Table 4:
FDA Benefit-Risk Analysis
| Dimension | Evidence and Uncertainties | Conclusions and Reasons |
|---|---|---|
| Analysis of Condition | • 14% of metastatic NSCLC is KRAS G12C-mutated • Therapies after first-line immunotherapy, which offers survival benefit, are limited in number and benefit. |
Metastatic KRAS G12C mutated NSCLC is a life-threatening condition with poor survival. |
| Current Treatment Options | • First line therapies for patients with metastatic NSCLC without a targetable mutation include platinum-based chemotherapy with or without an immune checkpoint inhibitor. Second line therapies include immune checkpoint inhibitors and pemetrexed if not already given and docetaxel with or without ramucirumab. • |
Prior to the approval of sotorasib, there were no FDA-approved targeted therapies for patients with KRAS G12C-mutated NSCLC. |
| Benefit | • The ORR in the primary efficacy population of patients with KRAS G12C-mutated NSCLC (n=124) enrolled in CodeBreaK 100 was 36% (95% CI: 28, 45). The median DOR was 10.0 months (range 1.3+, 11.1); 58% of patients had a DOR ≥6 months. • ORRs ranging from 25–50% were observed in NSCLC patients who received lower doses of sotorasib (180–960 mg QD). |
A meaningful improvement in durable ORR compared to FDA-approved therapies for the second- line treatment of patients with advanced KRAS G12C-mutated NSCLC was observed with sotorasib. A PMR was issued for a dose optimization study. |
| Risk and Risk Management | • The most common (≥20%) TEAEs observed in patients with NSCLC enrolled in CodeBreaK 100 were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. • SAEs occurring ≥ 2% of patients were pneumonia, hepatotoxicity, and diarrhea. |
Information in the Warnings and Precautions and Dosage and Administration sections of product labeling address these toxicities adequately. |
CI, confidence interval; DOR, duration of response; FDA, Food and Drug Administration; KRAS, Kirsten rat sarcoma; NSCLC, non-small cell lung cancer; ORR, overall response rate; PD-L1, programmed death-ligand 1; PMR, post-marketing requirement; SAE, serious adverse event; TEAE, treatment emergent adverse event
Source: U.S. FDA NDA Multi-disciplinary Review and Evaluation (NDA 214665) and Approval Package (ref. 19).