Sotorasib, an investigational small-molecule inhibitor of the KRAS p.G12C mutation, demonstrated promising activity and encouraging safety in patients with advanced solid tumors, in particular those with non–small-cell lung cancer (NSCLC), in the preliminary phase 1 CodeBreaK 100 trial. The findings were presented at the 2020 virtual meeting of the European Society for Medical Oncology (ESMO) and were recently published (Hong DS, et al. N Engl J Med. 2020;383:1207-1217).
Cancer with KRAS mutations, which account for 13% of NSCLC cases and 1% to 3% of colorectal and other cancers, are among the most difficult to treat.
The results of this clinical trial have garnered praise and attention because the development of a drug to target KRAS has been elusive since this target was first identified 4 decades ago.
“The KRASG12C inhibitor sotorasib has the potential to address the unmet need for treatment of tumors harboring the KRAS p.G12C mutation. Results of this phase 1 study showed that the novel first-in-class drug sotorasib produced durable disease control in heavily pretreated patients with NSCLC, and clinical activity was observed across a range of different biomarkers. We saw clinical benefit with mainly low-grade gastrointestinal and hepatic toxic effects in a heavily pretreated population,” said lead investigator David S. Hong, MD, Deputy Chair, Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, M.D. Anderson Cancer Center, Houston, TX.
“Sotorasib is a triumph of academic drug discovery,” observed invited discussant Colin Lindsay, BSc, MBChB, MRCP, PhD, Consultant in Medical Oncology, the Christie NHS Foundation Trust, Manchester, United Kingdom. “We know that over many years, more than 3 decades, KRAS has been very difficult to target. The efficacy of sotorasib is confined to the KRAS p.G12C mutation. We know this drug will not be toxic. It is safe, with no dose-limiting toxicity and manageable toxicity. The efficacy for smoking-related lung cancer continues to be impressive at follow-up of roughly 1 year. It is striking that the effects are dose-independent.”
Promising Responses in Patients with Refractory Disease
The phase 1 clinical trial enrolled 129 patients with locally advanced or metastatic solid tumors harboring the KRAS p.G12C mutation. Among the enrollees, 59 had NSCLC, 42 had colorectal cancer (CRC), and 28 had other solid tumors. “These cancers had been refractory to previous treatments,” Dr Hong noted.
In the dose-escalation phase of the study, 2 to 4 patients per cohort were assigned to receive oral sotorasib at doses of 180 mg, 360 mg, 720 mg, or 960 mg once daily. The recommended dose selected for phase 2 clinical trials was 960 mg.
The study met its primary end point of safety, with no dose-limiting toxicities or treatment-related fatal adverse events. At a median follow-up of 11.7 months, the best response to sotorasib was observed in patients with NSCLC (32.2% of patients achieved a confirmed objective response, 35.3% achieved a confirmed response among those who received the highest dose of 960 mg, and 88.1% had disease control).
Tumor shrinkage was observed at all dose levels. The median progression-free survival was 6.3 months, and the median duration of response was 10.9 months in those with partial responses and 4 months in those with stable disease. Responses were seen across a range of patients with tumors that harbored other mutations in addition to the KRAS mutations.
According to Dr Hong, these responses in heavily pretreated patients with advanced NSCLC compare favorably with those in historical controls.
“Responses and disease stability associated with sotorasib in these patients are encouraging. In the NSCLC subgroup, the fact that 32.2% of the patients across all dose levels and 35.3% at the target dose of 960 mg had a response was particularly promising,” said Dr Hong.
Results in Other Tumor Types
The median time to follow-up in the subgroup of patients with CRC was 12.8 months. Among the 42 patients with CRCs harboring the KRAS p.G12C mutation, the partial response rate was 7.1%. Stable disease was reported in 66.7% of patients, and 73.8% had disease control. The median duration of stable disease was 5.4 months.
Among patients with other tumor types with the KRAS p.G12C mutation, partial responses occurred in 1 patient each with melanoma, appendix, endometrial, and pancreatic cancers. Stable disease was observed in 17 patients, and 4 had progressive disease.
Efforts to improve outcomes in patients with CRC will focus on combining sotorasib with other agents, including EGFR inhibitors.
Other clinical trials are underway to evaluate sotorasib as monotherapy or as combination therapy in patients with NSCLC and other solid tumors.