FDA to Review Adagrasib/Cetuximab Combo in KRAS G12C-Mutated CRC

• The FDA has accepted a supplemental new drug application (sNDA) for priority review regarding the combination of adagrasib (Krazati) with cetuximab (Erbitux) for treating previously treated locally advanced or metastatic colorectal cancer (CRC) with a KRAS G12C mutation.

• Findings from the KRYSTAL-1 study (NCT03785249) supported this application, demonstrating encouraging clinical activity and manageable safety profiles for adagrasib and cetuximab in patients with metastatic CRC harboring a KRAS G12C mutation.

• The Prescription Drug User Fee Act (PDUFA) goal date for this review is June 21, 2024.

The FDA has accepted for priority review the supplemental new drug application (sNDA) for the combination of adagrasib with cetuximab for the treatment of patients with previously treated locally advanced or metastatic CRC harboring a KRAS G12C mutation.¹

The submission is supported by findings of the KRYSTAL-1 study which showed that adagrasib was well-tolerated and induced encouraging clinical activity among patients with metastatic CRC with a KRAS G12C mutation. The combination of adagrasib and cetuximab also had a manageable safety profile which was consistent with previous reports, as well as with the known safety profile of each drug individually.

The FDA assigned a PDUFA goal date of June 21, 2024.

“Pretreated KRAS G12C-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 at Bristol Myers Squibb, 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.”

Colorectal Cancer: © peterschreiber.media - stock.adobe.com

Adagrasib, a highly selective and potent oral small-molecule inhibitor of KRAS G12C, was created to sustain target inhibition. The agent was granted accelerated approval by the FDA for treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least 1 prior systemic therapy in 2022. While the agent was approved based on objective response rate (ORR) and duration of response (DOR) data, continued approval for this indication may depend on confirming a clinical benefit in 1 or more confirmatory trials.

Recently in 2024, the European Commission granted conditional marketing authorization for adagrasib for the treatment of adult patients with advanced NSCLC harboring a KRAS G12C-mutation and who had disease progression after at least 1 prior systemic therapy. The combination of adagrasib and cetuximab was also granted a breakthrough therapy designation by the FDA in 2022 for patients with KRAS G12C-mutated advanced CRC whose cancer progressed following prior treatment with chemotherapy and an anti-VEGF therapy, based on findings from the open-label, multicenter, multiple expansion cohort, phase 1/2 KRYSTAL-1 trial.

KRYSTAL-1 aims to evaluate the safety and efficacy of adagrasib for the treatment of patients with advanced solid tumors that harbor a KRAS G12C mutation. Adagrasib was assessed alone and in combination with other anticancer therapies. The primary end point for the phase 2 cohort of the trial was ORR. Secondary end points included DOR, progression-free survival (PFS), overall survival, and safety.

Enrollment in the trial was open to patients with histologically confirmed, unresectable/metastatic disease who had adequate organ function and were not eligible for or declined on standard therapy. Patients with a history of intestinal disease or major gastric surgery, inability to swallow oral medications, or another active cancer are excluded from the study.

Results were published in the New England Journal of Medicine,^2,3 showing that treatment with adagrasib given with or without cetuximab led to antitumor activity in the heavily pretreated study population. Among the 28 evaluable patients, the ORR was 46% (95% CI, 28%-66%) with a median 7.6-month DOR (95% CI, 5.7 to not estimable). The median PFS with adagrasib was 6.9 months (95% CI, 5.4-8.1).

For safety, there were no synergistic adverse effects seen with the combination of adagrasib and cetuximab. Among those given adagrasib alone, grade 3 or 4 treatment-related adverse events (TRAEs) were seen in 34% of patients vs 16% of patients who received adagrasib plus cetuximab. Moreover, no grade 5 TRAEs were seen.

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 20, 2024. http://tinyurl.com/2swbd3ry

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. Published December 21, 2022. doi: 10.1056/NEJMoa2212419

3. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. ClinicalTrials.gov. Updated December 7, 2024. Accessed February 20, 2024. https://clinicaltrials.gov/study/NCT03785249