FDA Approves Adagrasib Plus Cetuximab for KRAS G12C–Mutant CRC

The FDA has granted accelerated approval to the combination of adagrasib (Krazati) and cetuximab (Erbitux) for the treatment of adult patients with KRAS G12C–mutant locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.^1,2

Efficacy of the combination was evaluated in the multicenter, single-arm, phase 1/2 KRYSTAL-1 trial (NCT03785249) in which adagrasib plus cetuximab led to a confirmed overall response rate (ORR) of 34% (95% CI, 25%-45%) consisting of all partial responses according to RECIST v1.1 criteria per blinded independent central review (BICR). Additional findings from the trial, which were last presented at the 2024 AACR Annual Meeting with median follow-up of 11.9 months, demonstrated that the disease control rate was 85.1%.^3,4 Median duration of response (DOR) was 5.8 months (95% CI, 4.2-7.6) and 31% of responders experienced a DOR of at least 6 months.¹

A total of 94 patients were enrolled in the phase 1 and 2 cohorts of the trial. Eligible patients were required to have locally advanced or metastatic KRAS G12C–mutated CRC following prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and a VEGF inhibitor, if eligible. Investigators also required patients to have an ECOG performance status of 0 or 1 and no curative-intent treatment or have had refused/were ineligible for standard treatment.

Patients received 600 mg of adagrasib twice daily plus cetuximab which was administered either biweekly at 500 mg/m² every two weeks or weekly first at 400 mg/m² followed by 250 mg/m² weekly. Patients underwent tumor assessments every 6 weeks.

The primary end points were safety and ORR by BICR per RECIST v1.1 criteria, and secondary end points in the phase 1/2 portions were DOR, progression-free survival (PFS), and overall survival (OS), as well as safety in the phase 2 portion alone.

If patients had to discontinue adagrasib, cetuximab was also discontinued. However patients could continue adagrasib if cetuximab was discontinued.

Baseline characteristics of the enrolled population revealed that the median age was 57 years (range, 24-75). The majority of patients were female (53.2%), White (71.3%), not Hispanic or Latino (79.8%), and had an ECOG performance status of 1 (48.9%). Most patients were also heavily pretreated having received a median of 3 prior lines of therapy (range, 1-9).

Additional results from the trial indicated that the median PFS was 6.9 months (95% CI, 5.7-7.4) and the 6-month PFS rate was 57.7%. The median OS was 15.9 months (95% CI, 11.8-18.8) and the 6-month OS rate was 87.8%.

The most frequent adverse effects occurring in at least 20% of patients were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, cough, dizziness, constipation, and peripheral neuropathy.

According to the FDA label the recommended dose of adagrasib is 600 mg orally twice daily until disease progression or unacceptable toxicity.

References

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed June 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer
2. Phase 1/​2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. ClinicalTrials.gov. Updated June 21, 2024. Accessed June 21, 2024. https://clinicaltrials.gov/study/NCT03785249
3. Kopetz S, Uboha NV, Klempner SJ, et al. KRYSTAL-1: pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRASG12C mutation. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT013.
4. Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. Published April 8, 2024. doi:10.1158/2159-8290.CD-24-0217