FDA Grants Accelerated Approval to Krazati for Colorectal Cancer

The FDA has granted accelerated approval to Krazati (adagrasib) in combination with cetuximab to treat adult patients with KRASG12C -mutated locally advanced or metastatic colorectal cancer (CRC).

Krazati was developed by Mirati Therapeutics, which is now a Bristol Myers Squibb company.

This is the second approved indication for Krazati. The FDA granted accelerated approval for Krazati in December 2022 to treat patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). It launched with wholesale acquisition cost for Krazati is $237,000 per year, or a monthly cost of $19,750 for 200 mg tablet/180 count bottle. Mirati offers a free 30-day trial and a $0 copay program for commercially insured patients

Rona Yaeger, M.D.

“CRC with a KRASG12C mutation occurs in approximately 3% to 4% of CRC patients and has historically been challenging to treat,” Rona Yaeger, M.D., gastrointestinal oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, said in a news release. “The FDA approval of KRAZATI combined with cetuximab now provides a new treatment option to these patients when their tumors do not respond well to prior therapies.”

In 2024, there is expected to be about 152,000 new cases of colorectal cancer and 53,000 deaths, according to the National Cancer Institute. KRAS mutations impact about 30% to 50% of colorectal tumors, and KRASG12C mutations are present in lung and colon cancers.

The approval in colorectal cancer is based on results from cohorts of the phase 1/2 KRYSTAL-1 open-label study, which evaluated Krazati 600 mg tablets administered orally twice daily in combination with cetuximab in 94 patients with heavily pretreated CRC harboring a KRASG12C mutation.

The study met its primary endpoint, with a confirmed objective response rate of 34%, all of which were partial responses. The median duration of response, one of the secondary endpoints, was 5.8 months.

Serious adverse reactions occurred in 30% of 94 patients who received Krazati in combination with cetuximab. The most common adverse reactions (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.

In lung cancer, BMS released data in early June 2024 from the phase 3 KRYSTAL-12 study, which evaluated Krazati compared with standard of care chemotherapy in patients with locally advanced or metastatic KRASG12C -mutated non-small cell lung cancer. These data were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in June 2024.

At a median follow-up of 9.4 months, Krazati demonstrated a statistically significant improvement in progression-free survival (PFS), the study’s primary endpoint compared. Median progression-free survival was 5.5 months for Krazati compared with 3.8 months for docetaxel. Overall response rate (ORR) was also higher with Krazati compared with docetaxel (32% vs 9%). The median duration of response (mDOR) was 8.31 months versus 5.36 months for docetaxel.

Treatment-related adverse events (TRAEs) of any grade were reported in 94% of patients treated with Krazati and 86.4% with docetaxel. Grade ≥3 TRAEs occurred in 47% and 46% of patients, respectively.