Despite many years of research, there is no approved targeted therapy for patients with KRAS mutation-positive tumors – the most commonly mutated oncogene in human cancers. KRAS mutations are frequently associated with resistance to targeted therapies and poor prognosis, particularly in patients with metastatic disease. One of the most prevalent KRAS mutations is KRAS G12C, which occurs in approximately 13% of non-small cell lung cancer (NSCLC) cases, 3–5% of colorectal cancers (CRC), and 1–3% of other solid tumors. G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12 that results in an active form of the KRAS protein, which drives abnormal signaling and tumor growth. Sotorasib (AMG 510) is a novel, highly selective, first-in-class small molecule inhibitor that specifically and irreversibly inhibits KRAS^G12C and locks it in an inactive state. As such, sotorasib may address the unmet need for the treatment of tumors harboring the KRAS G12C mutation.

The multicenter, open-label, phase I clinical trial, CodeBreaK 100, was designed to evaluate the safety and efficacy of sotorasib in patients with advanced solid tumors harboring this mutation. Results from the trial were published recently in New England Journal of Medicine, and data from the NSCLC cohort were presented at the ESMO 2020 virtual meeting by David Hong, MD (The University of Texas MD Anderson Cancer Center, Houston, US). A total of 129 patients (59 with NSCLC, 42 with CRC, and 28 with other tumors) were included in dose escalation and expansion cohorts. Most patients were heavily pretreated, with a median of three previous lines of anticancer therapy for metastatic disease. A key exclusion criterion was untreated active brain metastases. Patients received sotorasib orally, once daily, at the planned dose levels of 180, 360, 720, and 960 mg, with each treatment cycle lasting 21 days. The primary endpoint of the trial was safety, including incidence of dose-limiting toxic effects, and key secondary endpoints were pharmacokinetics, response rates, duration of response, and progression-free survival. The median follow-up times were 11.7 months and 12.8 months for the NSCLC and CRC cohorts, respectively. No dose-limiting toxicity or treatment-related deaths were observed. The most common any-grade adverse events (AEs) were diarrhea (29.5%), fatigue (23.3%), and nausea (20.9%). Treatment-related AEs (TRAEs) were reported in 56.6% of patients, with 11.6% of patients experiencing grade 3/4 TRAEs, which included reversible elevations of aminotransferase levels, diarrhea, vomiting, and anemia. Based on pharmacokinetic and dose–response data, sotorasib 960 mg daily was the recommended dose for the expansion cohort and later trials. In the NSCLC cohort, a confirmed partial response (PR) was seen in 19 patients (32.2%) and stable disease in 33 patients (55.9%), with a median duration of response of 10.9 months. Among patients with CRC, 3 (7.1%) had a confirmed PR, which lasted for 4.9, 6.9, and 9.9+ months, and 28 (66.7%) had stable disease. In patients with other tumor types, 4 (14.3%) had a confirmed PR, which lasted for 4.4, 6.9+, 2.7, and 5.6 months, and 17 (60.7%) had stable disease. Hence, disease control (complete response [CR], PR, or stable disease) was seen in 88.1%, 73.8%, and 75.0% of patients with NSCLC, CRC, and other solid tumors, respectively. Median progression-free survival was 6.3 months and 4.0 months in the NSCLC and CRC cohorts, respectively.

The trial investigators concluded that sotorasib is generally well tolerated and shows promising anticancer activity in patients with heavily pre-treated KRAS G12C-mutant solid tumors. Authors of an accompanying editorial acknowledged that these results are very encouraging and indicate that ‘’drugging the undruggable’’ is indeed possible. They highlighted that tumor responses with sotorasib were much better than with the current standard of care. While it was noted that no CRs were reported, the authors commented that “informed combination strategies may improve the likelihood of achieving CR with KRAS^G12C inhibition”.

References

Hong DS, et al. N Engl J Med. 2020;383(13):1207–1217.

LoRusso PM, and Sebolt-Leopold JS. N Engl J Med. 2020;383:1277–1278.