Sotorasib in combination with pembrolizumab or atezolizumab in advanced KRASG12C NSCLC
The CodeBreak 100/101 study assessed safety and activity of sotorasib in combination with either pembrolizumab or atezolizumab in patients with advanced non-small cell lung cancer (NSCLC) with a KRASG12C mutation. The combination regimen resulted in a higher incidence of grade 3-4 TRAEs than with monotherapy. Overall, safety data from lead-in and concurrent cohorts support lower dose sotorasib and lead-in administration for better tolerability.
Sotorasib, a first-in-class small molecular inhibitor of KRASG12C , is approved as monotherapy in more than 40 countries for patients with previously treated KRASG12C-mutated advanced non-small cell lung cancer (NSCLC). In preclinical studies, combination of sotorasib with anti-programmed cell death protein-1 (PD-1) therapy increased infiltration of CD8+ T-cells into tumours and enhanced anti-tumour efficacy compared to treatment with either single agent in vivo. At WCLC 2022, Prof. Li provided the results of the first ever assessment of safety and activity of sotorasib in combination with either pembrolizumab or atezolizumab from the phase Ib initial dose exploration arms of the CodeBreak 100/101 trials.
Study design
The multicentre, open-label phase Ib CodeBreak 100/101 study included patients with advanced KRASG12C-mutated NSCLC who received prior standard therapies. Eligible patients could not have been treated with a prior KRASG12C inhibitor, and were not allowed to have active brain metastases. Patients were treated with varying doses of once-daily sotorasib (120, 240, 360, 720 and 960 mg) with either a fixed dose of intravenous atezolizumab (1,200 mg) or pembrolizumab (200 mg), administered every three weeks until dose-limiting toxicity, or disease progression (concurrent treatment). In two additional lead-in cohorts, patients initiated sotorasib at varying doses for either 21 or 42 days, then received atezolizumab or pembrolizumab concurrently with sotorasib. The primary endpoint is safety and tolerability.
Results
In total, 58 patients were treated with a median follow-up of 12.8 months. The median number of prior lines of therapy was one and 67% of patients received prior anti-PD(L)1 therapy. Higher rates of TRAEs were observed when using concurrent treatment with sotorasib plus pembrolizumab than with monotherapy, but without fatal TRAEs. TRAEs of grade ≥3 were observed in 40%, 25%, 100% and 75% of the patients (sotorasib 120 mg (N= 5), 360 mg (N= 8), 720 mg (N= 2), and 960 mg (N= 4), respectively). At lower doses of sotorasib, there was a trend towards less liver enzyme elevations, although sample sizes were limited. Given the safety data for this combination, sotorasib lead-in was explored. Regardless of the combination with atezolizumab or pembrolizumab, the lead-in cohorts had a lower incidence of grade 3-4 TRAEs and TRAEs leading to discontinuation than the concurrent cohorts. Overall, grade 3-4 hepatotoxicity first occurrence was outside dose-limiting toxicity (DLT) window in 88% of patients, and 97% of events resolved with corticosteroids, treatment modification, and/or discontinuation. The incidence of hepatotoxicity TRAEs was similar in immunotherapy-naïve vs. immunotherapy-pretreated patients. Overall safety data from lead-in and concurrent cohorts support lower dose sotorasib and lead-in administration for better tolerability.
Deep and durable responses were observed for this combination across all cohorts, including at low doses. The objective response rate was 29%, with a disease control rate of 83%. Among the 17 responders, median duration of response was 17.9 months. The response was similar in immunotherapy-naïve vs. –pretreated patients. Given its safety and efficacy profile, low dose sotorasib lead-in plus pembrolizumab is being persued. For all 58 patients across cohorts, the median overall survival was 15.7 months.
Conclusions
In most immunotherapy pre-treated patients with advanced KRASG12C-mutated NSCLC, sotorasib plus atezolizumab or pembrolizumab led to a higher incidence of grade 3-4 TRAEs than observed with sotorasib monotherapy. In the initial sotorasib + pembrolizumab concurrent studies, lower sotorasib doses trended toward less hepatotoxicity TRAEs, including grade ≥3 events. Sotorasib lead-in had lower rates of grade 3-4 TRAEs and TRAEs leading to discontinuation compared with concurrent administration. Lead-in cohorts demonstrated durable clinical activity and depth of response. Among the 17 responders, median duration of response was 17.9 months.
Reference
Li BT, Falchook GS,2 Durm GA et al. CodeBreaK 100/101: First report of safety and efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. Presented at IASCL WCLC 2022; Abstract OA03.06.
