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KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.


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.).

SUBMITTER: Hong DS 

PROVIDER: S-EPMC7571518 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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KRAS<sup>G12C</sup> Inhibition with Sotorasib in Advanced Solid Tumors.

Hong David S DS   Fakih Marwan G MG   Strickler John H JH   Desai Jayesh J   Durm Gregory A GA   Shapiro Geoffrey I GI   Falchook Gerald S GS   Price Timothy J TJ   Sacher Adrian A   Denlinger Crystal S CS   Bang Yung-Jue YJ   Dy Grace K GK   Krauss John C JC   Kuboki Yasutoshi Y   Kuo James C JC   Coveler Andrew L AL   Park Keunchil K   Kim Tae Won TW   Barlesi Fabrice F   Munster Pamela N PN   Ramalingam Suresh S SS   Burns Timothy F TF   Meric-Bernstam Funda F   Henary Haby H   Ngang Jude J   Ngarmchamnanrith Gataree G   Kim June J   Houk Brett E BE   Canon Jude J   Lipford J Russell JR   Friberg Gregory G   Lito Piro P   Govindan Ramaswamy R   Li Bob T BT  

The New England journal of medicine 20200920 13


<h4>Background</h4>No therapies for targeting <i>KRAS</i> mutations in cancer have been approved. The <i>KRAS</i> 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 KRAS<sup>G12C</sup>.<h4>Methods</h4>We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the <i>KRAS</i> p.G12C mutation. Patients received sotorasib  ...[more]

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