A phase II multicenter evaluation of ARQ 197 monotherapy in patients with relapsed or refractory germ cell tumors (GCTs).

Abstract

4638 Background: ARQ 197 is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the c-MET receptor tyrosine kinase. Preclinical and phase I data suggested a possible role for c-MET in the pathophysiology of GCTs and a potential clinical benefit from ARQ 197 in GCT patients. Methods: Men (≥ 16 years of age) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received continuous oral ARQ 197 (360 mg twice daily in 28-day cycles) until progressive disease (PD) or unacceptable toxicity. Responses were assessed every 4 weeks during the first 4 cycles, and every 8 weeks thereafter per RECIST v1.1. The primary endpoint was objective response rate within the first 4 cycles, with study termination for < 2 responses amongst the first 21 patients (Simon 2-stage optimal design). Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results: 27 patients (median age, 32 years) were enrolled from 9 sites in the US and Europe from February 2010 to November 2010. 25 had non-seminoma histology. Primary tumor sites included testis in 24, and mediastinum in 3. ECOG performance status was 0 (n = 9) or 1 (n = 18). All patients had received ≥ 2 prior lines of chemotherapy and 19/27 (70%) had received high-dose chemotherapy. Among 25 patients evaluable for efficacy, there were no objective responses and accrual was halted once the 21st patient became evaluable. Best response was stable disease in 7 and PD in 18. Median PFS was 32 days (95% CI = 29, 52) and 12-week PFS rate was 14%. Less than half (n = 12) patients have died. Reported grade 3/4 adverse events considered related to study drug were rare and included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions: ARQ 197 was well tolerated but did not demonstrate activity as a single agent in patients with relapsed/refractory GCTs. Correlative biologic data is pending but may provide insight into the lack of efficacy observed. Rapid accrual to this phase II trial was achieved in this rare patient population through multicenter collaboration. Future collaborative trials of novel targeted agents with sound biologic rationale are warranted in relapsed/refractory GCTs.