Efficacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient advanced pancreatic adenocarcinoma: An AGEO European Cohort.
Authors: Pilla Lorenzo , Sayah Lina , Heinrich Kathrin , Kunzmann Volker , Boileve Alice , Cirkel Geert A. , Lonardi Sara , Chibaudel Benoist , Turpin Anthony , Beller Tamar , Hautefeuille Vincent , Vivaldi Caterina , Mazard Thibault , Bauguion Lucile , Niger Monica , Prager Gerald W. , Coutzac Clélia , Westphalen Benedikt , Auclin Edouard , Taieb Julien 
Published: June 2023

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Background: Immune checkpoint inhibitors (ICI) have been approved for the use in solid tumors with MSI/dMMR. Nevertheless, the outcome of patients (pts) with MSI/dMMR pancreatic ductal adenocarcinoma (PDAC) seems poorer when compared to other malignancies. This multi-institutional analysis aimed to assess the efficacy and tolerability of ICIs in a large real-world cohort of pts with MSI/dMMR PDAC. Methods: Retrospective data were collected for pts with MSI/dMMR PDAC treated with ICIs from February 2016 to May 2022 in 16 different centers across Europe and Israel. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and objective response (OR) and disease control rate (DCR) were measured according to RECIST V1.1. Results: We identified 31 pts with metastatic MSI/dMMR PDAC. The mean age was 62.1 years (range: 37-82), 45.1% were female and ECOG PS status was predominantly 0 or 1 (83.9%). At the time of ICI treatment 1 pt had locally advanced and 30 had metastatic disease. MSH2/MSH6 deficiency (def) was found in 9 cases, MLH1/PMS2 def in 7, MSH 6 def in 4, MSH 2 def in 3, PMS2 def in 3 and MLH1/MSH6/PMS2 def and, a CpG highland methylator phenotype in 1 pt. MMR status was not available in 4 pts. Germline mutation testing was performed in 20/31 pts (64.5%) and Lynch syndrome was diagnosed in 8 pts (45%). Nineteen pts received pembrolizumab, 8 received nivolumab, 1 received lodapolimab and 3 received ipilimumab/nivolumab (ipi/nivo). The mean number of prior lines of chemotherapy was 1.5 (range 0-4). Among the 31 pts in this analysis, 15 (48,4%) had an OR (3: complete response and 12 partial response) and 6 (19,3%) had stable disease, resulting in a DCR of 67.7%. Ten pts had disease progression (PD) (32.3%). Median PFS was 26.7 months and median OS was not reached with median follow-up (FU) of 18 months. Median duration of response was not reached (95%CI:24.1-NR). Analysis of all responders, with a follow up of 12 months or more (n:14), showed that 100% of them maintained their response. In addition 71% of the pts of this cohort are still alive with a median time of follow up since the diagnosis of metastatic disease of 39.9 months. After ICIs discontinuation, 6 pts received chemotherapy. One pt who had PD after 15 months of pembrolizumab switched to ipi/nivo and achieved a CR. Immunotherapy was generally well tolerated; No Grade 3-5 adverse events (AEs) were reported and no therapy discontinuation due an adverse event was observed. Conclusions: This retrospective analysis suggests that ICIs are effective and well tolerated in pts with MSI/dMMR advanced PDAC. Hence, our work supports the use of PD-1 inhibition in this group of pts with high unmet medical need.