Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer.

Abstract

380 Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC). Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and a maximal response is achieved by combining FAK and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation (Jiang H et al, Nature Medicine 2016). Defactinib is an orally available, well-tolerated, potent ATP-competitive FAK inhibitor. Methods: Eligible patients are being treated according to the dose escalation schema (Table 1). A 3+3 design is being used. The study has an expansion portion for PDAC patients at the recommended phase 2 dose (RP2D). The primary endpoint is to determine the RP2D. Secondary endpoints include safety, toxicity, objective response rate, progression-free survival and overall survival. The exploratory endpoints include developing a molecular and immune profile for treatment response. Results: The dose escalation cohort has been completed with a total of 17 patients with refractory solid tumors being enrolled. The common treatment-related adverse events included fatigue (35%), nausea (29%), myalgia (29%), vomiting (24%), anorexia (24%), pruritus (24%) and fever (18%). No DLTs were observed, therefore the Level 5 dose was deemed to be the RP2D. Among the 13 patients evaluable for treatment response, 7 (54%) have stable disease. No partial or complete responses were observed to date. The median time on treatment was 127 days for all evaluable patients, and 104 days in the 6 PDAC patients with the longest time on treatment being 290 days. Paired biopsies in PDAC patients showed decreased p-FAK and changes in T cells infiltration and proliferation with treatment. Conclusions: The combination regimen is well tolerated. Dose Level 5 is the RP2D dose. The expansion cohort (PDAC only) is ongoing. Efficacy and correlative data is forthcoming. Dose LevelDefactinib D1-21 (BID)Pembrolizumab Gemcitabine (D1 and 8) Level 1 200 mg 200 mg- Level 2 400 mg 200 mg- Level 3 400 mg 200 mg 500 mg/m2 Level 4 400 mg 200 mg 750 mg/m2 Level 5 400 mg 200 mg 1,000 mg/m2 Clinical trial information: NCT02546531.