JCO Oncol Pract. 2026 Jun 1:OP2501315. doi: 10.1200/OP-25-01315. Online ahead of print.
ABSTRACT
PURPOSE: Sotorasib represents an early example in which the US Food and Drug Administration (FDA) requested formal dose optimization under Project Optimus. Although 960 mg remains the labeled dose, tolerability is often challenging. After the FDA Oncologic Drugs Advisory Committee discussion of CodeBreak100 part B, Ratain and Popat argued there was no clear basis for doses above 240 mg. We conducted a systematic review and meta-analysis comparing the efficacy and tolerability of standard versus reduced starting doses of sotorasib in KRAS G12C-mutated non-small cell lung cancer.
METHODS: We conducted a systematic search of PubMed, EMBASE, SCOPUS, CINAHL, and Web of Science through October 28, 2025. Eligible studies included randomized trials, prospective studies, and retrospective studies reporting objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs). Pooled estimates were calculated using a random-effects model.
RESULTS: Among 5,133 studies screened, 145 studies were reviewed, with 10 studies meeting inclusion criteria. The pooled ORR was 33% (95% CI, 29% to 36%) for patients starting at 960 mg (n = 1,347) versus 26% (95% CI, 19% to 34%) for those starting at reduced dose (n = 130), similar to the dose-optimization study (32.7% v 24.8%). There was no statistically significant improvement in ORR with the higher dose (risk ratio, 1.26 [95% CI, 0.87 to 1.83]). Similarly, pooled PFS did not favor 960 mg dosing (hazard ratio, 0.77 [95% CI, 0.56 to 1.05]). At 960 mg dose, TRAEs were common, with any-grade and grade ≥3 TRAE in 83% and 22%, respectively, with dose reductions in 17% and discontinuation in 10% of patients.
CONCLUSION: The labeled 960 mg dose did not demonstrate meaningful improvement in efficacy, while toxicity remained substantial. These findings support efforts under Project Optimus to identify the lowest effective dose. Lower doses, including 240 mg, may provide comparable outcomes while reducing toxicity, pill burden, and treatment costs.
PMID:42224643 | DOI:10.1200/OP-25-01315
