Adagrasib and Cetuximab Receive FDA Approval for KRAS G12C-Mutated Colorectal Cancer

On June 21, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc.) combined with cetuximab for advanced or metastatic colorectal cancer (CRC) with a KRAS G12C mutation. The approval applies to adult patients whose KRAS G12C mutation is detected by an FDA-approved test and who have previously received fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.

With this approval, adagrasib became the first KRAS inhibitor approved for colorectal cancer.

Adagrasib had previously received approval for non-small cell lung cancer (NSCLC) with a KRAS G12C mutation through an accelerated approval in December 2022 .

The Importance of KRAS G12C Mutations in Colorectal Cancer

KRAS is among the most frequently mutated  oncogenes  in human cancer. KRAS mutations drive the growth and proliferation of several cancer types through the RAS/MAPK signaling cascade.

The most common KRAS G12 mutations are G12D (36%), G12C (14%) and G12V (23%).

KRAS mutations were once considered untargetable and untreatable. However,  Lumakras, whose active ingredient is sotorasib , proved effective against KRAS G12C -mutated non-small cell lung cancer and received FDA approval. Thus, in May 2021, sotorasib became the first KRAS -targeted cancer treatment approved for use in the United States.

KRAS G12C mutations are rare in advanced colorectal cancer (CRC). The overall rate of KRAS mutations in colorectal cancer is known to be around 40%, but only a small proportion are G12C mutations. KRAS mutations have been identified as G12C in 8-10% of cases. Therefore, in advanced colorectal cancer, KRAS G12C mutation positivity is approximately 3-4% according to estimates.

FDA Approval Based on the KRYSTAL-1 Study

Efficacy was assessed in KRYSTAL-1, a multicenter, single-arm expansion cohort study. It enrolled patients with advanced or metastatic KRAS G12C-mutated CRC who had previously received fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and a VEGF inhibitor when appropriate.

Patients received adagrasib 600 mg twice daily and cetuximab either every two weeks (500 mg/m2 every two weeks) or weekly (an initial 400 mg/m2 followed by 250 mg/m2 weekly).

Tumors were assessed every 6 weeks. Cetuximab had to be discontinued if adagrasib was discontinued, but patients could continue adagrasib even if cetuximab was stopped.

Results

The main efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), assessed by blinded independent central review using RECIST v1.1 criteria.

Among the 94 patients enrolled:

• The overall response rate was 34% (95% CI: 25%, 45%).
• All responses were partial, and median response duration was 5.8 months (95% CI: 4.2, 7.6).
• Among responders, 31% had a response lasting at least 6 months.

Adverse Events and Dosing Information

The most common (occurring in 20% or more) adverse events included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, cough, dizziness, constipation and peripheral neuropathy.

The recommended adagrasib dose is 600 mg orally twice daily until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for cetuximab dosing.