Targeting B cells in pancreatic adenocarcinoma: does RESOLVE resolve the question?

Abstract

In this issue of Annals of Oncology, Tempero et al.1Tempero M. Oh D.-Y. Tabernero J. 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: 600-608Abstract Full Text Full Text PDF Scopus (19) Google Scholar report results of the RESOLVE phase III trial of ibrutinib added to gemcitabine and nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). In this global trial of 424 patients, there was no survival benefit with the addition of ibrutinib. Moreover, there were numerical trends for worse outcome in the experimental arm on most secondary endpoint analyses. RESOLVE joins a growing number of negative trials in metastatic PDAC. We continue to struggle in translating encouraging pre-clinical findings into improved survival in patients with metastatic PDAC. The median survival of such patients remains <12 months, a very disturbing statistic. It is therefore important to reflect on RESOLVE to see why we consistently fail in this deadly disease. Targeting the tumor microenvironment (TME) is currently a rational strategy in developing new therapies in PDAC and offers very exciting translational research opportunities. Pre-clinical evidence supported targeting Bruton's tyrosine kinase (BTK) to disrupt B-cell function in animal models of PDAC through multiple mechanisms including stromal reaction2Minici R.E. Lanzillotta M. Monno A. et al.B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma.Oncoimmunology. 2020; 9: 1794359Crossref PubMed Scopus (6) Google Scholar and immune modulation.3Roghanian A. Fraser C. Kleyman M. et al.B cells promote pancreatic tumorigenesis.Cancer Discov. 2016; 6: 230-232Crossref PubMed Scopus (30) Google Scholar,4Das S. Bar-Sagi D. BTK signaling drives CD1d(hi)CD5(+) regulatory B-cell differentiation to promote pancreatic carcinogenesis.Oncogene. 2019; 38: 3316-3324Crossref PubMed Scopus (27) Google Scholar It is not clear which, if any, are applicable to the human disease. Interfering with BTK signaling in malignant B cells may be different than targeting B cells in PDAC's microenvironment. B cells from the spleen are thought to be different than those that reside in the TME.5Spear S. Candido J.B. McDermott J.R. et al.Discrepancies in the tumor microenvironment of spontaneous and orthotopic murine models of pancreatic cancer uncover a new immunostimulatory phenotype for B cells.Front Immunol. 2019; 10: 542Crossref PubMed Scopus (39) Google Scholar Moreover, information from pre-clinical models is not consistent on the role of B cells in PDAC carcinogenesis and progression. There are also data supporting their role in enhancing antitumor immune response,5Spear S. Candido J.B. McDermott J.R. et al.Discrepancies in the tumor microenvironment of spontaneous and orthotopic murine models of pancreatic cancer uncover a new immunostimulatory phenotype for B cells.Front Immunol. 2019; 10: 542Crossref PubMed Scopus (39) Google Scholar with recent reports showing an association of B-cell tumor infiltration with longer survival in patients with PDAC.6Castino G.F. Cortese N. Capretti G. et al.Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma.Oncoimmunology. 2015; 5: e1085147Crossref PubMed Scopus (94) Google Scholar,7Brunner M. Maier K. Rümmele P. et al.Upregulation of CD20 positive B-cells and B-cell aggregates in the tumor infiltration zone is associated with better survival of patients with pancreatic ductal adenocarcinoma.Int J Mol Sci. 2020; 21: 1779Crossref Scopus (13) Google Scholar These uncertainties raise the question of whether scientific evidence supports targeting BTK in PDAC, especially as a single biological agent and in the absence of any hypothesis for patient selection. The reality is that, in the presence of a dynamic and complex TME as in PDAC, disruption in tumor biology resulting in a clinical benefit by ibrutinib alone is indeed very unlikely. In fact, the outcome of RESOLVE is no different than other trials targeting a single molecule or pathway in PDAC. RESOLVE and the vast majority of those studies were not founded on an association between a molecular target and clinical behavior (phenotype). Unfortunately, current pre-clinical models of PDAC do not faithfully recapitulate the very complex human TME. Hypotheses that underlie clinical new drug testing may very well be detached from the human reality. It is not surprising that all of the single molecule targeting studies in PDAC have been failures, with the exception of poly(ADP-ribose) polymerase inhibition which was based on a firm phenotype–genotype association.8Golan T. Colombo G. Scambia B.-G. et al.Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 317-327Crossref PubMed Scopus (765) Google Scholar Identification of an association must therefore come from comprehensive human investigation alongside pre-clinical experiments in relevant models to discover a robust scientific rationale. RESOLVE underscores the need for a higher level of scrutiny in launching a phase III trial. There is no consensus on how to advance from single-arm, small pilot phase I/II studies to costly phase III trials that have a reasonable chance of success. Understandably, decisions on new drug development in PDAC are influenced by the urgent need for new therapies, which lowers the threshold for moving forward. The question would be which signals in initial patient population will be sufficient to launch a phase III trial in PDAC? The launch of RESOLVE was based on a very small phase Ib study that also attempted to explore immune modulatory effects of ibrutinib in patients with metastatic PDAC.9Sinha M. Betts C. Griffith M. et al.Immune modulatory effects of ibrutinib in pancreatic ductal adenocarcinoma (abstract P-146).Ann Oncol. 2019; 30: iv40Abstract Full Text Full Text PDF Google Scholar Another issue with RESOLVE is the significantly lower cumulative exposure of patients to the cytotoxic agents in the experimental arm, suggesting that the combination may have been less well tolerated, less efficacious, or both, when compared to the control arm. It further emphasizes the downside of insufficient evaluation of experimental combinations before phase III setting. A formal phase I/II evaluation must always precede phase III, not only to detect efficacy signals but also to establish tolerability and dose optimization of a combination, unless compelling science and early clinical evidence justifies forgoing formal phase II testing before embarking on a phase III trial. Negative clinical trials in oncology provide invaluable knowledge on disease biology, and RESOLVE is no exception. We would very much like to learn more on why RESOLVE did not succeed despite pre-clinical and early clinical expectations. We would be interested to know whether the target was indeed engaged by ibrutinib and how closely the immune perturbations were related to ibrutinib's pharmacodynamics. Based on the track record of failed clinical trials in PDAC, the concern is that a negative outcome will dampen or even end further studies of the drug and/or the target in PDAC. Targeting B cells is worthy of further exploration, especially in combination with other TME-targeting agents.10Zhao Y. Shen M. Feng Y. et al.Regulatory B cells induced by pancreatic cancer cell-derived interleukin-18 promote immune tolerance via the PD-1/PD-L1 pathway.Oncotarget. 2017; 9: 14803-14814Crossref PubMed Scopus (19) Google Scholar,11Schwartz M. Zhang Y. Rosenblatt J.D. B cell regulation of the anti-tumor response and role in carcinogenesis.J Immunother Cancer. 2016; 4: 40Crossref PubMed Scopus (132) Google Scholar Treatments to enhance cytotoxic T-cell activity may benefit from the inclusion of a B-cell inhibitory treatment12Gunderson A.J. Kaneda M.M. Tsujikawa T. et al.Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer.Cancer Discov. 2016; 6: 270-285Crossref PubMed Scopus (290) Google Scholar,13Tong D.N. Guan J. Sun J.H. et al.Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients.Clin Exp Pharmacol Physiol. 2020; 47: 1342-1349Crossref PubMed Scopus (4) Google Scholar with recent data confirming B-cell role in T-cell exclusion.14Mirlekar B. Michaud D. Lee S.J. et al.B cell-derived IL35 drives STAT3-dependent CD8(+) T-cell exclusion in pancreatic cancer.Cancer Immunol Res. 2020; 8: 292-308Crossref PubMed Scopus (21) Google Scholar We should also test other agents that target B cells beyond BTK.15Burger J.A. Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances.Nat Rev Cancer. 2018; 18: 148-167Crossref PubMed Scopus (152) Google Scholar Work must also dissect the clinical roles of subsets of B cells in human PDAC to better define patients who benefit from treatment and how to optimize combinations with other drugs such as immune modulators.6Castino G.F. Cortese N. Capretti G. et al.Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma.Oncoimmunology. 2015; 5: e1085147Crossref PubMed Scopus (94) Google Scholar,16Ligeiro D. Rao M. Maia A. et al.B Cells in the gastrointestinal tumor microenvironment with a focus on pancreatic cancer: opportunities for precision medicine?.Adv Exp Med Biol. 2020; 1273: 175-195Crossref PubMed Scopus (2) Google Scholar In conclusion, RESOLVE did not resolve the question of targeting B cells in PDAC, but the field of modulating the TME in PDAC remains widely open with increasing and exciting research opportunities. Success in future clinical trials in PDAC will largely depend on better characterization of the human TME, judicious use of relevant pre-clinical models, and improved clinical trial design.