Therapies in Development for KRAS G12C–Mutated NSCLC

The Kirsten rat sarcoma (KRAS) oncogene is the second most frequent lung cancer mutation found in patients with lung cancer. KRAS mutation occurs in 30% of all cases of non–small-cell lung cancer (NSCLC) and has long been considered to be undruggable. KRAS plays a role in molecular switching by converting guanosine triphosphate molecules to guanosine diphosphate molecules, the inactive molecule state. Mutated KRAS protein maintains KRAS in the active state, leading to unregulated oncogene signaling and tumor proliferation. The most common mutation subtype in KRAS-mutated NSCLC is G12C, occurring in 13% of cases in Western countries and 3% to 5% in Asian countries. Recent advances in therapy have given patients with KRAS G12C mutation treatment options with the development of direct KRAS inhibitors. A review published in Cancer Management and Research summarized the targeted therapies and immunotherapy and ongoing clinical trials for patients with NSCLC harboring the G12C mutation.

In May 2021, the FDA granted accelerated approval for sotorasib, a small molecule that irreversibly binds to a small pocket in the KRAS G12C protein, locking it in an inactive state. The approval is for patients with previously treated locally advanced or metastatic NSCLC harboring the KRAS G12C mutation. The CodeBreak 100 phase 1/2 study demonstrated the safety of sotorasib monotherapy along with encouraging antitumor activity in previously treated metastatic NSCLC, whereas the phase 3 CodeBreak 200 study found sotorasib significantly improved progression-free survival compared with docetaxel in patients with previously treated NSCLC harboring the KRAS G12C mutation. In addition, a phase 2 clinical trial found that sotorasib use in patients with previously treated advanced or metastatic KRAS G12C NSCLC resulted in an objective response rate (ORR) of 40.7% and a disease control rate (DCR) of 83.7%. Adagrasib is a KRAS G12C inhibitor under investigation in the KRYSTAL-1 phase 1/2 study. The study demonstrated that adagrasib had favorable safety and efficacy in 116 patients with advanced or metastatic NSCLC harboring KRAS G12C mutations, with 98% of patients having prior treatment. The ORR was 43% and the DCR was 80%. D-1553 is a selective KRAS G12C inhibitor being evaluated in patients with previously treated KRAS G12C–positive NSCLC. The ORR was 40.4% and the DCR was 90.4% in this phase 1 clinical trial.

Immunotherapy clinical trials for treatment of KRAS G12C NSCLC are also underway. Anti–PD-L1 single agents are being investigated in the Checkmate 057 trial (nivolumab versus chemotherapy), the OAK trial (atezolizumab), KEYNOTE-042 trial (pembrolizumab), and IMMUNTRGET study. Anti–PD-L1 combined therapy trials likewise are underway. The KEYNOTE-189 trial is investigating pembrolizumab plus chemotherapy versus chemotherapy alone. The IMPOWER 150 study is evaluating ABCP (atezolizumab, bevacizumab, carboplatin, and paclitaxel), ACP (atezolizumab, carboplatin, and paclitaxel), and BCP (bevacizumab, carboplatin, and paclitaxel) in patients with KRAS G12C mutations and has found the ABCP regimen has better overall survival and progression-free survival when compared with ACP and BCP treatment regimens.

Source: Shu CL, Liu YL. The path to personalized treatment in KRAS-mutant non-small cell lung cancer: a review of targeted therapies and immunotherapy. Cancer Manag Res. 2022;14:3485-3492.