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Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90 Page 5 of 17

benefitted patients with a wide variety of solid tumors, they have shown limited success in patients with
PDAC [44,45] .

One of the first studies to test single agent immunotherapy for the treatment of PDAC was a phase II trial
with ipilimumab, a CTLA4 inhibitor. It was given to 27 patients with PDAC including 20 patients with
metastatic disease and 7 patients with locally advanced disease. There were no responders by response
evaluation criteria in solid tumors criteria (RECIST ver.1.1) and three subjects experienced grade 3
or higher immune-mediated adverse events (colitis, encephalitis, and hypophysitis) leading to early
[45]
discontinuation of the trial . In a larger phase I study in 2012 with 207 patients, 14 of whom had PDAC,
patients were treated with anti-PD-L1 antibody, and no responses were seen in patients with metastatic
[46]
PDAC . In 2015, another smaller phase I study of pembrolizumab (PD-1 inhibitor) in patients with
[47]
advanced solid tumors showed similar results in 1 out of 30 patients with PDAC who did not respond .
ICIs have shown benefit in a small group of PDAC patients whose tumor harbors mismatch repair (MMR)
deficiency, which comprise 1%-3% of PDAC diagnoses [48,49] . In a phase II trial, which included 8 patients
with PDAC, who were MMR deficient and treated with pembrolizumab, there was a 62% objective
[50]
response among PDAC patients . There has been one case report for the benefit of pembrolizumab in
MMR-proficient PDAC, but with high TMB potentially highlighting a new population that would benefit
[51]
from immunotherapy . Pembrolizumab is the first ICI to receive approval from FDA for tumor agnostic
indication for use in patients with MMR-deficient malignancies . Based on the success of pembrolizumab
[50]
in patients with refractory, metastatic cancers with MMR deficiency, the National Comprehensive Cancer
Network (NCCN) now recommends consideration of MSI or MMR testing in patients with locally
advanced or metastatic PDAC.

Combination of chemotherapy, immunotherapy, and radiation
Given the lack of response with single agent ICIs in treatment of PDAC, combination with chemotherapy
or with other immunotherapies has also been studied.

Phase I studies
A phase Ib dose finding study of ipilimumab and gemcitabine showed partial response in 15% (2 patients)
[52]
and stable disease in 38% (5 patients) . In a follow up phase Ib dose expansion study 2 out of 16 patients
had partial response and 5 out of 16 had stable disease. Median PFS was 2.5 months (95%CI: 0.8-4.8 months)
[53]
and medial OS of 8.5 months (95%CI: 2.2-10.3 months) .

Phase II studies
One of the largest phase II trials was a study comparing durvalumab (PD-L1 inhibitor) in combination
with tremilimumab (CTLA-4 inhibitor) vs. durvalumab alone in 65 patients with metastatic PDAC. The
objective response rate (ORR) was 3.1% and median OS of 3.1 months in the combination arm and ORR of
[54]
0% with median OS of 3.6 months in the monotherapy arm. Median PFS was 1.5 months in both arms .
Due to the low patient numbers, the trial was not powered to observe the association between treatment
response and PD-L1 expression or MSI status. Therefore, combination ICIs thus far have shown minimal
benefit in treatment of PDAC.

Combination with chemotherapy and radiation
The combination of radiation with chemotherapy (chemoXRT) and immunotherapy is also being explored
in the treatment of PDAC. The rationale of combining radiation is based on a previously recognized
phenomenon called the abscopal effect whereby a local treatment (i.e., ionizing radiation) results in
systemic or off-target shrinkage of tumor. The abscopal effect is postulated to be induced by anti-tumor T
cell response mediated by immunogenic cell death after radiation [55,56] . Therefore, it has been proposed that