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

FDA

The FDA approved sotorasib (Lumakras) with panitumumab (Vectibix) for the treatment of adult patients with KRAS G12C–mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.¹

The agency also gave the green light to therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) for use as a companion diagnostic device to assist in the identification of patients with CRC whose tumors harbor KRAS G12C mutations and who may be candidates to receive the doublet.

The decision was supported by data from the phase 3 CodeBreaK 300 study (NCT05198934).^2,3 Sotorasib given at a daily dose of 960 mg in combination with panitumumab (n = 53) led to a median progression-free survival (PFS) of 5.6 months (95% CI, 4.2-6.3) vs 2 months (95% CI, 1.9-3.9) with standard of care (SOC), which was investigator’s choice of trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga; n = 54; HR, 0.48; 95% CI, 0.3-0.78; 2-sided P = .005).²

Moreover, 960 mg of sotorasib plus panitumumab led to an objective response rate (ORR) of 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) with SOC; the complete response rates in the respective arms were 1.9% and 0%. The median duration of response (DOR) with the combination was 4.4 months (range, 1.9+ to 6+).

The study was not statistically powered for overall survival (OS) and the final analysis of OS was not determined to be of statistical significance. The median OS with sotorasib at 960 mg plus panitumumab was not reached (NR; 95% CI, 8.6-NR) vs 10.3 months (95% CI, 7-NR) with SOC (HR, 0.7; 95% CI, 0.41-1.18).

In a recent interview, Marwan G. Fakih, MD, professor in the Department of Medical Oncology & Therapeutics Research; associate director of Clinical Sciences; medical director of the Briskin Center for Clinical Research; division chief of GI Medical Oncology; and co-director of the Gastrointestinal Cancer Program at City of Hope, in Duarte, CA, discussed data from the final OS analysis presented during the 2024 ASCO Annual Meeting.

Decoding CodeBreaK 300: Population, Treatment, Objectives

The global, randomized, open-label, active-controlled study enrolled patients with KRAS G12C–mutated mCRC who were at least 18 years of age, had an ECOG performance status no higher than 2, and received at least 1 prior line of therapy for metastatic disease. Patients must have received fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication. They were required to have at least 1 measurable lesion by RECIST 1.1 criteria.

Participants were randomized 1:1:1 to receive sotorasib at a daily dose of 960 mg plus panitumumab at 6 mg/kg every 2 weeks (n = 53), sotorasib at 240 mg daily plus panitumumab at 6 mg/kg every 2 weeks (n = 53), or SOC (n = 54). Stratification factors included previous antiangiogenic therapy (yes vs no), time from diagnosis of mCRC (≥18 months vs <18 months), and ECOG performance status (0 vs 1/2).

Treatment continued until progressive disease, lack of clinical benefit, or treatment intolerance. Moreover, to discontinue sotorasib, panitumumab also needed to be discontinued; however, patients could still receive sotorasib even if panitumumab was discontinued. A total of 4 patients who were in the sotorasib 960-mg/panitumumab arm continued sotorasib monotherapy after panitumumab discontinuation.

The primary end point of the study was PFS by blinded independent central review and RECIST 1.1 criteria and key secondary end points included OS, ORR, and DOR.

When looking at the population of patients who received sotorasib at 960 mg plus panitumumab or the control arms, the median age was 64 years (range, 34-81), with 46% of patients at least 65 years. Half of the patients were female, and most were White (74%) and had an ECOG performance status of 0 or 1 (97%). Primary disease sites included the colon (69%) or the rectum (31%). Patients had received a median of 2 prior lines of therapy for metastatic disease. All had previously received fluoropyrimidine, 99% had prior oxaliplatin, 93% had prior irinotecan, and 18% had prior trifluridine/tipiracil or regorafenib.

Additional Efficacy Findings

Data from the final PFS analysis indicated that those who received sotorasib at a dose of 240 mg plus panitumumab did not experience a statistically significant PFS benefit vs SOC.

Safety Spotlight

In those who received sotorasib at 960 mg once daily plus panitumumab, 36% were exposed to sotorasib for longer than 6 months and 6% were exposed to the agent for longer than 1 year.

Twenty-six percent of patients in this dosing group experienced serious adverse effects (AEs). Moreover, 26% of patients experienced an AE that led to a dose interruption of sotorasib. One patient who experienced nausea needed a dose reduction of sotorasib, and 1 patient who experienced decreased corrected calcium permanently discontinued the agent.

The most common AEs experienced by at least 20% of patients who received sotorasib at 960 mg plus panitumumab included rash, dry skin (all grade, 28%; grade 3/4, 0%), diarrhea (28%; 6%), stomatitis (26%; 0%), fatigue (21%; 0%), and musculoskeletal pain (21%; 2.1%).¹ The most common laboratory abnormalities that were grade 3 or 4 in severity and were reported in 2 or more patients were decreased magnesium (24%), decreased potassium (7%), decreased corrected calcium (4.3%), and increased potassium (4.3%).

References

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed January 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer
2. Lumakras. Prescribing information. Amgen Inc.; January 2025. Accessed January 16, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Lumakras/lumakras_pi_hcp_english.pdf
3. Fakih M, Salvatore L, Esaki T, et al. Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRAS G12C-mutated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(17). doi:10.1200/JCO.2024.42.17_suppl.LBA3510