Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized phase 2 PRINCE trial Journal Article

   

Authors:	Padrón, L. J.; Maurer, D. M.; O’Hara, M. H.; O’Reilly, E. M.; Wolff, R. A.; Wainberg, Z. A.; Ko, A. H.; Fisher, G.; Rahma, O.; Lyman, J. P.; Cabanski, C. R.; Yu, J. X.; Pfeiffer, S. M.; Spasic, M.; Xu, J.; Gherardini, P. F.; Karakunnel, J.; Mick, R.; Alanio, C.; Byrne, K. T.; Hollmann, T. J.; Moore, J. S.; Jones, D. D.; Tognetti, M.; Chen, R. O.; Yang, X.; Salvador, L.; Wherry, E. J.; Dugan, U.; O’Donnell-Tormey, J.; Butterfield, L. H.; Hubbard-Lucey, V. M.; Ibrahim, R.; Fairchild, J.; Bucktrout, S.; LaVallee, T. M.; Vonderheide, R. H.
Article Title:	Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized phase 2 PRINCE trial
Abstract:	Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials. © 2022, The Author(s).
Keywords:	adult; cancer chemotherapy; controlled study; human tissue; treatment response; aged; major clinical study; overall survival; clinical trial; fatigue; neutropenia; diarrhea; drug efficacy; drug safety; drug withdrawal; side effect; treatment duration; antineoplastic agents; gemcitabine; paclitaxel; cancer patient; pancreatic neoplasms; antineoplastic agent; progression free survival; neutrophil count; phase 2 clinical trial; sensory neuropathy; anemia; nausea; randomized controlled trial; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; myalgia; peripheral neuropathy; carcinoma, pancreatic ductal; pathology; tumor marker; monoclonal antibody; alanine aminotransferase blood level; aspartate aminotransferase blood level; chill; coughing; dyspnea; fever; pancreas carcinoma; pruritus; rash; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; hyponatremia; hypotension; antibodies, monoclonal; albumins; multicenter study; pancreas tumor; cd4+ t lymphocyte; peripheral edema; open study; alkaline phosphatase blood level; headache; leukocyte count; phase 1 clinical trial; cd4 antigen; cancer control; alopecia; lymphocyte count; urticaria; platelet count; albuminoid; dysgeusia; motor neuropathy; tumor microenvironment; decreased appetite; pancreatic ductal carcinoma; cytokine release syndrome; nivolumab; humans; human; male; female; article; multiomics; sotigalimab
Journal Title:	Nature Medicine
Volume:	28
Issue:	6
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Date Published:	2022-06-01
Start Page:	1167
End Page:	1177
Language:	English
DOI:	10.1038/s41591-022-01829-9
PUBMED:	35662283
PROVIDER:	scopus
PMCID:	PMC9205784
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85131291377&doi=10.1038%2fs41591-022-01829-9&partnerID=40&md5=8ce462ec98bde2885a9ccfaa0c0e1218
Notes:	Article -- Export Date: 1 August 2022 -- Source: Scopus

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