Sotorasib shows activity in advanced colorectal cancer with KRAS G12C mutation
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Sotorasib demonstrated antitumor activity among patients with heavily pretreated advanced KRAS G12C-mutated colorectal cancer, according to results of the phase 2 CodeBreak 100 trial published in The Lancet Oncology.
Sotorasib (Lumakras, Amgen), a first-in-class, irreversible and selective KRAS inhibitor, also demonstrated a favorable safety profile.
“Patients with KRAS and NRAS mutations have limited treatment options, especially after progressing on fluoropyrimidines, oxaliplatin and irinotecan. KRAS G12C is an activating KRAS mutation occurring at a frequency of 4% in colorectal cancer cases and has been associated with a worse overall outcome in comparison with the rest of RAS mutations, making it even more important to develop treatment options for this patient population,” Marwan G. Fakih, MD, co-director of the gastrointestinal cancer program at City of Hope, told Healio. “Sotorasib is a small-molecule KRAS G12C inhibitor that locks KRAS G12C in its inactive GDP-bound state, therefore effectively blocking its downstream signaling. A phase 1 clinical trial of sotorasib in KRAS G12C solid tumors showed preliminary activity in colorectal cancer. This phase 2 clinical trial was conducted to determine the response rate, disease control rate, PFS and OS in this patient population.”
The ongoing, single-arm CodeBreak 100 trial included 62 patients with KRAS G12C-mutated colorectal cancer across 33 centers in nine countries who received at least one dose of 960 mg oral sotorasib once daily. All patients had progressed on treatment with fluoropyrimidine, oxaliplatin and irinotecan, and 73% had progressed on at least three prior lines of anticancer therapy.
Objective response rate served as the study’s primary endpoint.
Results showed an ORR of 9.7% (95% CI, 3.6-19.9), which fell short of the protocol-specified benchmark. The six patients who demonstrated response all had partial responses, and two of them remained on treatment at data cutoff with ongoing responses.
Eighty-two percent of patients achieved disease control. Researchers reported median PFS of 4 months and median OS of 10.6 months.
“The response rate, disease control rate, median PFS and OS in this population of patients with refractory metastatic colorectal cancer is encouraging and clinically significant,” Fakih said. “Patients enrolled on this study would otherwise have limited treatment options, such as regorafenib [Stivarga, Bayer] or [trifluridine and tipiracil (Lonsurf, Taiho Oncology)], both of which have been associated with limited activity.”
The most common adverse events included grade 3 or higher diarrhea (3%). One patient experienced grade 4 blood creatine phosphokinase increase, and two patients experienced back pain and acute kidney injury. No treatment-related deaths occurred.
“This study confirmed the favorable safety profile of sotorasib, with only a few patients experiencing grade 3 or above treatment-related adverse events,” Fakih said. “While sotorasib monotherapy held significant promise based on this study’s results, recent clinical data suggest potential synergy between sotorasib and the anti-EGFR inhibitor panitumumab [Vectibix, Amgen]. The addition of panitumumab overcame sotorasib monotherapy resistance in sotorasib pretreated patients and increased the response rate in sotorasib-naive patients. A phase 3 clinical trial is currently underway to compare sotorasib plus panitumumab to physicians’ choice of trifluridine [and tipiracil] or regorafenib in patients with the KRAS G12C mutation who progressed on prior fluoropyrimidine, oxaliplatin and irinotecan.”
Although sotorasib monotherapy did not achieve the study’s prespecified primary endpoint, the promising biological signal associated with treatment merits further evaluation in combination with other drugs inhibiting the MAPK pathway to overcome resistance, Per Pfeiffer, MD, PhD, professor at University of Southern Denmark and senior consultant in the department of oncology at Odense University Hospital in Denmark, and Camilla Qvortrup, MD, PhD, oncologist in the department of oncology at Odense University Hospital in Denmark, wrote in an accompanying editorial.
“The identification of selective KRAS G12C inhibitors is a major and important step forward,” they wrote. “However, KRAS G12C-mutated colorectal cancer still only represents 7% of the KRAS-mutated metastatic colorectal cancer population, thus, there is a need for future emphasis on alternative approaches in targeting RAS in the majority of patients with KRAS-mutated metastatic colorectal cancer.”
References:
Fakih MG, et al. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00605-7.
Pfeiffer P and Qvortrup C. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00652-5.
For more information:
Marwan G. Fakih, MD, can be reached at City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010.
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