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Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes –Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

2015; Lippincott Williams & Wilkins; Volume: 33; Issue: 12 Linguagem: Inglês

10.1200/jco.2014.57.4244

1527-7755

Dung T. Le, Andrea Wang‐Gillam, Vincent J. Picozzi, Tim F. Greten, Todd S. Crocenzi, Gregory M. Springett, Michael A. Morse, Herbert J. Zeh, Deirdre Jill Cohen, Robert L. Fine, Beth Onners, Jennifer N. Uram, Daniel A. Laheru, Eric R. Lutz, Sara Solt, Aimee Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas W. Dubensky, Dirk G. Brockstedt, Elizabeth M. Jaffee,

Immunotherapy and Immune Responses

Purpose GVAX pancreas, granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes–expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Patients and Methods Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. Results A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Conclusion Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.