A phase II study of the c-Met inhibitor tivantinib (tiv) in combination with FOLFOX for the treatment of patients (pts) with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach.

Abstract

4065 Background: C-Met protein is a receptor tyrosine kinase that is amplified in gastric and esophageal cancers causing downstream activation of multiple signaling pathways. Tivantinib is an orally bioavailable c-met inhibitor. This phase II study evaluated the response rate (RR) of the combination of tiv plus FOLFOX as treatment for pts with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. Methods: Pts with advanced GE cancer received standard mFOLFOX6 day 1 and tiv (360mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every 4 cycles. The primary endpoint was RR. Secondary endpoints included progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety. Results: Thirty-four pts were enrolled: median age 65 yrs (range, 34-88), 76% male, 53% KPS 90. Forty-seven percent of pts underwent prior surgery, 32% received prior radiation, and 15% received prior systemic treatment. Two pts did not receive treatment due to patient request and anemia prior to cycle 1 day 1. 32 pts were treated for a median of 8 cycles (range, 1-38). Treatment-related toxicities (% G1/2; % G3/4) included neutropenia (9%; 53%), fatigue (47%; 9%), diarrhea (41%; 9%), nausea (44%; 0), and peripheral neuropathy (44%; 0). Of the 26 pts evaluable for response, 10 pts (38%) achieved objective response (1 CR, 9 PRs), with a best response of stable disease noted in 13 pts (50%). The overall RR was 29%. Median PFS was 6.1 months (95% CI: 3.6-8) with a median TTP of 6.1 months (95% CI: 5.2-11.5). Median OS was 9.6 months (95% CI: 7.2-NA). Three pts remain on study and have been on treatment for a median of 16 months (range, 14-19). Their best response was PR (2) and SD (1). One of these pts was met high by IHC. Met status by FISH is unknown at this time. Conclusions: The combination treatment of tiv plus mFOLFOX6 in pts with advanced GE cancer showed a RR and PFS in the range of historical controls for first-line FOLFOX therapy. However, 3 pts had extended time on study treatment, and these pts may represent pts with met-driven tumors. Clinical trial information: NCT01611857.