Background
Phase III, open-label RCT (KRYSTAL-12). N=453 patients with KRAS G12C–mutated locally advanced or metastatic NSCLC previously treated with both platinum-based chemotherapy and anti-PD-1/L1 therapy, ECOG PS 0–1. 2:1 randomization (adagrasib:docetaxel), stratified by region and prior treatment sequence.
Interventions and follow up
Arm A: Adagrasib 600 mg PO BID continuously (N=301)
Arm B: Docetaxel 75 mg/m² IV q3wk (N=152)
Primary endpoint: PFS by blinded independent central review (BICR)
mFollow up: 7.2 mo
Arm B: Docetaxel 75 mg/m² IV q3wk (N=152)
Primary endpoint: PFS by blinded independent central review (BICR)
mFollow up: 7.2 mo
Results
PFS (BICR): 5.5 vs 3.8 months, HR 0.58, 95% CI 0.45–0.76, P<.0001
OS: not mature at primary analysis
Grade ≥3 AEs: 47% (adagrasib) vs 46% (docetaxel)
Treatment-related deaths: 4 (1.3%) adagrasib vs 1 (0.7%) docetaxel
OS: not mature at primary analysis
Grade ≥3 AEs: 47% (adagrasib) vs 46% (docetaxel)
Treatment-related deaths: 4 (1.3%) adagrasib vs 1 (0.7%) docetaxel
Adverse events
Overall: grade ≥3 47% (adagrasib) vs 46% (docetaxel) — comparable.
Adagrasib (GI): nausea 51% all-grade, diarrhea 22% all-grade.
Adagrasib (hepatic/cardiac): elevated ALT/AST 4%, QTc prolongation.
Docetaxel: neutropenia, alopecia, fatigue.
Adagrasib (GI): nausea 51% all-grade, diarrhea 22% all-grade.
Adagrasib (hepatic/cardiac): elevated ALT/AST 4%, QTc prolongation.
Docetaxel: neutropenia, alopecia, fatigue.
Conclusions
Adagrasib significantly improved PFS vs docetaxel in previously treated KRAS G12C+ NSCLC (HR 0.58), the first phase III trial demonstrating PFS benefit for adagrasib as a KRAS G12C inhibitor in this setting. Grade ≥3 toxicity was comparable between arms, unlike most targeted therapy trials.
Key Limitations
Short follow-up (7.2 months) at primary analysis; OS data immature. Absolute PFS benefit modest (1.7 months; 5.5 vs 3.8 months). Grade ≥3 AEs were comparable (47% vs 46%) — no clear tolerability advantage over docetaxel, unlike other targeted therapy comparisons. Four treatment-related deaths with adagrasib vs one with docetaxel. No active comparator vs sotorasib (CodeBreaK 200). First author is Barlesi F; Mok TSK is the corresponding/senior author.
Clinical Context
KRYSTAL-12 builds on accelerated approval (KRYSTAL-1 phase 2) to provide phase III evidence for adagrasib in 2L KRAS G12C+ NSCLC. Alongside CodeBreaK 200 (sotorasib, HR 0.66 PFS vs docetaxel), adagrasib is positioned as 2L preferred option after chemotherapy + IO. KRAS G12C accounts for ~13% of NSCLC adenocarcinomas. Combination strategies (adagrasib + cetuximab) under investigation. ESMO-MCBS score pending OS.