As reported in The Lancet by Barlesi et al, the phase III KRYSTAL-12 trial has shown a significant progression-free survival benefit with adagrasib over docetaxel in patients with previously treated locally advanced or metastatic KRAS G12C–mutated non–small cell lung cancer (NSCLC).
Study Details
In the open-label trial, 453 patients from sites in 22 countries were randomly assigned 2:1 between February 2021 and November 2023 to receive adagrasib at 600 mg twice daily (n = 301) or docetaxel at 75 mg/m² every 3 weeks (n = 152). Treatment continued until disease progression or unacceptable toxicity. All patients had previously received platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy. The primary endpoint was progression-free survival assessed by blinded independent central review in the intention-to-treat population.
Key Findings
Median follow-up was 7.2 months (95% confidence interval [CI] = 5.8–8.7 months).
Median progression-free survival was 5.5 months (95% CI = 4.5–6.7 months) in the adagrasib group vs 3.8 months (95% CI = 2.7–4.7 months) in the docetaxel group (hazard ratio = 0.58, 95% CI = 0.45–0.76, P < .0001).
Objective response rates on blinded independent central review were 32% (complete response in 1%) vs 9% (odds ratio = 4.68, 95% CI = 2.56–8.56, P < .0001). Median response durations were 8.3 months (95% CI = 6.1–10.4 months) vs 5.4 months (95% CI = 2.9–8.5 months). Disease control rates were 78% vs 59%. Overall survival data were not mature at time of analysis.
Among 78 vs 36 patients with brain metastases at baseline, the intracranial objective response rate was 24% (complete response in 11 patients) vs 11% (complete response in 3 patients).
Grade 3 and above treatment-related adverse events occurred in 47% of the adagrasib group vs 46% of the docetaxel group; the most common were increased alanine aminotransferase (8%), increased aspartate aminotransferase (6%), and diarrhea (5%) in the adagrasib group and decreased neutrophil count (11%), neutropenia (10%), and asthenia (10%) in the docetaxel group. Treatment-related adverse events led to a discontinuation of treatment in 8% vs 14% of patients. Treatment-related death occurred in four patients (1%) in the adagrasib group (due to epilepsy, hepatic failure, hepatic ischemia, and unknown cause, respectively) and in one patient (1%) in the docetaxel group (due to sepsis).
The investigators concluded: “Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRAS G12C–mutated NSCLC, without new safety signals.”
Tony S. K. Mok, MD, of State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Mirati Therapeutics, a Bristol Myers Squibb company. For full disclosures of all study authors, visit thelancet.com.
