First results of sotorasib plus pembrolizumab in KRAS p.G12C-mutated NSCLC

Low-dose sotorasib as lead-in therapy, followed by pembrolizumab, demonstrated promising safety and efficacy data in patients with KRAS p.G12C-mutated advanced non-small cell lung cancer (NSCLC). Therefore, these results from the phase 1b CodeBreaK 100/101 study will lead to further exploration of this combination [1].

“Sotorasib is an approved monotherapy in the US, EU, and other countries for patients with previously treated KRAS p.G12C-mutated advanced NSCLC,” said Dr Bob Li (Memorial Sloan Kettering Cancer Center, NY, USA). The CodeBreaK 100/101 study (NCT03600883) explored combinations of sotorasib, from 120 mg to 960 mg once daily, with either atezolizumab or pembrolizumab in patients with previously treated KRAS p.G12C-mutated NSCLC (n=58). Sotorasib was administered as lead-in therapy followed by combination with one of the PD-1 inhibitors (n=29), or as concurrent treatment (n=29).

“After a median follow-up of 12.8 months, the concurrent treatments displayed higher rates of treatment-related adverse events (AEs) than monotherapies of the involved agents,” stated Dr Li. “However, the data implicated that lower doses of sotorasib may result in fewer AEs.” Also, sotorasib as lead-in therapy demonstrated a lower incidence of grade 3 or 4 treatment-related AEs than the concurrent therapies (30–53% vs 60–79%). In addition, 88% of the first occurrences of grade 3 or 4 hepatotoxicity were outside of the dose-limiting toxicity window, and 97% of these events could be resolved with treatment modification, corticosteroids, or treatment discontinuation. In general, if sotorasib was combined with a PD-1 inhibitor, lower doses of sotorasib, and lead-in administration appeared to be more tolerable.

In terms of efficacy, the overall response rate was 29% in the total study population and the disease control rate was 83%. Among the 17 responders, the median duration of response was 17.9 months. Furthermore, the median overall survival was 15.7 months in the complete study population. After showing all relevant results of the CodeBreaK 100/101 study, Dr Li concluded that the combination of low-dose sotorasib as lead-in therapy, followed by combination with pembrolizumab, displayed the most promising data in terms of efficacy and safety, and will therefore be studied in first-line patients with advanced NSCLC in future studies.

1. Li BT, 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. OA03.06, WCLC 2022, Vienna, Austria, 06–09 August.

 

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Posted on 23 August 202228 March 2024