Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors

Abstract

Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies.This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100 %) followed by diarrhea (15 patients; 88 %), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.

Review: Angiogenesis inhibitors in the treatment of non-small cell lung cancer

“…This occurred at doses lower than the single-agent doses. There is also phase I evidence that sorafenib (400 mg bid) can be safely combined with the EGRF inhibitors erlotinib (150 mg) and gefitinib (250 mg) with promising antitumor activity [Adjei et al 2007;Duran et al 2007]. Four phase II trials are evaluating the efficacy of sorafenib with erlotinib in patients with advanced NSCLC in the first-line setting.…”

A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer

“…Recent clinical data show efficacy of sorafenib monotherapy in NSCLC (6)(7)(8). In addition, a phase I study established the safety and tolerability of combining sorafenib and erlotinib with promising antitumor activity for solid tumors, whereas preclinical data show synergism even in EGFR inhibitor-resistant NSCLC (9,10).…”

Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.

“…[16,17] Prior pharmacokinetic studies show sorafenib at a dose of 200 mg twice daily continuously dosing leads to drug concentration levels that cover inhibition of Flt-3, RET, KIT, VEGFR-2, VEGFR-3, and PDGRF-b based upon biochemical and cellular IC 50 data. [18,19].…”