From the Journals

First combo trial of mTOR/BRAF inhibition shows potential

 

Key clinical point: A combination of the mTOR inhibitor everolimus and the BRAF inhibitor vemurafenib is safe and effective against some treatment-refractory, BRAF-mutated solid tumors.

Major finding: Twenty-two percent (22%) of patients had a partial response to therapy.

Study details: A phase I, dose-escalation trial involving 20 patients with advanced, BRAF-mutated cancer that had progressed on MEK and/or BRAF inhibitor therapy.

Disclosures: The authors reported affiliations with Bayer, Baxter, Novartis, Roche, Trovagene, and others.

Source: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.


 

FROM JCO PRECISION ONCOLOGY

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

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