Long-Term Outcomes of Sotorasib in KRAS-G12C Non–Small-Cell Lung Cancer

1. Sotorasib showed prolonged efficacy with a median OS of 12.5 months (33% at 24 months) and an ORR of 41% (50.6% of those remained in response at 12 months).

2. The safety profile of Sotorasib was favourable with common adverse events including diarrhea and hepatotoxicity.

Evidence Rating Level: 2 (Good)

Study Rundown: Sotorasib, an irreversible KRAS inhibitor has been approved for patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) after prior treatment. In a recent phase II trial, sotorasib showed promising results. This study follows the previous and reported the 2-year pooled analysis of the phase I/II trial. The phase I primary endpoint was safety and tolerability with secondary endpoints including duration of response (DoR) and progression-free survival (PFS). The phase II primary endpoint was objective response rate (ORR) with secondary endpoints including DOR, PFS, overall survival (OS), and safety. ORR was 41%; with 72.8% and 50.6% of patients with a confirmed response and remained in response at 6 and 12 months, respectively. The median DOR was 12.3 months. Median PFS was 6.3 months and 23% of patients had long-term clinical benefit (PFS ≥ 12). The median OS was 12.5 months with OS at 51% and 33% at 12 and 24 months, respectively. Biomarker analysis found a clinical benefit across PD-L1 expression levels with no significant difference across levels. With regards to safety, there were 20% grade 3 and 1% grade 4 treatment-related adverse events (TRAEs) with the most common being diarrhea (30%), increased ALT (18%), and increased AST (18%). The strengths of this paper included the long-term follow-up, and the included biomarker analysis. The limitations of this paper included the small sample size and the single-arm design. Overall sotorasib has shown some long-term efficacy in treatment-resistant advanced NSCLC.

Click to read the study in JCO

Relevant Reading: Sotorasib for Lung Cancers with KRAS p.G12C Mutation

In-Depth [prospective cohort]: This multicenter single-group phase I/II trial enrolled adults (174 patients, 48 in phase I, 126 in phase II) with KRAS G12C-mutated locally advanced or metastatic NSCLC after progression on prior therapies and started them on sotorasib (960mg daily). Median treatment was 5.6 months and the median DOR was 12.3 months (95%CI, 7.1 to 15.0). The ORR (though blinded independent central review) was 41% (95%CI, 33.3 to 48.4), 72.8% (95%CI, 60.0 to 82.2) and 50.6% (37.4 to 62.4) of patients with confirmed response remained in response at 6 and 12 months, respectively. Median PFS was 6.3 months (95%CI, 5.3 to 8.2) with 23% of patients having long-term clinical benefit (PFS ≥ 12). The median OS was 12.5 months (95%CI, 10.0 to 17.8) with OS estimates at 51% (95%CI, 42.8 to 58.2) and 33% (95%CI, 25.0 to 40.2) at 12 and 24 months, respectively. Biomarker analysis was done and found a nonsignificant trend of benefit with PD-L1 tumour proportion score <1% versus ≥1% with OR 0.36 (0.12 to 1.12), and no significant differences between PD-L1 1%-49% and ≥50% with OR 0.83 (0.07 to 9.69). With regards to safety, there were 20% grade 3 and 1% grade 4 treatment-related adverse events (TRAEs), with treatment reduction or interruption in 22% and treatment discontinuation in 6%. The most common TRAEs were diarrhea (30%), increased ALT (18%), and increased AST (18%). Overall sotorasib has shown some long-term efficacy in treatment-resistant advanced NSCLC.

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