Compared with docetaxel, adagrasib shows significant progression-free survival (PFS) benefits in patients with non–small cell lung cancer (NSCLC).
Adagrasib (Krazati; Bristol Myers Squibb) demonstrated a statistically significant improvement in progression-free survival (PFS) compared with docetaxel (Taxotere; Sanofi-Aventis) in patients with previously treated KRAS G12C-mutated non–small cell lung cancer (NSCLC), according to results from the phase 3 KRYSTAL-12 trial (NCT04685135), which were published in The Lancet. Notably, adagrasib did not demonstrate any new safety signals in this population, with adverse events (AEs) relatively minor in severity.1,2
Trial Name: Phase 3 Study of MRTX849 (Adagrasib) vs Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-12)
ClinicalTrials.gov ID: NCT04685135
Sponsor: Mirati Therapeutics Inc.
Completion Date (Estimated): July 2, 2026
Adagrasib is a targeted therapy indicated for adults with KRAS G12C-positive advanced NSCLC or colorectal cancer who were previously treated. Its initial FDA approval was based on the multicenter, single-arm, open-label clinical trial KRYSTAL-1 (NCT03785249), which assessed patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.3
The current phase 3 trial, KRYSTAL-12, is a randomized, multicenter, open-label trial conducted at 230 medical centers across 22 countries. A total of 453 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC were enrolled and randomly assigned to receive either 600 mg of adagrasib orally twice per day (n = 301; 66%) or 75 mg/m2 of docetaxel intravenously every 3 weeks (n = 152; 34%), both of which were administered in 21-day cycles. Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death.1,2
The primary end point was PFS assessed by blinded independent central review in all randomized patients (intention-to-treat [ITT] population) up to 143 weeks. Secondary end points include overall survival, objective response rate (ORR), duration of response, and 1-year survival rate. Safety was also assessed in all treated patients. This trial is active but no longer recruiting, wrote the authors.1,2
The findings demonstrated that, in the ITT population (median follow-up: 7.2 months [95% CI, 5.8–8.7]), the median PFS was about 5.5 months (95% CI, 4.5–6.7) with adagrasib and 3.8 months (95% CI, 2.7–4.7) with docetaxel (HR, 0.58; 95% CI, 0.45–0.76; P < .0001). Additionally, ORR was also observed to favor adagrasib over docetaxel. The investigational treatment demonstrated improved intracranial activity and longer duration of symptom burden control compared with docetaxel.1
Grade 3 and above treatment-related AEs occurred in approximately 47% (n = 140) of patients treated with adagrasib and 46% (n = 64) of those receiving docetaxel. There were 4 (1%) treatment-related deaths in the adagrasib group and 1 (1%) in the docetaxel group.1
The authors wrote that the current study met its primary end point of improved PFS, with adagrasib resulting in a significant decrease in the relative risk of disease progression or death compared with docetaxel in patients with previously treated KRAS G12C-mutated advanced NSCLC. These data confirm the initial results from KRYSTAL-1 while reinforcing adagrasib as an efficacious treatment option for this patient population after disease progression on prior chemotherapy and immunotherapy.1
“In the phase 3 KRYSTAL-12 trial, adagrasib demonstrated a statistically significant improvement in PFS by BICR compared with docetaxel. Furthermore, a significantly higher proportion of patients had objective tumor responses (by BICR) with adagrasib vs docetaxel, and these responses appeared to be more durable,” the authors concluded.1
