectal cancer (CRC).¹

The sNDA was supported by data from the multicohort phase 1b/2 KRYSTAL-1 study (NCT03785249), in which treatment with adagrasib alone or in combination with other anticancer agents led to clinically meaningful activity and had a tolerable toxicity profile for patients with KRAS G12C–mutant advanced solid tumors.^1,2 In the CRC cohort of the trial, adagrasib alone or in combination with cetuximab generated encouraging responses within this patient population.³

At a median follow-up of 17.5 months, a total of 28 patients experienced an objective response rate (ORR) of 46% (95% CI, 28%-66%) with the combination. All responses were partial; the remaining 54% of patients had stable disease. The median duration of response was 7.6 months (95% CI, 5.7-not estimable).³

Notably, the FDA has assigned the sNDA for the combination therapy a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.¹

“Pretreated KRAS G12C–mutated CRC is associated with poor outcomes and the current standard of care offers limited clinical benefit for patients,” Anne Kerber, senior vice president and head of late clinical development for Hematology, Oncology, Cell Therapy at Bristol Myers Squibb, stated in a press release. “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.”

Adagrasib is a potent and highly selective oral small molecule inhibitor of KRAS G12C that is optimized for sustained target inhibition. KRAS G12C mutations are oncogenic drivers, occurring in approximately 14% of patients with non–small cell lung cancer (NSCLC), between 3% and 4% of those with CRC, and between 1% and 2% of those with other cancers. In December 2022, adagrasib received accelerated approval from the FDA for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic NSCLC based on findings from KRYSTAL-1.¹

Results from KRYSTAL-1 also supported the FDA breakthrough therapy designation in December 2022 for the combination therapy in patients with KRAS G12C–mutated advanced CRC following prior treatment with chemotherapy and anti-VEGF therapy.^1,4

The open-label, nonrandomized trial enrolled adult patients over the age of 18 with a histologically confirmed diagnosis of advanced, unresectable, or metastatic CRC with a KRAS G12C mutation. Furthermore, patients had to have no other available treatment options; an ECOG performance score 0 or 1; and measurable disease. Exclusion criteria included active central nervous system metastases; carcinomatous meningitis; and systemic or radiation therapy within 2 weeks prior to the initiation of adagrasib treatment.³

In the pilot phase 1b cohort, patients received a combination of oral adagrasib at 600 mg twice daily and intravenous cetuximab. Cetuximab was administered with an initial loading dose of 400 mg/m2 of body-surface area, followed by a dose of 250 mg/m2 once a week or every 2 weeks at a dose of 500 mg/m2.³

The primary end point for the phase 1b combination cohort was safety; secondary end points included tumor-response outcomes.^1,3

The median time to response with the combination was 1.4 months (range, 1.2-19.2) and among all patients in the CRC cohort (n = 32), the median progression-free survival was 6.9 months (95% CI, 5.4-8.1). Notably, the median overall survival was 13.4 months (95% CI, 9.5-20.1).³

Regarding safety, treatment-related adverse effects (TRAEs) of any grade occurred in 100% of patients. TRAEs that occurred in at least 20% of patients included nausea (62%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), dry skin (41%), headache (31%), dizziness (25%), maculopapular rash (25%), and stomatitis (22%).³ Sixteen percent of patients had grade 3 or 4 TRAEs.

Notably, eleven patients had their dose of either adagrasib (n = 10; 31%) or cetuximab (n = 1; 3%) reduced due to TRAEs. Discontinuation of treatment with cetuximab was seen in 5 patients due to infusion-related reactions (n = 3), malaise (n = 1), and vascular flushing (n = 1).

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 metastatic colorectal cancer (CRC) for priority review. News release. Bristol Meyers Squibb. February 20, 2024. Accessed February 20, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option
2. Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
3. 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
4. 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. December 21, 2022. Accessed February 20, 2024. https://www.prnewswire.com/news-releases/mirati-announces-adagrasib-krazati-receives-breakthrough-therapy-designation-from-fda-for-patients-with-advanced-kras-mutated-colorectal-cancer