The Kirsten rat sarcoma (KRAS) gene occurs in 25% of all patients with non–small-cell lung cancer (NSCLC) with the G12C mutation occurring in approximately 13% of KRAS-driven NSCLC. The KRAS mutation confers a poor patient prognosis and only recently have a handful of therapies demonstrated efficacy against this mutation. The normal mechanism of action of the KRAS protein is via switching between an inactive form (GDP-RAS) and an active form (GTP-RAS), which leads to a reduction in cell growth and proliferation. The GTP-RAS bond is strong and has proven difficult to use as a target for therapy. Palma and colleagues assessed the chemistry, pathway alterations, and clinical outcomes of selected KRAS G12C inhibitors to gain a better understanding of KRAS G12C therapies currently available and under research.
Sotorasib and adagrasib are inhibitors of KRAS G12C. In the CodeBreak 100 study on the use of sotorasib in patients with KRAS G12C–harboring NSCLC, sotorasib demonstrated a partial response in half the study population with 4 patients having stable disease during the phase 1 portion of the study. A year later, updated results reported 19 of 59 patients had a partial response and 33 of 50 patients had stable disease. The median progression-free survival was 6.3 months. In the phase 2 study, 126 patients with NSCLC were evaluated. Partial responses were reported for 43 patients, 3 had complete responses, and the overall response rate (ORR) was 37.1%. The median duration of response was 10.0 months, the median progression-free survival was 6.8 months, and the disease control rate was 80.6%. In the KRYSTAL-01 clinical trial, 51 patients with NSCLC received 600 mg of adagrasib twice a day. Partial response was found in 45% of patients and 51% had stable disease with a disease control rate of 96%.
Further analysis of both sotorasib and adagrasib was performed to determine response when other mutations occurred concurrently with the KRAS G12C mutation. With sotorasib use, an ORR of 50% was found in 22 patients with KRAS G12C and STK11 mutations and 23% with STK11 and KEAP1 mutations. When adagrasib use in patients with KRAS G12C mutation and STK11 mutation was evaluated, the ORR was 64%. Other KRAS G12C–inhibiting molecules are under investigation offering the possibility of future therapeutics. These are targeting other sites on the oncogene or have higher potency. Combination approaches are also being investigated, including immune checkpoint inhibitors, MEK inhibitors, CDK inhibitors, EGFR inhibitors, and mTOR inhibitors.
Source
Palma G, Khurshid F, Lu K, et al. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. NPJ Precis Oncol. 2021;5:98.
