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

Albumins Antibodies, Monoclonal / therapeutic use Antineoplastic Agents / therapeutic use Antineoplastic Combined Chemotherapy Protocols / adverse effects Carcinoma, Pancreatic Ductal / drug therapy Humans Nivolumab / therapeutic use Pancreatic Neoplasms / drug therapy Tumor Microenvironment Pancreatic Neoplasms

Journal

Nature medicine

ISSN: 1546-170X

Titre abrégé: Nat Med

Pays: United States

ID NLM: 9502015

Informations de publication

Date de publication:
06 2022

Historique:

received: 20 12 2021

accepted: 15 04 2022

pubmed: 7 6 2022

medline: 22 6 2022

entrez: 6 6 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41591-022-01829-9 PMID: 35662283 PMC: PMC9205784

pubmed: 35662283

doi: 10.1038/s41591-022-01829-9

pii: 10.1038/s41591-022-01829-9

pmc: PMC9205784

doi:

Substances chimiques

Albumins 0

Antibodies, Monoclonal 0

Antineoplastic Agents 0

Nivolumab 31YO63LBSN

Banques de données

ClinicalTrials.gov

['NCT03214250']

Types de publication

Clinical Trial, Phase II Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1167-1177

Subventions

Organisme : NCI NIH HHS

ID : P30 CA008748

Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Références

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. 74, 2913–2921 (2014).

pubmed: 24840647 doi: 10.1158/0008-5472.CAN-14-0155

Sharma, P. et al. The next decade of immune checkpoint therapy. Cancer Discov. 11, 838–857 (2021).

pubmed: 33811120 doi: 10.1158/2159-8290.CD-20-1680

O’Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, 1431–1438 (2019).

pubmed: 31318392 pmcid: 6647002 doi: 10.1001/jamaoncol.2019.1588

Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

pubmed: 20842054 pmcid: 7322622 doi: 10.1097/CJI.0b013e3181eec14c

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. 21, 4286–4293 (2015).

pubmed: 25977344 doi: 10.1158/1078-0432.CCR-14-2607

Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

pubmed: 22658128 pmcid: 3563263 doi: 10.1056/NEJMoa1200694

Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).

pubmed: 29132146 pmcid: 6145146 doi: 10.1038/nature24462

Balli, D., Rech, A. J., Stanger, B. Z. & Vonderheide, R. H. Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer. Clin. Cancer Res. 23, 3129–3138 (2017).

pubmed: 28007776 doi: 10.1158/1078-0432.CCR-16-2128

Stromnes, I. M., Hulbert, A., Pierce, R. H., Greenberg, P. D. & Hingorani, S. R. T-cell localization, activation, and clonal expansion in human pancreatic ductal adenocarcinoma. Cancer Immunol. Res. 5, 978–991 (2017).

pubmed: 29066497 pmcid: 5802342 doi: 10.1158/2326-6066.CIR-16-0322

Byrne, K. T. & Vonderheide, R. H. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 15, 2719–2732 (2016).

pubmed: 27292635 pmcid: 4917417 doi: 10.1016/j.celrep.2016.05.058

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 3, 399–411 (2015).

pubmed: 25678581 pmcid: 4390506 doi: 10.1158/2326-6066.CIR-14-0215

O’Hara, M. H. 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. 22, 118–131 (2021).

pubmed: 33387490 doi: 10.1016/S1470-2045(20)30532-5

Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

doi: 10.1056/NEJMoa1304369

Choueiri, T. K. et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin. Cancer Res. 22, 5461–5471 (2016).

pubmed: 27169994 pmcid: 5106340 doi: 10.1158/1078-0432.CCR-15-2839

Mathew, D. et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 369, eabc8511 (2020).

pubmed: 32669297 pmcid: 7402624 doi: 10.1126/science.abc8511

Romero, P. et al. Four functionally distinct populations of human effector-memory CD8

pubmed: 17371966 doi: 10.4049/jimmunol.178.7.4112

Byrne, K. T. et al. Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin. Cancer Res. 27, 4574–4586 (2021).

pubmed: 34112709 pmcid: 8667686 doi: 10.1158/1078-0432.CCR-21-1047

Wainberg, Z. A. et al. Open-label, phase I study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin. Cancer Res. 26, 4814–4822 (2020).

pubmed: 32554514 doi: 10.1158/1078-0432.CCR-20-0099

Filbert, E. L., Bjorck, P. K., Srivastava, M. K., Bahjat, F. R. & Yang, X. APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application. Cancer Immunol. Immunother. 70, 1853–1865 (2021).

pubmed: 33392713 pmcid: 8195934 doi: 10.1007/s00262-020-02814-2

Brahmer, J. R. 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. 28, 3167–3175 (2010).

pubmed: 20516446 pmcid: 4834717 doi: 10.1200/JCO.2009.26.7609

Stebegg, M. et al. Regulation of the germinal center response. Front. Immunol. 9, 2469 (2018).

pubmed: 30410492 pmcid: 6209676 doi: 10.3389/fimmu.2018.02469

Cohn, L. et al. Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3

pubmed: 23569326 pmcid: 3646496 doi: 10.1084/jem.20121251

Haniffa, M. et al. Human tissues contain CD141

pubmed: 22795876 pmcid: 3476529 doi: 10.1016/j.immuni.2012.04.012

Diamond, M. S., Lin, J. H. & Vonderheide, R. H. Site-dependent immune escape due to impaired dendritic cell cross-priming. Cancer Immunol. Res. 9, 877–890 (2021).

pubmed: 34145076 pmcid: 8655819 doi: 10.1158/2326-6066.CIR-20-0785

Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178–193 (2018).

pubmed: 29958801 pmcid: 6707727 doi: 10.1016/j.immuni.2018.06.006

Sharma, P. et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA 104, 3967–3972 (2007).

pubmed: 17360461 pmcid: 1820692 doi: 10.1073/pnas.0611618104

Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 (2017).

pubmed: 28886381 pmcid: 8034392 doi: 10.1016/j.cell.2017.08.027

Tokito, T. et al. Predictive relevance of PD-L1 expression combined with CD8

pubmed: 26771872 doi: 10.1016/j.ejca.2015.11.020

Yang, Z. et al. Tumor-Infiltrating PD-1

pubmed: 34604032 pmcid: 8479164 doi: 10.3389/fonc.2021.695006

Beltra, J. C. et al. Developmental relationships of four exhausted CD8

pubmed: 32396847 pmcid: 8360766 doi: 10.1016/j.immuni.2020.04.014

Ding, C. et al. Integrin CD11b negatively regulates BCR signalling to maintain autoreactive B cell tolerance. Nat. Commun. 4, 2813 (2013).

pubmed: 24264377 doi: 10.1038/ncomms3813

van Hooren, L. et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat. Commun. 12, 4127 (2021).

pubmed: 34226552 pmcid: 8257767 doi: 10.1038/s41467-021-24347-7

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. 32, 600–608 (2021).

pubmed: 33539945 doi: 10.1016/j.annonc.2021.01.070

Lyman, J. P. et al. Feasibility and utility of synthetic control arms derived from real-world data to support clinical development. J. Clin. Oncol. 40, 528 (2022).

doi: 10.1200/JCO.2022.40.4_suppl.528

Upadhaya, S. et al. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat. Rev. Drug Discov. 20, 168–169 (2021).

pubmed: 33177720 doi: 10.1038/d41573-020-00204-y

Tang, J. et al. Trial watch: the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov. 17, 854–855 (2018).

pubmed: 30482962 doi: 10.1038/nrd.2018.210

Hartmann, F. J. et al. Comprehensive immune monitoring of clinical trials to advance human immunotherapy. Cell Rep. 28, 819–831 (2019).

pubmed: 31315057 pmcid: 6656694 doi: 10.1016/j.celrep.2019.06.049

Spitzer, M. H. et al. IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science 349, 1259425 (2015).

pubmed: 26160952 pmcid: 4537647 doi: 10.1126/science.1259425

Assarsson, E. et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE 9, e95192 (2014).

pubmed: 24755770 pmcid: 3995906 doi: 10.1371/journal.pone.0095192

Patwardhan, A. et al. Achieving high-sensitivity for clinical applications using augmented exome sequencing. Genome Med. 7, 71 (2015).

pubmed: 26269718 pmcid: 4534066 doi: 10.1186/s13073-015-0197-4

Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

pubmed: 23104886 doi: 10.1093/bioinformatics/bts635

DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

pubmed: 21478889 pmcid: 3083463 doi: 10.1038/ng.806

McKenna, A. et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

pubmed: 20644199 pmcid: 2928508 doi: 10.1101/gr.107524.110