Multiple Studies Investigating KRAS G12C Inhibitors in NSCLC

Smoking remains the leading cause of lung cancer. In the United States, lung cancer is the second most common malignancy and the leading cause of death. In 2022 it affected more than 200,000 people, and in 2020 led to an estimated 100,000 deaths. Non–small cell lung cancer (NSCLC) accounts for most lung cancer cases, and the estimated 5-year survival rate is between 18% and 25%. The majority of people with NSCLC are diagnosed in advanced stages, with the most common symptom being a cough. Traditional treatments include surgery, cytotoxic chemotherapy, and radiation therapy; for certain patients, immunotherapy is a first-line treatment option. KRAS is the second most common mutation in NSCLC and is found in 30% of adenocarcinoma cases and 5% of squamous cell carcinomas. Because KRAS mutations are common in NSCLC, there is interest in it as a targetable biomarker; however, it has been a challenging target, as it binds strongly to guanosine triphosphate and does not have easily targetable binding sites for drugs.

An article published in The Journal of Oncology Pharmacy Practice reviewed the currently available and upcoming KRAS-targeted treatments for lung cancer. Sotorasib was approved by the FDA in 2021 based on the results of the phase 2 CodeBreaK 100 trial for previously treated patients with locally advanced or metastatic NSCLC harboring the KRAS G12C mutation. This multicenter study enrolled 126 patients with advanced KRAS G12C NSCLC who received 960 mg of oral sotorasib once daily until disease progression or intolerable adverse events occurred. Disease control was observed in 80.6% of patients, with 33.9% of patients having a partial response and 3.2% having a complete response. In patients with a response, the median time to response was 1.4 months, and the median duration of response was 11.1 months. The median progression-free survival was 6.8 months, and the median overall survival was 12.5 months. Treatment-related adverse events were observed in 69.8% of patients, and the most common adverse events were diarrhea, nausea, increased liver enzymes, and fatigue. Grade 3 or 4 adverse events occurred in 20.6% of patients; no grade 5 adverse events were observed.

Currently the CodeBreaK 200 trial is ongoing to compare the efficacy and safety of sotorasib combined with docetaxel as second-line treatment in patients with KRAS G12C advanced NSCLC. Adagrasib is also approved as treatment for previously treated patients with NSCLC harboring the KRAS G12C mutation. This review is based on the results of the phase 1/2 KRYSTAL-1 trial of 116 patients with previously treated KRAS G12C–mutated NSCLC. One patient achieved a complete response, whereas 42.9% had a confirmed objective response. Tumor shrinkage occurred in 79.5% of patients. The phase 3 KRYSTAL-12 study will compare adagrasib to docetaxel in the subsequent-line setting, and the KRYSTAL-7 phase 2 trial will compare adagrasib alone and in combination with pembrolizumab in the first-line setting for KRAS G12C NSCLC. Other KRAS G12C inhibitors under investigation include D-1553, BI 1701963, and JNJ-74699147.

Source: Yun J, Nakagawa R, Tham K. KRAS-targeted therapy in the treatment of non-small cell lung cancer. J Oncol Pharm Pract. 2023;29(2):422-430.