Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
Lacey J Padrón, Deena M Maurer, Mark H O'Hara, Eileen M O'Reilly, Robert A Wolff, Zev A Wainberg, Andrew H Ko, George Fisher, Osama Rahma, Jaclyn P Lyman, Christopher R Cabanski, Jia Xin Yu, Shannon M Pfeiffer, Marko Spasic, Jingying Xu, Pier Federico Gherardini, Joyson Karakunnel, Rosemarie Mick, Cécile Alanio, Katelyn T Byrne, Travis J Hollmann, Jonni S Moore, Derek D Jones, Marco Tognetti, Richard O Chen, Xiaodong Yang, Lisa Salvador, E John Wherry, Ute Dugan, Jill O'Donnell-Tormey, Lisa H Butterfield, Vanessa M Hubbard-Lucey, Ramy Ibrahim, Justin Fairchild, Samantha Bucktrout, Theresa M LaVallee, Robert H Vonderheide, Lacey J Padrón, Deena M Maurer, Mark H O'Hara, Eileen M O'Reilly, Robert A Wolff, Zev A Wainberg, Andrew H Ko, George Fisher, Osama Rahma, Jaclyn P Lyman, Christopher R Cabanski, Jia Xin Yu, Shannon M Pfeiffer, Marko Spasic, Jingying Xu, Pier Federico Gherardini, Joyson Karakunnel, Rosemarie Mick, Cécile Alanio, Katelyn T Byrne, Travis J Hollmann, Jonni S Moore, Derek D Jones, Marco Tognetti, Richard O Chen, Xiaodong Yang, Lisa Salvador, E John Wherry, Ute Dugan, Jill O'Donnell-Tormey, Lisa H Butterfield, Vanessa M Hubbard-Lucey, Ramy Ibrahim, Justin Fairchild, Samantha Bucktrout, Theresa M LaVallee, Robert H Vonderheide
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.
Conflict of interest statement
A.H.K., E.M.O., R.H.V., M.H.O., G.F. and E.J.W. report grants from the Parker Institute for Cancer Immunotherapy (PICI) during the conduct of this study. A.H.K. reports grants from Celgene, Apexigen and Bristol Myers Squibb (BMS) outside the submitted work. E.M.O. reports research funding from MSK, Genentech/Roche, Celgene/BMS, BioNTech, AstraZeneca, Arcus and Elicio and consulting/DSMB for Cytomx Therapeutics, Rafael Therapeutics, Silenseed, Tyme, Seagen, Boehringer Ingelheim, BioNTech, Ipsen, Merck, IDEAYA, AstraZeneca, Noxxon, BioSapien, Cend Therapeutics, Thetis, Bayer (spouse), Genentech/Roche (spouse), Celgene/BMS (spouse) and Eisai (spouse). L.H.B. declares the following unrelated advisory activities: StemImmune/Calidi, Western Oncolytics, Torque Therapeutics, Khloris, Pyxis, Cytomix, DCprime, RAPT, Takeda and EnaraBio. O.R. reports personal fees from Merck, Celgene, Five Prime Therapeutics, GlaxoSmithKline, Bayer, Roche/Genentech, Puretech, Imvax and Sobi outside the submitted work and has a patent pending for methods that make use of pembrolizumab and trebananib. P.F.G. reports stock ownership in Teiko.bio. R.H.V. reports grants from FibroGen, Inovio, Janssen and Eli Lilly and personal fees from MedImmune, Eli Lilly, Celgene, Celldex Therapeutics and Verastem Oncology outside the submitted work; is an inventor on a licensed patent relating to cancer cellular immunotherapy and cancer vaccines; and receives royalties from Children’s Hospital Boston for a licensed research-only monoclonal antibody. R.O.C. is an employee of Personalis, a company that PICI paid to produce sequence information for some samples reported in this paper as part of a collaboration. R.O.C. is also an inventor on US patent number 09183496 issued to Personalis, which describes the genomic analyses in the Personalis sequencing platform used to sequence the samples in this study. T.M.L. reports Coherus Biosciences employment; LISCure Biosciences Scientific Advisory Board membership; stock ownership in AstraZenca; and consulting outside the submitted work for Grey Wolf Therapeutics and BiOneCure. V.M.H.-L. is an employee of BMS and holds stock. Z.A.W. reports grants from Novartis, Five Prime Therapeutics, Plexxikon and BMS and personal fees from Merck, Eli Lilly, Daiichi, AstraZeneca and Bayer outside the submitted work. M.S. reports consulting for Natera. M.H.O. reports grants from BMS and Celldex; grants and non-financial support from Stand Up To Cancer; and personal fees from Natera outside the submitted work. M.T. is an employee of Biognosys AG. G.F. reports personal fees from Merck, Roche/Genentech and CytomX outside the submitted work; and his spouse owns stock in Seattle Genetics. E.J.W. is a consultant or an advisor for Merck, Elstar, Janssen, Related Sciences, Synthekine and Surface Oncology; is a founder of Surface Oncology and Arsenal Biosciences; and is an inventor on US patent number 10,370,446, submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. L.J.P., D.M.M., R.A.W., J.P.L., C.R.C., J.X.Y., S.M.P., J.X., J.K., R.M., C.A., K.T.B., T.J.H., J.S.M., D.D.J., X.Y., L.S., U.D., J.O.-T., R.I., J.F. and S.B. report no competing interests related to the work presented.
© 2022. The Author(s).
Figures
References
- Rahib L, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921.
- Sharma P, et al. The next decade of immune checkpoint therapy. Cancer Discov. 2021;11:838–857.
- O’Reilly EM, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:1431–1438.
- Royal RE, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 2010;33:828–833.
- Patnaik A, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin. Cancer Res. 2015;21:4286–4293.
- Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012;366:2455–2465.
- Balachandran VP, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551:512–516.
- Balli D, Rech AJ, Stanger BZ, Vonderheide RH. Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer. Clin. Cancer Res. 2017;23:3129–3138.
- Stromnes IM, Hulbert A, Pierce RH, Greenberg PD, Hingorani SR. T-cell localization, activation, and clonal expansion in human pancreatic ductal adenocarcinoma. Cancer Immunol. Res. 2017;5:978–991.
- Byrne KT, Vonderheide RH. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 2016;15:2719–2732.
- Winograd R, et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol. Res. 2015;3:399–411.
- O’Hara MH, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 2021;22:118–131.
- Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013;369:1691–1703.
- Choueiri TK, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin. Cancer Res. 2016;22:5461–5471.
- Mathew D, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science. 2020;369:eabc8511.
- Romero P, et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J. Immunol. 2007;178:4112–4119.
- Byrne KT, et al. Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin. Cancer Res. 2021;27:4574–4586.
- Wainberg ZA, et al. Open-label, phase I study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin. Cancer Res. 2020;26:4814–4822.
- Filbert EL, Bjorck PK, Srivastava MK, Bahjat FR, Yang X. APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application. Cancer Immunol. Immunother. 2021;70:1853–1865.
- Brahmer JR, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 2010;28:3167–3175.
- Stebegg M, et al. Regulation of the germinal center response. Front. Immunol. 2018;9:2469.
- Cohn L, et al. Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation. J. Exp. Med. 2013;210:1049–1063.
- Haniffa M, et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 2012;37:60–73.
- Diamond MS, Lin JH, Vonderheide RH. Site-dependent immune escape due to impaired dendritic cell cross-priming. Cancer Immunol. Res. 2021;9:877–890.
- Li J, et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. 2018;49:178–193.
- Sharma P, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA. 2007;104:3967–3972.
- Ribas A, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170:1109–1119.
- Tokito T, et al. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur. J. Cancer. 2016;55:7–14.
- Yang Z, et al. Tumor-Infiltrating PD-1hiCD8+-T-cell signature as an effective biomarker for immune checkpoint inhibitor therapy response across multiple cancers. Front. Oncol. 2021;11:695006.
- Beltra JC, et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020;52:825–841 e828.
- Ding C, et al. Integrin CD11b negatively regulates BCR signalling to maintain autoreactive B cell tolerance. Nat. Commun. 2013;4:2813.
- van Hooren L, et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat. Commun. 2021;12:4127.
- Tempero M, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann. Oncol. 2021;32:600–608.
- Lyman JP, et al. Feasibility and utility of synthetic control arms derived from real-world data to support clinical development. J. Clin. Oncol. 2022;40:528.
- Upadhaya S, et al. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat. Rev. Drug Discov. 2021;20:168–169.
- Tang J, et al. Trial watch: the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov. 2018;17:854–855.
- Hartmann FJ, et al. Comprehensive immune monitoring of clinical trials to advance human immunotherapy. Cell Rep. 2019;28:819–831.
- Spitzer MH, et al. IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science. 2015;349:1259425.
- Assarsson E, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE. 2014;9:e95192.
- Patwardhan A, et al. Achieving high-sensitivity for clinical applications using augmented exome sequencing. Genome Med. 2015;7:71.
- Dobin A, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
- DePristo MA, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011;43:491–498.
- McKenna A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303.
Source: PubMed