Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort

Abstract

Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.

Results: 19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited.

Conclusions: Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients.

Trial registration number: NCT02834013.

Keywords: Immune Checkpoint Inhibitor; Ipilimumab; Neuroendocrine and Adrenal Tumor; Nivolumab; Solid tumor.

Figure 1. Waterfall plot of tumor measurements. Gray lines at −30% and 20% indicate lines for partial response and progression per RECIST V.1.1, respectively. Crosshatch-indicated tumor measurements not available due to: progression due to new lesions at first assessment (n=3), death before assessment (n=1), and symptomatic deterioration (n=2).

Figure 2. RECIST V.1.1 progression-free survival and overall survival.

Figure 3. Swimmer plot (n=19) (see also online supplemental table 2).

Figure 4. PD-L1 expression, genomic analysis and immune infiltration in analyzed cohort. PD-L1 expression as detected by chromogenic IHC stratified by (A) best overall response (n=12). (B) Genomic features and TMB (n=4). The orange line indicates 10 mutations per mB. (C) representative mIF staining of two panels in patient 1 (left) and heatmap of cell types detected by multiplex immunofluorescence including clinical features and TMB (n=4) (right). CR, complete response; CTL, cytotoxic T lymphocyte; IHC, immunohistochemistry; mB, megaBase; MC, malignant cell; mIF, multiplex immunofluorescence; PD, progressive disease; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease; TIL, tumor infiltrating lymphocyte; TMB, tumor mutational burden; Treg, regulatory T cell.

Figure 5. Increased cytotoxicity profiles in circulation associate with response. Cytometry by time-of-flight profiling of PBMCs after activation with PMA/ionomycin at baseline (base), cycle 2 week 9 (C2W9) and progression (prog) time points. Cell types are graphed as a proportion of total immune cells. Patients with response are shown in red (PR, solid red; SD>6 months, hashed red; n=1 each). Blue dots represent patients with PD or SD<6 months with a hashed line connecting paired longitudinal time points. (A) Changes in frequencies of major T-cell lineages (total T cells, CD4+T cells, CD8+T cells and Tregs) over time are shown with decreases in Tregs observed in PR patient. (B) Memory states in CD4+T cells (top row) and CD8+T cells (bottom row) show expansion of effector memory and TEMRA subsets in PR patient. (C) Cytotoxicity profile as determined by granzyme B (GZMB), perforin and interferon-γ production post stimulation within the CD4+effector memory T cells (EM; top row) and CD8+EM T cells (bottom row). Increased expression of granzyme B (GZM_B) and perforin is observed in PR patient. C2W9, course 2 week 9; EM, effector memory; PBMC, peripheral blood mononuclear cells; PMA, phorbol myristic acetate; PR, partial response; Prog, progression; SD, stable disease; TEMRA, CD45RA+T cells; Treg, regulatory T cell.