Attempts for developing inhibitors of RAS-driven oncogenesis has failed over the last three decades, until an allele-specific covalent inhibitor, sotorasib (previously known as AMG 510), was granted fast track designation by the United States Food and Drug Administration (US FDA).¹Moore AR et al. Nat Rev Drug Discov. 2020;19(8):533-552. Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Results of a phase 1 trial of sotorasib in patients with advanced solid tumours harbouring KRAS G12C mutation were recently published in the New England Journal of Medicine.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

The phase 1, multicentre, open-label trial aimed to evaluate the safety, pharmacokinetics, and efficacy of sotorasib in advanced solid tumours with mutated KRAS G12C.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients were aged ≥18, with histologically confirmed locally advanced or metastatic cancer that was confirmed to have a KRAS G12C mutation by local molecular testing on tumour tissues.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients with NSCLC were allowed previous platinum-based combination therapy, targeted therapies, or both, and patients with colorectal cancer (CRC) were allowed two previous lines of systemic therapy for metastatic disease.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients with solid tumours other than NSCLC or CRC had to have received at least one previous line of systemic therapy.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

The trial had dose escalation and expansion cohorts, and sotorasib was administered orally once daily.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The planned dose levels for escalation cohorts were 180, 360, 720, and 960mg.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The primary endpoint was safety.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Secondary endpoints included maximum plasma concentration, time to achieve maximum plasma concentration, objective response, duration of response, disease control, and progression-free survival (PFS).³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

A total of 129 patients, of which 59 had NSCLC and 42 had CRC, were enrolled in this trial.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median follow-up was 11.7 months, and treatment discontinuation occurred in 82.9% of patients.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The most common reason for discontinuation was disease progression.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median age of the study population was 62 years, with a median of 3 previous lines of anticancer therapy for metastatic disease.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. No dose-limiting toxic effects were observed with sotorasib.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Adverse events of any cause were reported in 96.9% of patients, with the most common events being diarrhoea (29.5%), fatigue (23.3%), and nausea (20.9%).³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Grade ≥3 TEAEs included an increase in alanine aminotransferase (ALT) levels, diarrhoea, and anaemia.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. One patient reported a grade 4 TEAE of elevated ALT, which returned to baseline after reducing the sotorasib dose and tapering glucocorticoids.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

The maximum plasma concentration of sotorasib was 7.50μg/mL, with a median time to maximum plasma concentration of 2.0 hours.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The mean elimination half-life was 5.5 hours.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The 960mg dose once daily was identified as the dose for the dose expansion cohort.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

Of the 59 NSCLC patients, 19 had a confirmed partial response, and 33 had stable disease.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Responses were seen across all dose levels.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Tumour shrinking of any magnitude was observed in 71.2% of patients at the first assessment in week 6.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median time to response was 1.4 months, and median duration of response 10.9 months.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Median duration of stable disease was 4.0 months.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. In the CRC patients, a confirmed partial response was observed in 7.1% of patients, and 66.7% had stable disease.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median duration of stable disease was 5.4 months.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median PFS was 4.0 months for all CRC patients.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

These results show that sotorasib demonstrated promising activity in patients with heavily pre-treated KRAS G12C mutated solid tumours, although the differences in response between NSCLC and CRC patients indicate that KRAS G12C may not be the dominant oncogenic driver in CRC.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Majority of patients receiving sotorasib experienced adverse events, although majority were of low grade.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The study authors indicate that other trials evaluating sotorasib as monotherapy or in combination for NSCLC or other solid tumours are underway.³Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.