EGFR Inhibitor Rociletinib Active in EGFR T790M Mutation–Positive NSCLC Previously Treated With EGFR Inhibitors
In a phase I/II study reported in The New England Journal of Medicine, Sequist et al found that rociletinib—an EGFR inhibitor active in the presence and absence of the EGFR T790M mutation known to mediate resistance to available EGFR inhibitors—produced a high response rate in patients with T790M-positive non–small cell lung cancer (NSCLC) who had progressed on prior EGFR inhibitor therapy. Responses were also observed in patients with T790M-negative disease.
Study Details
The study included 92 evaluable patients with EGFR-mutant NSCLC that had progressed on treatment with an EGFR inhibitor who were treated with a free-base form of rociletinib (first group of enrolled patients) at a dose of 900 mg twice daily (10 with centrally confirmed presence or absence of T790M mutation) or a hydrogen bromide salt form at doses of 500 mg twice daily to 1,000 mg twice daily (all remaining patients; 53 with centrally confirmed presence or absence of T790M mutation).
A total of 83 patients were evaluable for response. Among 46 patients with centrally confirmed T790M-positive tumors, 59% (95% confidence interval [CI] = 45%–73%) had a partial response, and 35% had stable disease (disease control rate = 93%). Response rates were similar in patients with deletion 19 or L858R EGFR mutations. Estimated median progression-free survival at the time of analysis was 13.1 months (95% CI = 5.4–13.1 months), with data censored for 82% of patients. Among 17 patients with T790M-negative tumors on central testing, the response rate was 29% (95% CI = 8%–51%), and 29% had stable disease (disease control rate = 59%). Estimated median progression-free survival in these patients was 5.6 months (95% CI = 1.3 months to not reached). Among 20 patients whose tumors were not assessable for T790M mutation, the response rate was 15%.
Safety
No maximum tolerated dose was identified. The most common dose-limiting adverse event was hyperglycemia. Among 92 patients receiving therapeutic doses of rociletinib, the most common treatment-related adverse events of any grade were hyperglycemia (47%), nausea (35%), fatigue (24%), and diarrhea (22%); QTc prolongation occurred in 12%. The most common grade 3 adverse events were hyperglycemia (22%) and QTc prolongation (5%). Glucose-lowering treatment was required in 38% of patients. Grade 3 QTc prolongation was asymptomatic and managed by dose reduction. Overall, 48% of patients had dose reduction.
The investigators concluded: “Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation.”
Lecia V. Sequist, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, is the corresponding author of The New England Journal of Medicine article.
The study was funded by Clovis Oncology. For full disclosures of the study authors, visit www.nejm.org.
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