KRYSTAL-12: Adagrasib Significantly Improved PFS, Response in Certain Form of NSCLC

Patients with previously treated KRAS–^G12C-mutated non-small cell lung cancer (NSCLC) treated with adagrasib had significantly improved progression-free survival (PFS) and overall response rate (ORR) compared with docetaxel, according to the results of the KRYSTAL-12 study.

In addition, adagrasib showed intracranial efficacy among patients with brain metastases at baseline, with a response rate double that of patients assigned to docetaxel, Tony S.K. Mok, MD, of The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China, reported at the 2024 American Society of Clinical Oncology Annual Meeting.

Adagrasib has Food and Drug Administration accelerated approval and conditional approval in the European Union and the United Kingdom for KRAS–^G12C-mutated locally advanced or metastatic NSCLC. Dr. Mok reported the results of the confirmatory, phase-3 KRYSTAL-12 trial.

The study enrolled 453 patients with locally advanced or metastatic KRAS^G12C-mutated NSCLC who had been previously treated with platinum-based therapy and anti-PD-(L)1 therapy. Patients were randomly assigned 2:1 to adagrasib 600 mg twice daily or docetaxel 75 mg/m² every 3 weeks. Patients could crossover to adagrasib upon disease progression; 44% of patients crossed over.

Patients assigned adagrasib had significantly improved PFS per blinded independent committee review (hazard ratio [HR]=0.58; 95% CI, 0.45-0.76; P<.0001). The median PFS was 5.5 months with adagrasib compared with 3.8 months with docetaxel. The 6-month PFS was 45% with adagrasib compared with 30% with docetaxel. Investigator review of PFS showed a similar benefit in favor of adagrasib (HR=0.57; 95% CI, 0.45-0.74).

The PFS benefit seen with adagrasib remained in subgroup analysis looking at patients in the Asia-Pacific versus non-Asia Pacific region, in patients with or without baseline brain metastases, and in patients who received sequential versus concurrent chemoimmunotherapy.

Thirty-two percent of patients assigned adagrasib responded to therapy compared with 9% of patients assigned docetaxel. Dr. Mok said that overall the responses were “deep and more durable”.  The median duration of response was 8.3 months with adagrasib compared with 5.4 months with docetaxel.

Among patients with baseline central nervous system metastases, 24% of patients assigned to adagrasib experienced intracranial response compared with 11% of patients assigned docetaxel; intracranial disease control rate was 64% and 20%, respectively.

The safety profiles seen in KRYSTAL-12 were consistent with previous reports with no new safety signals.

“Overall, KRYSTAL-12 confirmed the role of adagrasib compared to docetaxel in terms of improvement of PFS, response rate and intracranial response,” Dr. Mok said. “Such as, it can be utilized in patients in the second-line situation that harbor KRAS^G12C mutations.”

Reference

Mok TSK, Yao W, Duruisseaux M, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS^G12C mutation. Presented at the 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024, Chicago, Illinois.