NEW YORK – The first data from a trial of Amgen's KRAS inhibitor Lumakras (sotorasib) combined with its anti-EGFR monoclonal antibody Vectibix (panitumumab) and chemo in first-line KRAS G12C-mutant metastatic colorectal cancer showed that more than three-fourths of patients in a cohort of 40 saw their tumors shrink.
Data from a cohort in the Phase Ib CodeBreaK 101 study, presented at the European Society for Medical Oncology Congress in Barcelona, Spain, showed nearly all patients experienced disease control on the Lumakras-Vectibix-FOLFIRI regimen.
Amgen has previously reported data on Lumakras combinations in the second-line or later setting. In the Phase III CodeBreaK 300 trial, Lumakras plus Vectibix without chemo demonstrated a 30 percent response rate and progression-free survival of 5.6 months in chemo-refractory KRAS G12C-mutant metastatic colorectal cancer patients. In another cohort of the CodeBreaK 101 study, researchers explored the Lumakras-Vectibix-chemo combo in metastatic colorectal cancer patients who had gotten any prior treatment and showed that this regimen had an acceptable safety profile and a 58 percent response rate.
In the previously treated colorectal cancer setting, Amgen said last year it planned to discuss the CodeBreaK 300 results on Lumakras-Vectibix without chemo with regulators. But this June, Bristol Myers Squibb reached the US market first, gaining approval for Krazati (adagrasib) plus Eli Lilly's anti-EGFR monoclonal antibody Erbitux (cetuximab) as a treatment for previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer.
Regardless, Amgen has ambitions to move the Lumakras-Vectibix combination with chemo to the front-line setting for advanced KRAS G12C-mutated colorectal cancer. Based on this regimen's activity in single-arm investigations like the latest CodeBreaK 101 cohort, Amgen has begun recruiting advanced, KRAS G12C-mutated colorectal cancer patients into a randomized Phase III CodeBreaK 301 trial. In this study, researchers are pitting Lumakras-Vectibix-FOLFIRI in the first-line setting against FOLFIRI with or without Amgen's Mvasi (bevacizumab-awwb), a biosimilar to Genentech's Avastin (bevacizumab).
Approximately 3 percent of metastatic colorectal cancer patients carry an oncogenic KRAS G12C mutation. At the ESMO Congress, Salvatore Siena, professor of medical oncology at the University of Milan, who presented the CodeBreaK 101 results, reported that the overall response rate among 40 patients in the study was 78 percent. However, all patients in the study experienced some tumor shrinkage on Lumakras-Vectibix-FOLFIRI, Siena noted, and 95 percent achieved disease control. Only one patient experienced disease progression on the regimen.
Median progression-free survival was not mature at the time of analysis. Siena highlighted that 68 percent of responding patients were still in the study and responding as of the data cutoff with a median follow-up of 6.7 months.
Patients with both right- and left-sided colorectal tumors saw their tumors shrink on the regimen, with 82 percent of patients with left-sided tumors and 60 percent of those with right-sided tumors responding. All seven patients with liver metastases also responded to the Lumakras-Vectibix-chemo treatment.
A majority of patients, 88 percent, experienced treatment-related adverse events and needed dose reductions or interruptions, and 18 percent of patients discontinued treatment due to adverse events with most of these patients discontinuing the chemo regimen. Still, Siena described the safety profile of the combination as manageable. The most common grade 3 or higher adverse events included decreased neutrophil count, dermatitis acneiform, and diarrhea.
In a discussion of the CodeBreaK 101 results, Clara Montagut Viladot, head of the gastrointestinal cancer unit at Hospital del Mar in Barcelona, noted that these first-line results were promising but needed to be confirmed in the ongoing Phase III CodeBreaK 301 study.
"This is exciting because we are quickly moving precision medicine to the first line [in metastatic colorectal cancer]," Viladot said. "The CodeBreaK 301 trial adds to the current [landscape of] ongoing randomized trials evaluating drugs against oncogenic drivers plus chemotherapy in first-line metastatic colorectal cancer. [These trials] will hopefully reshape the treatment of first-line metastatic colorectal cancer."