OBR OncologyApproved Sotorasib Dose May Be Excessive

Exploring Optimal Dosing in KRAS G12C–Mutated NSCLC: Rethinking Sotorasib’s Efficacy and Safety

A recent analysis of the CodeBreaK 100 study, presented at the European Society of Medical Oncology (ESMO) Virtual Plenary, raises critical questions about the current FDA-approved dosage of sotorasib (Lumakras) for treating advanced KRAS G12C–mutated non-small cell lung cancer (NSCLC). The study, which contrasts the standard 960 mg dose with a quarter of that amount, offers insights into efficacy, safety, and economic implications, challenging the status quo in NSCLC treatment strategies.

Key Points:

1. FDA Approval and Study Design: In 2021, sotorasib received accelerated FDA approval for NSCLC at a daily dose of 960 mg, with a postmarketing requirement for a randomized trial to compare this dose with a 240 mg dose.
2. Study Results – Efficacy: The CodeBreaK 100 phase 2 trial, involving 209 patients, revealed a slightly higher overall response rate (ORR) and disease control rate at the 960 mg dose, but similar progression-free survival rates for both dosages.
3. Safety Profile: Although both doses had comparable rates of treatment-emergent adverse events, the higher dose showed a greater incidence of severe (grade 3 and above) events, particularly gastrointestinal-related.
4. Economic Considerations: Assigned study discussant Sanjay Popat, MD, of Royal Marsden Hospital, United Kingdom, highlighted potential economic benefits of the lower dose, noting a significant reduction in cost from $20,000 to $5,000 for a 30-day supply under the US Medicare pricing.
5. Expert Opinions: Experts, including Drs. Popat and American Association for Cancer Research (AACR) expert commentator, Mark J. Ratain, MD, of the University of Chicago, questioned the need for the higher dose, suggesting the 240 mg dose as optimal for both current clinical practice and future development.
6. Patent Applications Insight: Dr. Ratain pointed out inconsistencies between Amgen’s study conclusions and its patent applications, which proposed the lower dose shortly after filing for the higher dose.
7. Regulatory Implications: There’s a suggestion for global regulators and payers to reconsider the appropriateness of the 960 mg dose, with implications for future FDA actions.
8. Comparative Studies: Further studies comparing lower dose sotorasib with alternatives like docetaxel are anticipated.
9. Broader Implications for KRAS-G12C Inhibitors: The study’s findings are influencing the development and dose-optimization strategies of other KRAS-G12C inhibitors.

“This was not a formal equivalence or noninferiority study, but was designed to identify the best dose for future development. The 240-mg dose, I would suggest, is the optimal monotherapy dose for use in clinical practice today, and also for future development in NSCLC, with no meaningful evidence from this trial that an increased dose improves efficacy.” – Sanjay Popat, MD

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