Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
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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.
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CD40 agonists reprogram macrophages to a less immunosuppressive status, leading to CD8 T cell infiltration and conversion from a cold to a hot tumor.
“CD40 agonists to reprogram macrophages to a less immunosuppressive status, leading to CD8 T cell infiltration that would drive the conversion from a “cold” to a “hot tumor”183”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [183]
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- 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.
- Affiliations
- Parker Institute for Cancer Immunotherapy (US)
- Abramson Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Stanford University (US)
- Dana-Farber Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Biognosys (Switzerland) (CH)
- Personalis (United States) (US)
- Apexigen (United States) (US)
- Bristol-Myers Squibb (United States) (US)
- Cancer Research Institute (US)
- Corresponding author
- Padrón, Lacey J.
- Vonderheide, Robert H.
- ORCID
- Padrón, Lacey J.
- Maurer, Deena M.
- O’Hara, Mark H.
- O’Reilly, Eileen M.
- Wolff, Robert A.
- Wainberg, Zev A.
- Ko, Andrew H.
- Fisher, George
- Rahma, Osama
- Lyman, Jaclyn P.
- Cabanski, Christopher R.
- Yu, Jia Xin
- Pfeiffer, Shannon M.
- Xu, Jingying
- Gherardini, Pier Federico
- Mick, Rosemarie
- Alanio, Cécile
- Byrne, Katelyn T.
- Hollmann, Travis J.
- Moore, Jonni S.
- Jones, Derek D.
- Tognetti, Marco
- Chen, Richard O.
- Yang, Xiaodong
- Salvador, Lisa
- Wherry, E. John
- Dugan, Ute
- O’Donnell-Tormey, Jill
- Butterfield, Lisa H.
- Hubbard-Lucey, Vanessa M.
- Ibrahim, Ramy
- Fairchild, Justin
- Bucktrout, Samantha
- LaVallee, Theresa M.
- Vonderheide, Robert H.
- Venue
- Nature Medicine
- Published
- 2022-06
- Volume
- 28
- Issue
- 6
- Pages
- 1167-1177
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9205784
- OpenAlex
- W4282037063
- Cited by
- 384
- References
- 45
- Citations by year
- 2026: 98 · 2025: 88 · 2024: 109 · 2023: 66 · 2022: 23
- FWCI
- 30.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Cancer Research Institute
- Bristol-Myers Squibb
- University of Pennsylvania
- Memorial Sloan-Kettering Cancer Center
- Parker Institute for Cancer Immunotherapy
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- nivolumab, metastatic pancreatic ductal adenocarcinoma, first-line therapy, chemoimmunotherapy, anti-PD-1, gemcitabine, nab-paclitaxel, overall survival, tumor immune microenvironment, peripheral blood T cells, CD4+ T cell infiltration, treatment response biomarkers
- MeSH terms
- Nivolumab, Albumins, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Tumor Microenvironment
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