As reported in The Lancet by Adrianus Johannes de Langen, MD, PhD, of the Netherlands Cancer Institute, Amsterdam, and colleagues, the phase III CodeBreaK200 trial has shown a small but significant improvement in progression-free survival with sotorasib vs docetaxel in previously treated advanced non–small cell lung cancer (NSCLC) with KRAS G12C mutation.1
Sotorasib received accelerated approval in this setting in May 2021 on the basis of overall response rate and duration of response in a subset of patients in the phase II CodeBreaK100 trial.2
In the open-label trial, 345 patients from sites in 22 countries with disease progression after platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor were randomly assigned between June 2020 and April 2021 to receive sotorasib at 960 mg once daily (n = 171) or docetaxel at 75 mg/m2 every 3 weeks (n = 174), with treatment continued until disease progression or unacceptable toxicity. Randomization was stratified by the number of previous lines of therapy in advanced disease, Asian vs non-Asian ethnicity, and history of central nervous system metastases. Crossover from docetaxel to sotorasib was allowed after confirmed radiologic disease progression. The primary endpoint was progression-free survival on blinded independent central review in the intention-to-treat population.
Adrianus Johannes de Langen, MD, PhD
Luis Paz-Ares, MD, PhD
Median follow-up was 17.7 months (interquartile range = 16.4–20.1 months). Median progression-free survival was 5.6 months (95% confidence interval [CI] = 4.3–7.8 months) in the sotorasib group vs 4.5 months (95% CI = 3.0–5.7 months) in the docetaxel group (hazard ratio [HR] = 0.66, 95% CI = 0.51–0.86, P = .0017). Kaplan-Meier curves showed early and sustained separation between the two treatment groups. The rate at 12 months was 24.8% vs 10.1%.
In stratification subgroups, hazard ratios for progression-free survival for the sotorasib group vs docetaxel group were 0.70 (95% CI = 0.47–1.04) among 77 vs 78 patients with one previous line, 0.61 (95% CI = 0.40–0.92) among 65 vs 69 patients with two previous lines, and 0.74 (95% CI = 0.37–1.46) among 29 vs 27 patients with at least two previous lines of therapy in advanced disease; 0.33 (95% CI = 0.14–0.80) among 21 Asian patients who received sotorasib vs 22 Asian patients who received docetaxel; 0.71 (95% CI = 0.54–0.95) among 149 non-Asian patients who received sotorasib vs 151 non-Asian patients who received docetaxel; 0.53 (95% CI = 0.34–0.82) among 58 patients with a history of central nervous system involvement who received sotorasib vs 60 patients with a history of central nervous system involvement who received docetaxel; and 0.74 (95% CI = 0.53–1.03 ) among 113 patients without a history of central nervous system involvement who received sotorasib vs 114 without a history of central nervous system involvement who received docetaxel.
The objective response rate was 28.1% (95% CI = 21.5%–35.4%) vs 13.2% (95% CI = 8.6%–19.2%; P < .001), and the disease control rate was 82.5% vs 60.3%. Tumor shrinkage was observed in 80% vs 63%. Median response duration was 8.6 months (95% CI = 7.1–18.0 months) vs 6.8 months (95% CI = 4.3–8.3 months).
Subsequent therapy was received by 36% of patients in the sotorasib group and 42% of patients in the docetaxel group. A total of 34% of the docetaxel group received a KRAS G12C inhibitor, including 26% who crossed over to sotorasib. Chemotherapy was received by 21% of the sotorasib group. Median overall survival was 10.6 months (95% CI = 8.9–14.0 months) in the sotorasib group vs 11.3 months (95% CI = 9.0–14.9 months) in the docetaxel group (HR = 1.01, 95% CI = 0.77–1.33, P = .53).
The median duration of treatment exposure was 19.9 weeks (range = 0.4–101.3 weeks) in the sotorasib group and 12.0 weeks (range = 3.0–101.0 weeks) in the docetaxel group. Treatment-related grade ≥ 3 adverse events occurred in 33% of the sotorasib group vs 40% of the docetaxel group; the most common were diarrhea (12%), increased alanine aminotransferase 8%), and increased aspartate aminotransferase (5%) in the sotorasib group and neutropenia (9%), fatigue (6%), and febrile neutropenia (5%) in the docetaxel group. Serious treatment-related adverse events occurred in 11% vs 23% of patients. Treatment-related adverse events led to dose interruption in 36% vs 15% of patients, dose reduction in 15% vs 27%, and discontinuation of study treatment in 10% vs 11%. Fatal treatment-related adverse events occurred in one patient in the sotorasib group (interstitial lung disease) and in two patients in the docetaxel group (ileus and multiorgan failure).
The investigators concluded: “Sotorasib significantly increased progression-free survival and had a more favorable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRAS G12C mutation and who had been previously treated with other anticancer drugs.”
Luis Paz-Ares, MD, PhD, of the Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, is the corresponding author of The Lancet article.
DISCLOSURE: The study was funded by Amgen. Dr. de Langen has received institutional research funding from BMS, MSD, Boehringer, and AstraZeneca. Dr. Paz-Ares has received research funding from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati Therapeutics, GSK, Janssen, Takeda, and Daiichi Sankyo; and honoraria for lectures, presentations, or speakers bureau activities from AstraZeneca, Janssen, Merck, and Mirati Therapeutics.
1. de Langen AJ, Johnson ML, Mazieres J, et al: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: A randomised, open-label, phase 3 trial. Lancet. February 7, 2023 (early release online).
2. Skoulidis F, Li BT, Dy GK, et al: Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 384:2371-2381, 2021.