Adagrasib Demonstrates Favorable PFS in Advanced KRAS G12C-Mutated 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

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

REFERENCES

1. Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503). doi:10.1016/S0140-6736(25)00866-9

2. 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 identifier: NCT04685135. Updated January 22, 2025. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT04685135

3. US Food & Drug Administration. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. December 12, 2022. Accessed September 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc