Background: Vemurafenib (Vem) is approved by the US Food and Drug Administration for the treatment of BRAF V600-mutant melanoma. Vem also has demonstrated activity in BRAF V600-mutant non-melanoma cancers. However, with monotherapy, all patients eventually experience disease progression, and more effective treatments are needed. On the basis of preclinical studies showing that combined inhibition of the BRAF and PI3K/mTOR pathways may overcome the primary or innate resistance mechanisms in BRAF-mutant malignancies, we conducted a phase I trial combining Vem with the mTOR inhibitor everolimus (Eve).

Objectives: Primary objectives of this open-label phase I trial were to evaluate safety and tolerability, and to determine the maximum tolerated dose (MTD) of the Vem and Eve combination in patients with BRAF-mutant advanced cancers; the secondary objective was to assess efficacy.

Methods: Escalating doses of Vem twice daily (BID) and Eve once daily (QD) were combined using the standard 3 + 3 design, and then an expansion cohort was enrolled and treated at the MTD. Treatment was administered in 28-day cycles. MTD was defined as the highest dose studied in which incidence of dose-limiting toxicity (DLT) was less than 33%. Younger patients were enrolled at the accruing dose level, with body surface area-based dose adjustments for smaller children.

Results: Twenty patients (14 male, 6 female) with BRAF-mutant (18 V600E, 1 V600K, 1 G469A) melanoma (n = 7) or central nervous system (n = 5), thyroid (n = 4), non-small cell lung (n = 1), colorectal (n = 1), appendiceal (n = 1), or unknown primary (n = 1) cancer were enrolled. The median age of the 18 adult patients was 64 years (range 16-85 years); the 2 pediatric patients were aged 10 and 13 years. Prior therapies included surgery (n = 18, 90%), radiation (n = 11, 55%), cytotoxic chemotherapy (n = 14, 70%), and a prior phase I trial (n = 10, 50%). Ten patients (50%) had prior treatment with BRAF/MEK inhibitor(s). Ten patients had received 2 or more lines of systemic therapies. No dose-limiting toxicity was observed at dose level 1 (Vem 720 mg BID, Eve 5 mg QD). Two DLTs (rash, fatigue) were observed at dose level 2 (Vem 720 mg BID, Eve 10 mg QD). Dose level 1 was determined to be the MTD. Grade >3 toxic effects included rash (n = 4), fatigue (n = 4), photosensitivity (n = 1), anemia (n = 1), hyperglycemia (n = 1), and hypertriglyceridemia (n = 1). After excluding 1 patient who withdrew consent before restaging, we found that 5 patients (26%) had a partial response (melanoma = 1, non-melanoma = 4), 9 (47%) had stable disease, and 5 (26%) had progression as the best response. Among 9 evaluable patients with a history of prior treatment with BRAF/MEK inhibitors, 2 had a partial response and 5 had stable disease. Two patients are continuing the treatment after 5 and 16 cycles.

Conclusion: The combination of Vem (720 mg BID) and Eve (5 mg QD) is safe, well-tolerated, and has activity in patients with BRAF-mutant advanced cancers, including those previously treated with a BRAF/MEK inhibitor.

Citation Format: Muhammad Rizwan Khawaja, Soumen Khatua, Daniel Karp, Filip Janku, David Hong, Javier Munoz, Apostolia Tsimberidou, Wafik Zaky, Steven I. Sherman, Patrick Hwu, Funda Meric-Bernstam, Vivek Subbiah. A phase I dose escalation trial of vemurafenib in combination with the mTOR inhibitor everolimus for melanoma and non-melanoma cancers with a BRAF aberration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT052.