Rociletinib for EGFR-mutated Non–Small-Cell Lung Cancer

Summary and Comment |
April 29, 2015

Rociletinib for EGFR-mutated Non–Small-Cell Lung Cancer

  1. Anne S. Tsao, MD

This EGFR mutant-selective inhibitor overcomes T790M-mediated resistance.

  1. Anne S. Tsao, MD

In patients with non–small-cell lung cancer (NSCLC), resistance to first-generation epidermal

growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is usually mediated by the T790M EGFR gene mutation. Rociletinib is an oral EGFR mutant-selective inhibitor that has demonstrated activity against EGFR-mutated NSCLC with or without T790M mutation.

Investigators have now conducted an industry-supported, phase 1–2 dose-escalation and expansion trial of rociletinib in patients with EGFR-mutated NSCLC who acquired resistance to EGFR TKIs; the expansion segment of the study (phase 2) involved patients with confirmed T790M-positive disease. Of 130 patients, 38 received free-base rociletinib at a dose of <900 mg twice daily, which was considered subtherapeutic. The following results were reported for the remaining 92 patients who received ≥900 mg twice daily of free-base rociletinib or any dose of the hydrogen bromide form of rociletinib:

  • The maximum tolerated dose was not reached. The main dose-limiting toxicity was grade 3 hyperglycemia, which occurred in 22% of patients; another 5% experienced grade 3 QTc prolongation, but all were managed with dose-reductions.

  • Among 46 patients with centrally confirmed T790M-positive disease, the response rate was 59%, the disease-control rate was 93%, and the median progression-free survival (PFS) was 13.1 months.

  • Among 17 patients with centrally confirmed T790M-negative disease, the response rate was 29%, the disease-control rate was 59%, and the median PFS was 5.6 months.

Comment

Because rociletinib is EGFR-mutant selective and spares EGFR wild-type receptors, it results in fewer common EGFR TKI-associated adverse effects of rash and diarrhea. However, hyperglycemia is a toxicity that requires monitoring, as 38% of patients required dose reduction or an oral hypoglycemic or both. Although rociletinib has FDA breakthrough designation and is anticipated to be indicated for EGFR-TKI–resistant NSCLC, its usage may evolve as ongoing TIGER trials evaluate its efficacy in front-line and salvage settings.

Editor Disclosures at Time of Publication

  • Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Speaker’s bureau Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG Leadership positions in professional societies American Medical Association (Member); American Association of Cancer Research (Member); American Society of Clinical Oncology (Member); AACR-Women in Cancer Research (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); RTOG (Member)

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