The U.S. Food and Drug Administration (FDA) has granted approval to Amgen's Lumakras (sotorasib) in combination with Vectibix (panitumumab) for the treatment of adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC) who have previously undergone fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This approval marks a significant advancement in targeted therapy for a subset of mCRC patients with limited treatment options. The decision is based on the pivotal Phase 3 CodeBreaK 300 study, which demonstrated a superior progression-free survival (PFS) compared to standard-of-care (SOC).
CodeBreaK 300 Trial Results
The CodeBreaK 300 clinical trial compared Lumakras, at doses of 960 mg daily, in combination with Vectibix to the investigator's choice of SOC (trifluridine and tipiracil or regorafenib) in patients with chemorefractory KRAS G12C-mutated mCRC. The results indicated a significant improvement in median PFS for patients treated with the Lumakras and Vectibix combination, with 5.6 months (4.2, 6.3) compared to 2 months (1.9, 3.9) on investigator's choice of care, with a hazard ratio (HR) of 0.48 (95% Confidence Interval [CI]: 0.3, 0.78) and a p-value of 0.005. The study also demonstrated an improved overall response rate (ORR) of 26% (95% CI: 15, 40) compared to 0% with investigator's choice (95% CI: 0, 7). While the study was not statistically powered for overall survival (OS), the data trended in favor of the combination therapy.
Clinical Significance
"Colorectal cancer is the third leading cause of cancer-related deaths in the United States, and fewer than one in five people diagnosed with metastatic disease survive beyond five years after diagnosis," said Jay Bradner, M.D., executive vice president of Research and Development at Amgen. He added, "Lumakras plus Vectibix offers a targeted, biomarker-driven combination therapy that helps delay disease progression more effectively than the investigated standard of care. This new option validates our combination approach to improve outcomes for patients living with advanced KRAS G12C-mutated metastatic colorectal cancer."
Marwan G. Fakih, M.D., primary study investigator and co-director of the Gastrointestinal Cancer Program, City of Hope, emphasized the importance of this new treatment option, stating, "Designed for dual blockade of KRAS G12C and EGFR pathways, the combination of sotorasib plus panitumumab provides a needed new treatment option to better overcome cancer's escape mechanisms. The CodeBreaK 300 study showed superior progression-free survival compared to the investigated standard of care and represents a clinically meaningful benefit for patients with KRAS G12C-mutated metastatic colorectal cancer."
Dosage and Administration
The recommended dose of Lumakras is 960 mg daily, administered orally. Vectibix is administered intravenously at a dose of 6 mg/kg every two weeks. Treatment continues until disease progression or unacceptable toxicity.
Adverse Reactions
The most common adverse reactions observed in the clinical trial (=20%) were rash (87%), dry skin (28%), diarrhea (28%), stomatitis (26%), fatigue (21%), and musculoskeletal pain (21%).
KRAS G12C Mutation in mCRC
The KRAS G12C mutation is present in approximately 3-5% of colorectal cancers, as determined by an FDA-approved biomarker test. This highlights the critical role of comprehensive biomarker testing in mCRC to identify eligible patients for targeted therapies. Michael Sapienza, chief executive officer of the Colorectal Cancer Alliance, noted, "This new combination approach is an important breakthrough for patients with KRAS G12C-mutated metastatic colorectal cancer, offering a new beneficial treatment option for patients living with this devastating and challenging disease."
