This is the first phase 3 trial to evaluate a KRAS G12C-inhibitor plus an anti-epidermal growth factor receptor antibody for this type of colorectal cancer.
Combination therapy of sotorasib (Lumakras; Amgen) and panitumumab (Vectibix; Amgen) significantly improved the survival outcomes of patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC) compared to standard of care, according to data from the primary analysis of the phase 3 CodeBreaK 300 study (NCT05198934) which were published in the New England Journal of Medicine.1 These data, which also include updated secondary endpoint and adverse event (AE) findings, were presented at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain.1,2
According to the study investigators, the primary endpoint, defined as progression-free survival (PFS), was more than double among patients taking a higher dose of sotorasib (960 mg) with panitumumab compared to the PFS associated with standard of care.
"With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these 2 biomarker-directed therapies," said Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale deiTumori, in a press release.1
The novel treatment combination was evaluated in CodeBreaK 300, which is a phase 3, multicenter, open-label, randomized trial comparing sotorasib (960 mg daily) plus intravenous (IV) panitumumab (6 mg/kg), sotorasib (240 mg daily) plus panitumumab (6 mg/kg), andstandard of care trifluridine and tipiracil (Lonsurf; Taiho Oncology) or regorafenib (Stivarga; Bayer) in 160 patients with KRAS G12C-mutated mCRC who have never received treatment with a KRAS G12C inhibitor.2,3
As assessed by blinded independent central review, PFS at the 7.8-month median follow-up was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) for patients in the 960-mg sotorasib plus panitumumab arm. PFS among patients in the 240 mg sotorasib plus panitumumab and standardof care arms was 3.9 months and 2.2 months (95% CI, 1.9 to 3.9), respectively. Further, this endpoint was recognized across subgroups—tumor sidedness, primary tumor location, prior lines of therapy, and liver metastases status.1
The key secondary endpoint of objective response rate (ORR) was 26.4% (95% CI, 15.3 to 40.3) with 960-mg sotorasib plus panitumumab, 5.7% (95% CI, 1.2 to 15.7) with 240-mg sotorasibplus panitumumab, and 0% (95% CI, 0.0 to 6.6) with standard of care group. Other key secondary endpoints include disease control rate (DCR)—71.7 % and 67.9% in the 960-mg and 240-mg sotorasib plus panitumumab arms, respectively, and 46.3% in the standard of care arm—and overall survival (OS), where data remains immature.3
Common AEs (grade 3 or higher) associated with dosage of the combination treatment includedermatitis acneiform (4-11%) hypomagnesemia (6-8%), rash 2-6%), and diarrhea (4-6%). A few patients discontinued treatment due to AEs.1,2
Colorectal cancer is the second most common cause of cancer-related deaths globally. At least 3% of patients with mCRC have a mutation of the KRAS G12C gene, and metastatic disease is associated with a worse survival rate. 1,2
"Fewer than 20% of people diagnosed with mCRC survive beyond 5 years, and additional treatment options are clearly needed, particularly for the patients with KRAS mutations for whom evidence-based targeted options were not yet available," Pietrantionio said in the press release.1
This is the first ever phase 3 study to evaluate a KRAS-inhibitor that specifically targets the G12C-mutation with an anti-EGFR antibody for chemorefractory mCRC.3 Investigators will submit the treatment to regulatory authorities following these positive data.1
"The CodeBreaK 300 trial demonstrated the benefit of sotorasib plus panitumumab to deliver statistically significant PFS outcomes for patients compared to the investigator's choice of therapy, offering new hope to this population with historically poor outcomes," said David M. Reese, MD, executive vice president, Research and Development at Amgen, in the press release.1
1. Amgen presents new LUMAKRAS® (sotorasib) plus VECTIBIX® (panitumumab) data in patients with KRAS G12C-mutated metastatic colorectal cancer. Amgen. October 22, 2023. Accessed on October 23, 2023. https://www.prnewswire.com/news-releases/amgen-presents-new-lumakras-sotorasib-plus-vectibix-panitumumab-data-in-patients-with-kras-g12c-mutated-metastatic-colorectal-cancer-301963791.html2. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. The NEJM. October 22, 2023. DOI: 10.1056/NEJMoa23087953. LBA10 - Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study. ESMO. Abstract. October 22, 2023. Accessed October 23, 2023.