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Clinical Trial
. 2020 Sep 24;383(13):1207-1217.
doi: 10.1056/NEJMoa1917239. Epub 2020 Sep 20.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

David S Hong  1 , Marwan G Fakih  1 , John H Strickler  1 , Jayesh Desai  1 , Gregory A Durm  1 , Geoffrey I Shapiro  1 , Gerald S Falchook  1 , Timothy J Price  1 , Adrian Sacher  1 , Crystal S Denlinger  1 , Yung-Jue Bang  1 , Grace K Dy  1 , John C Krauss  1 , Yasutoshi Kuboki  1 , James C Kuo  1 , Andrew L Coveler  1 , Keunchil Park  1 , Tae Won Kim  1 , Fabrice Barlesi  1 , Pamela N Munster  1 , Suresh S Ramalingam  1 , Timothy F Burns  1 , Funda Meric-Bernstam  1 , Haby Henary  1 , Jude Ngang  1 , Gataree Ngarmchamnanrith  1 , June Kim  1 , Brett E Houk  1 , Jude Canon  1 , J Russell Lipford  1 , Gregory Friberg  1 , Piro Lito  1 , Ramaswamy Govindan  1 , Bob T Li  1
Affiliations
Clinical Trial

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

David S Hong et al. N Engl J Med. .

Abstract

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.

Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.

Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

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Figures

Figure 1.
Figure 1.. Change from Baseline in Tumor Burden in Patients with NSCLC Receiving Sotorasib.
Panel A shows the best percent change from baseline in tumor burden (defined by the sum of the longest diameters- of all target lesions) in 57 of 59 patients with NSCLC for whom postbaseline tumor data were available. PD denotes progressive disease, PR partial response, and SD stable disease. Panel B shows computed tomographic scans of two target lesions from a 55-year-old female patient with NSCLC, at baseline and after 10 and 16 weeks of treatment with sotorasib. The patient had a partial response. Scans and the tumor measurements are from independent central radiologic review.
Figure 2.
Figure 2.. Efficacy of Sotorasib in Patients with NSCLC.
Panel A shows the time to response, the duration of treatment, and patient status by the data cutoff date for all 59 patients with NSCLC, according to the dose of sotorasib. Panel B shows the change in tumor burden over time in 57 of 59 patients with NSCLC for whom postbaseline tumor data were available. Panel C shows Kaplan–Meier curve of progression-free survival for all 59 patients with NSCLC.
See this image and copyright information in PMC

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References

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