Adagrasib versus docetaxel in KRAS-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial.

Background: Adagrasib is a KRAS inhibitor that demonstrated promising activity against KRAS-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRAS-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy.

Methods: KRYSTAL-12 is a randomised, multicentre, open-label, phase 3 trial conducted at 230 centres in 22 countries. Patients with Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutated locally advanced or metastatic NSCLC, who had previously received both platinum-based chemotherapy and anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy, were randomly allocated in a 2:1 ratio to receive 600 mg adagrasib (twice a day orally) or 75 mg/m docetaxel (every 3 weeks intravenously) using a centralised interactive web response system. Randomisation was stratified by region (non-Asia-Pacific vs Asia-Pacific) and previous treatment (sequential vs concurrent chemotherapy or immunotherapy). Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomised patients (intention-to-treat [ITT] population). Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov (NCT04685135), and is active but no longer recruiting.

Findings: Between Feb 23, 2021, and Nov 16, 2023, 453 patients were randomly allocated to receive adagrasib (301 [66%]) or docetaxel (152 [34%]). In each group, 298 (99%) patients received adagrasib and 140 (92%) received docetaxel. In the ITT population (median follow-up 7·2 months [95% CI 5·8-8·7]), median progression-free survival was 5·5 months (95% CI 4·5-6·7) with adagrasib and 3·8 months (95% CI 2·7-4·7) with docetaxel (hazard ratio 0·58 [95% CI 0·45-0·76]; p<0·0001). Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with docetaxel. There were four (1%) treatment-related deaths in the adagrasib group and one (1%) treatment-related death in the docetaxel group.

Interpretation: Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRAS-mutated NSCLC, without new safety signals.

Funding: Mirati Therapeutics, a Bristol Myers Squibb company.