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Nature reviews | CliniCal OnCOlOgy Attempts to therapeutically target the products of the RAS oncogenes, frequently mutated in cancer, have had disappointing results thus far. The small molecules MRTX849 and AMG 510, from two independent drug discovery programmes, covalently bind to KRAS G12C, keeping it predominantly in an inactive state. Two articles now describe the activity of these drugs in preclinical models and initial clinical responses in patients with KRASG12Cmutant cancers. Following promising findings in cellline based studies, MRTX849 and AMG 510 inhibited 2D and 3D cell growth of KRASG12Cmutant cancer cell lines to variable degrees. Both agents inhibited the growth of mouse xenograft tumours derived from KRASG12Cmutant human cell lines or patientderived xenograft tumours in a dosedependent manner with a toxicity profile deemed tolerable. Tumour regression was observed with both agents at the highest doses tested. Of note, treatment with 200 mg/kg AMG 510 led to complete regression of tumours derived from CRISPRgenerated KRASG12Cmutant syngeneic CT-26 cells in 8 of 10 immunecompetent mice, but not in mice lacking T cells. MRTX849 and AMG 510 are currently being tested in firstinhuman clinical trials (NCT03785249 and NCT03600883, respectively) involving patients with KRASG12Cmutant solid tumours, mostly nonsmall-cell lung carcinoma (NSCLC) or colorectal carcinoma. The results of these trials were presented at the 2019 ASCO Annual Meeting (AMG 510) and at the 2019 AACR–NCI–EORTC joint conference (MRTX849). The majority of 17 patients receiving MRTX849 had grade 1–2 treatmentrelated adverse events (TRAEs), and one patient had grade 3 fatigue. Twelve patients were evaluable for response: four had partial responses (PRs) and eight had stable disease (SD). All patients who had PRs received a dose of 600 mg twice daily; one with NSCLC had a 43% reduction of the target lesion and one with CRC had a 47% reduction, both 6 weeks after starting treatment. A total of 35 patients received AMG 510; 28 events of grade 1–2 TRAEs were reported and 29 patients were evaluable for response: 5 PR, 18 SD and 6 patients had progressive disease. In two patients with NSCLC who had PRs, reduction of the target lesion was 34% and 67% after 6 weeks of treatment with doses of 180 mg and 360 mg, respectively. Owing to the role of T cells in the response of mice to AMG 510, this agent was tested in combination with antiPD-1 antibodies in immunocompetent mice harbouring KRASG12CCT-26 tumours, leading to complete and durable responses in 9 of 10 mice. “We are dissecting the effect of AMG 510 on the immune phenotype to determine which treatment combinations might be the most effective in tumour elimination”, comments investigator Jude Canon. MRTX849 is also being explored in combination, although investigator James Christensen believes that these agents could be used as monotherapies in some patients: “we need to understand KRAS mutations in a broader genetic context in treated patients to determine if there is a refined way to select patients for monotherapy.” The optimal treatment strategy for these agents is only one of several aspects that remain to be determined. The results of large, prospective randomized trials designed to determine the degree and duration of clinical benefit from these agents, their toxicities, and mechanisms of resistance, are eagerly awaited.