Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies.

Abstract

PURPOSE:

Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors.

PATIENTS AND METHODS:

We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily.

RESULTS:

Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles.

CONCLUSION:

The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

• Authors: Vivek Subbiah, Shiraj Sen, Kenneth R Hess, Filip Janku, David S Hong, Soumen Khatua, Daniel D Karp, Javier Munoz, Gerald S Falchook, Roman Groisberg, Apostolia M Tsimberidou, Steven I Sherman, Patrick Hwu, Funda Meric-Bernstam
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 2 ( 2018) ISSN: 2473-4284 [Electronic] United States
• PMID: 32913986 (Publication Type: Journal Article)
• Copyright: © 2018 by American Society of Clinical Oncology.