A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results.

Abstract

177^ Background: Immunotherapy for pancreatic ductal adenocarcinoma (PDA) is likely to require synergistic combinations. One approach is to use heterologous prime boost vaccinations to capitalize on immunostimulatory features of distinct vectors. GVAX is irradiated, GM-CSF-secreting allogeneic pancreatic cell lines given intradermally to elicit a broad antigenic response. Low-dose cyclophosphamide (CY) is given prior to GVAX to inhibit regulatory T-cells. CRS-207 is live-attenuated Listeria monocytogenes (Lm) which expresses mesothelin and stimulates innate and adaptive immunity. In mouse tumor models, Lm/GVAX vaccines are synergistic and in the Phase 1 study of CRS-207, 3 PDA patients who had received prior GVAX lived ≥15 months (mos). Methods: Metastatic PDA patients (ECOG 0-1; adequate organ function) who received or refused ≥1 prior chemotherapy were randomized 2:1 to receive either 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Courses could be repeated. The primary endpoint was to compare overall survival (OS) between the arms. Secondary endpoints were safety, clinical and immune responses. One-sided p-values are reported. Results: 90 patients (Full Analysis Set [FAS]; A: 61, B: 29), of which 51% had received ≥2 chemotherapy regimens for metastatic PDA, were treated. After a median follow-up of 7.8 mos, median OS in FAS was 6.1 vs 3.9 mos (A vs B; HR=0.54, p=0.011). Median OS in patients who received ≥3 doses (per protocol [PP] set: 2 doses of CY/GVAX and ≥1 dose of CRS-207 in A or ≥3 doses of CY/GVAX in B) was 9.7 vs 4.6 mos (A vs B; HR=0.44, p=0.0074). The treatment effect was particularly evident in patients who received ≥2 prior regimens for metastatic PDA with median OS of 5.1 vs 3.7 mos (A vs B; HR=0.34, p=0.001). OS in the PP set was 8.2 vs 4.0 mos (A vs B; HR=0.23, p=0.0003). CA19-9 stabilization was seen in 32% vs 13% of patients (A vs B; p=0.06). Toxicities included local reactions after GVAX and transient fevers, rigors and lymphopenia after CRS-207. Conclusions: CY/GVAX followed by CRS-207 shows extended survival with manageable toxicity in previously-treated metastatic PDA and warrants further study. Clinical trial information: NCT01417000.