Responses to immune checkpoint inhibition among MSI-H pancreatic ductal adenocarcinoma: A multi-institutional case series.

Abstract

4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence <2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for >5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.