The KRAS G12C mutation is found in 14% to 30% of patients with lung adenocarcinoma, primarily those with a history of smoking.1,2 The KRAS mutation occurs due to a cysteine substitution for glycine at codon 12.1 Normally, KRAS alternates between the active guanosine diphosphate (GDP)-bound and inactive GDP-bound states, but the KRAS G12C mutation is left in an active state that accelerates downstream signalling.1 This leads to cell and tumor proliferation.1 The KRAS G12C mutation has been difficult to target because it is small, lacks binding pockets, and has an overabundance of active GTP in the cell cytoplasm.1
Based upon the results of the CodeBreak 100 clinical trial, sotorasib was granted accelerated Food and Drug Administration (FDA) approval in May 2021 for the treatment of previously treated patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring the KRAS G12C mutation.1 Sotorasib is a KRAS G12C inhibitor targeting the inactive form of KRAS.1 First-line treatment for KRAS G12C–positive NSCLC is generally an immune checkpoint inhibitor plus chemotherapy, and second-line treatment with progression is docetaxel with or without ramucirumab.2 The CodeBreak 200 clinical trial is a global, confirmatory, randomized, phase 3 trial comparing 960 mg of sotorasib orally once daily with 75 mg/m2 of docetaxel intravenously every 3 weeks.1
The results of this trial were presented at the European Society of Medical Oncology 2022 meeting3 and later published in the Lancet.4 The primary study end point was progression-free survival (PFS). In this study, 171 patients were randomly assigned to sotorasib and 174 patients received docetaxel.1 The median PFS with sotorasib was 5.6 months, and with docetaxel the PFS was 4.5 months. The 12-month PFS rate was 24.8% for sotorasib and 10.1% for docetaxel.1 The overall response rate (ORR) was 28.1% for sotorasib compared with 13.2% for docetaxel.1 Patients who received sotorasib had a time to response of 1.4 months compared with 2.8 months for those receiving docetaxel.2
These results, along with demonstrative clinical activity against other solid tumors harboring the KRAS G12C mutation, led Brazel and colleagues to conclude that sotorasib has led to a true breakthrough in treating KRAS G12C–positive NSCLC.1 However, Zhang and colleagues found that the phase 3 trial results produced lower PFS and ORR values compared with the CodeBreak 100 trials.2 Sotorasib therapy costs $17,000 USD per month, whereas docetaxel therapy is $1700 USD per month.2 They argued that due to the lower PFS results, sotorasib should not be considered a true breakthrough, leaving space for other KRAS G12C inhibitors such as adagrasib.2 Adagrasib recently achieved FDA accelerated approval for patients with NSCLC based on the results of the KRYSTAL-1 study.2 This study found adagrasib had a 43% response rate, with a median duration of response of 8.5 months.2 Finally, many patients will have comutations, which may lower tumor susceptibility to sotorasib; data are limited on sotorasib central nervous system (CNS) penetration because patients with active CNS metastases were excluded from clinical trials.2
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