Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Abstract

Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced nonŝ mall cell lung cancer. Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21days followed by a 7-day washout with crossover to the other agent for an additional 21days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C max (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease z4 months.The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non^small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

“…The median PFS interval in our study was 2.8 months, similar to previously reported data [37]. However, some studies of less heavily pretreated or treatment-naïve patients with NSCLC reported better outcomes, with median PFS times of 4 -5 months [32,38]. In advanced/metastatic NSCLC, the median OS time on first-line therapy rarely exceeds 11 months and the median PFS duration is usually around 5 months [39 -42].…”

“…In addition, data obtained from our phase I clinic on 683 participants having various tumor types showed that patients treated with low dose levels did not fare worse [31]. Previously reported RRs in heavily pretreated NSCLC patients treated in disease-specific phase I clinical trials were in the range of 3%-15% [32][33][34]. Most of our patients with NSCLC (77 of 85, 90.5%) were enrolled in studies that administered targeted agents.…”

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.…”

Molecular targeted therapies for cancer: Sorafenib mono�therapy and its combination with other therapies (Review)

“…combination (53) Sorafenib + gefitinib Evaluated this combination in Sorafenib combined with gefitinib was well tolerated, with advanced NSCLC (54) promising efficacy in patients with advanced NSCLC.…”