Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer

Abstract

Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes-expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).

Patients and methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates.

Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7-8.6] and 6.1 (95% CI, 3.5-7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55-1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8⁺ T cells and a decrease in CD68⁺ myeloid cells, were observed in long-term survivors in Arm A only.

Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.

Figure 1.. Treatment schema.

Patients with previously treated, metastatic pancreatic cancer were randomized 1:1 to 2 treatment arms (Arm A: Cy/GVAX & CRS-207 + Nivolumab vs. Arm B: Cy/GVAX & CRS-207). Cycles were administered at 3 week intervals. Cyclophosphamide and nivolumab were administered on days 1, GVAX and CRS-207 were administered on days 2. A course was 6 cycles and courses could be repeated.

Figure 2.. Overall survival.

A comparison of overall survival in months for treatment groups A versus B.

Figure 3.. Treatment Effect by Baseline Characteristics.

Forest plot of the treatment effect within subgroups defined by baseline demographic, disease, and treatment characteristics. N_A and N_B represent the number within in each subgroup in Arms A and B, respectively. Both the hazard ratio within each subgroup and the hazard ratio of the interaction comparing the subgroups are provided. RZ = randomization.

Figure 4.. Maximum decrease in the sum of longest diameters in the target lesions

Figure 5.. Delayed response after RECIST v.1.1 progression and associated immune infiltration.

A-C) Baseline, week 10, and week 30 scans of a patient treated on Arm A demonstrating growth followed by regression (immune related response at week 30). D) Top panel: Archived pancreas tumor shows expression of PD-L1 membranous staining and few CD8 and CD3 T cells. Bottom panel: On treatment lung metastases shows expected pattern of PD-L1 expression on CD68 macrophages as well CD8 and CD3 T cell infiltration.

Figure 6.. Longitudinal changes of immune cell complexity profiles in association with overall survival (OS).

FFPE tissue sections derived from biopsies obtained at baseline and at the post cycle (Cy 3) were subjected to immune-detection by the three 12-marker panels of lymphoid and myeloid lineages, and T cells (Supplementary Table 1). (A) Immune cell densities (cell number per mm²) of CD8⁺ T cell, other lymphoid lineages cells, CD68⁺CSF1R⁺ tumor associated macrophages (TAMs), CD66b⁺ granulocytes, and other myeloid cell lineages are shown, comparing baseline and post Cy3 status among short and long OS groups. (B) The ratios of lymphoid to myeloid cell densities are shown, comparing baseline and post Cy3 status among short and long OS groups. (C, E) Multiplex IHC images for T cell lineages (C) and myeloid cell lineages (E), comparing baseline and post Cy3 of ADU-CL-06–001-022 in arm A. Color annotations and scales were shown. (D, F) Frequency of CD8⁺ T cells (D) and CD68⁺ myeloid cells (F) are exhibited as cell percentages of total CD45⁺ immune cells, comparing baseline and post Cy3 status among short and long OS groups. * and ** indicate P < 0.05 and 0.01, respectively.