FDA Approves Adagrasib for KRAS G12C-Mutated Metastatic Colorectal Cancer

FDA Approves Adagrasib for KRAS G12C-Mutated Metastatic Colorectal Cancer

The FDA has granted accelerated approval to adagrasib (Krazati) with cetuximab (Erbitux) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) previously treated with oxaliplatin-, fluoropyrimidine-, and irinotecan-based chemotherapy.¹

Of note, a patients’ KRAS G12C status would be determined by an FDA-approved test, according to a statement from the agency.

The accelerated approval was based on findings from the KRYSTAL-1 trial. In this multicenter, single-arm expansion cohort trial, patients had locally advanced or metastatic KRAS G12C-mutated CRC previously treated with oxaliplatin-, fluoropyrimidine-, and irinotecan-based chemotherapy and, if eligible, a VEGF inhibitor. In the trial, 94 patients were treated with 600 mg of adagrasib twice per day plus cetuximab administered either weekly (at an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly) or biweekly (500 mg/m2 every 2 weeks).

In the trial, researchers performed tumor assessments every 6 weeks. Patients who discontinued treatment with adagrasib also needed to discontinue treatment with cetuximab, although patients could continue treatment with adagrasib is cetuximab was stopped.

The major efficacy outcome measures for the trial were confirmed overall response rate (ORR) and duration of response (DOR) assessed by blinded independent central review per RECIST v1.1.

The ORR for patients in the KRYSTAL-1 trial was 34% (95% CI, 25%-45%), with all responses considered to be partial responses. The median DOR was 5.8 months (95% CI, 4.2-7.6). Nearly a third of patients (31%) experienced a DOR of at least 6 months.

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

According to the FDA’s notice, the recommended dose of adagrasib is 600 mg given orally twice per day until unacceptable toxicity or disease progression.

Adagrasib, an inhibitor of the RAS GTPase family, was originally approved by the FDA in December 2022 for the treatment of KRAS G12C-mutated non-small cell lung cancer.²

The therapy comes in 200-mg tablet form to be swallowed whole with or without food. Although there are no contraindications, there are several warnings and precautions, according to the drug’s prescribing information. These include gastrointestinal adverse reactions, QTc interval prolongation, hepatotoxicity, and interstitial lung disease/pneumonitis, for which monitoring is suggested for all of these.

There may be some drug interactions with adagrasib including strong CYP3A4 inducers, inhibitors, and substrates, in addition to drugs that prolong QT interval. It is suggested that these drugs should not be used concomitantly with adagrasib.

References

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News release. 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. Adagrasib. Mirati Therapeutics. June 2024. Accessed June 21, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216340s005lbl.pdf