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

Study Details

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

Progression-Free Survival

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). 

Adverse Events

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.

REFERENCES

1. de Langen AJ, Johnson ML, Mazieres J, et al: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS^G12C 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.