FDA Approves Sotorasib Plus Panitumumab for KRAS G12C-Mutated Colorectal Cancer

On 16 January 2025, the US Food and Drug Administration (FDA) approved treatment for KRAS G12C-mutated metastatic colorectal cancer (mCRC) in adults who had previously received fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, using sotorasib (Lumakras, Amgen Inc.) with panitumumab (Vectibix, Amgen Inc.) as a combination.

The FDA also approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH), a companion diagnostic device to help identify patients with KRAS G12C-mutated colorectal cancer who may be eligible for treatment with Lumakras and Vectibix.

For KRAS G12C-mutated colorectal cancer, this development represents the second FDA approval. 

RELATED TOPICS

• For KRAS G12C-mutated lung cancer, sotorasib previously received FDA approval in May 2021 . The new approval is the second FDA approval for this drug.
• On 21 June 2024, the FDAgranted accelerated approval to the combination of adagrasib (Krazati; Mirati Therapeutics, Inc.) and cetuximab for KRAS G12C-mutated colorectal cancer. 

FDA Approval Based on the CodeBreaK 300 Trial

Efficacy and Safety: Efficacy was evaluated in CodeBreaK 300, a randomized, open-label, controlled trial in patients with KRAS G12C-mutated mCRC who had previously received fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.

Mutations were prospectively identified in tumor tissue samples using the QIAGEN therascreen KRAS RGQ PCR kit.

A total of 160 patients were randomized (1:1:1) to sotorasib 960 mg orally once daily with panitumumab 6 mg/kg IV every 2 weeks, or investigator's choice of standard care with trifluridine/tipiracil or regorafenib.

Results

The primary efficacy outcome measure was progression-free survival (PFS) . Other efficacy outcome measures included overall survival, overall response rate and duration of response.

The trial was not statistically powered for overall survival.

• Median PFS was 5.6 months (95% CI: 4.2, 6.3) in the sotorasib 960 mg/panitumumab arm and 2 months (95% CI: 1.9, 3.9) in the standard-treatment arm (hazard ratio 0.48 [95% CI: 0.3, 0.78]; two-sided p-value 0.005).
• The final analysis of overall survival was not statistically significant.
• The objective response rate was 26% (95% CI: 15, 40) in the sotorasib 960 mg/panitumumab arm and 0% (95% CI: 0, 7) in the standard-treatment arm.
• Median duration of response was 4.4 months in the sotorasib 960 mg/panitumumab arm (range: 1.9+, 6+).
• The final PFS analysis comparing the sotorasib 240 mg/panitumumab arm with the standard-treatment arm was not statistically significant.

Side Effects

The most common adverse reactions to sotorasib 960 mg/panitumumab, occurring in 20% or more of patients, were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain.

The most common grade 3-4 laboratory abnormalities included decreased magnesium, decreased potassium, decreased corrected calcium and increased potassium.

Dosage

The recommended sotorasib dose is 960 mg orally once daily. The recommended panitumumab dose is 6 mg/kg by IV infusion every 14 days until disease progression, unacceptable toxicity, or sotorasib is withheld or discontinued. Administer the first sotorasib dose before the first panitumumab infusion.