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.

Fig 1.

(A) Waterfall plot depicting best response as percent change in target lesions in all 18 evaluable patients with advanced cancer treated with vemurafenib and everolimus. Patients previously treated with a BRAF and/or MEK inhibitor are in blue. Stars indicate patients still on trial without disease progression at the time of analysis. (B) Representative restaging images of a patient with metastatic melanoma and a PTEN (P95S) mutation who had a partial response on vemurafenib and everolimus after disease progression on vemurafenib and PX866, an investigational PI3K inhibitor. Astro, anaplastic astrocytoma; AT, anaplastic thyroid; CRC, colorectal cancer; CUP, cancer of unknown primary; Glio, glioblastoma; Glioma, optic nerve glioma; Mel, melanoma; PT, papillary thyroid.

Fig 2.

Graphical depiction of a patient’s circulating tumor DNA level of BRAF^V600E (shown as copies per milliliter of plasma) while on treatment with vemurafenib plus everolimus with representative restaging scans and response to therapy, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. PD, progression of disease; PR, partial response.