RE-ARMing the Immune Response to Bladder Cancer with Radiotherapy

Abstract

Following demonstration of significant activity of atezolizumab in refractory metastatic urothelial cancer [[1]Powles T. Eder J.P. Fine G.D. Braiteh F.S. Loriot Y. Cruz C. et al.MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature. 2014; 515: 558-562https://doi.org/10.1038/nature13904Crossref PubMed Scopus (1777) Google Scholar], randomised trials showed improved survival with PD1/PD-L1 agents compared with second-line chemotherapy [[2]Bellmunt J. Bajorin D.F. Pembrolizumab for advanced urothelial carcinoma.N Engl J Med. 2017; 376: 2304https://doi.org/10.1056/NEJMc1704612Crossref PubMed Scopus (26) Google Scholar]. As a result, treatment with PD1/PD-L1 immune checkpoint inhibitors (ICIs) has become a standard National Institute for Health and Care Excellence (NICE) and European Society for Medical Oncology (ESMO)-approved treatment for metastatic urothelial cancer. Despite these successes, with some patients being long-term survivors on therapy, disappointingly most patients experience early progression on treatment. For these patients there is a paucity of options. Targeted agents have yet to gain real clinical traction in bladder cancer – some biomarker-led approaches, e.g. the fibroblast growth factor receptor inhibitor erdafitinib, show promise [[3]Loriot Y. Necchi A. Siefker-Radtke A.O. Erdafitinib in urothelial carcinoma.Reply N Engl J Med. 2019; 381: 1594-1595https://doi.org/10.1056/NEJMc1911187Crossref PubMed Scopus (2) Google Scholar], but, as only about 15% of patients have the sensitive mutations, these are unlikely to benefit the majority of patients and remain at some distance from routine clinical use. Antibody-conjugated chemotherapy may also be an option [[4]Powles T. Rosenberg J.E. Sonpavde G.P. Loriot Y. Duran I. Lee J.L. et al.Enfortumab vedotin in previously treated advanced urothelial carcinoma.N Engl J Med. 2021; 384: 1125-1135https://doi.org/10.1056/NEJMoa2035807Crossref PubMed Scopus (139) Google Scholar], but it is uncertain whether this will be readily available in the clinic in the near future. There is, therefore, a clear clinical need to try to make ICIs work better and for more people. An intriguing observation in the ImVigor 210 trial of the PD-L1 inhibitor atezolizumab in patients with metastatic urothelial cancer was that 17% of patients experienced a late clinical response after initial progression on treatment – this was on top of the 15% of patients showing an early response shortly after initiation of atezolizumab [[5]Rosenberg J.E. Hoffman-Censits J. Powles T. van der Heijden M.S. Balar A.V. Necchi A. et al.Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.Lancet. 2016; 387: 1909-1920https://doi.org/10.1016/S0140-6736(16)00561-4Abstract Full Text Full Text PDF PubMed Scopus (2416) Google Scholar]. It has been shown that radiotherapy increases expression of PD-L1 in both murine and human models of urothelial cancer [[6]Wu C.T. Chen W.C. Chang Y.H. Lin W.Y. Chen M.F. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer.Sci Rep. 2016; 6: 19740https://doi.org/10.1038/srep19740Crossref PubMed Scopus (119) Google Scholar], leading to various radiotherapy/ICI combinations being evaluated in the radical setting. As recently reviewed in Clinical Oncology [[7]Wilkins A. Ost P. Sundahl N. Is there a benefit of combining immunotherapy and radiotherapy in bladder cancer?.Clin Oncol. 2021; 33: 407-414https://doi.org/10.1016/j.clon.2021.02.014Abstract Full Text Full Text PDF Scopus (4) Google Scholar], these observations raise the intriguing possibility that addition of radiotherapy could tip the immunological balance to further enhance responses and increase the number of patients who, after failing to show an initial response to ICIs, have a delayed response. The RE-ARM trial (ISRCTN12606219) addresses this hypothesis in a randomised phase II design with a trial schema as shown in Figure 1. One hundred and two patients with stable disease at best after three to six cycles of atezolizumab, given as part of routine care, will be randomised between palliative radiotherapy (20 Gy in five fractions) plus atezolizumab, or continuation of atezolizumab alone. The primary end point of RE-ARM is the objective radiological response rate (complete or partial response) at 9 weeks after the start of study treatment according to RECIST v1.1 criteria, excluding the planned radiotherapy site. The trial aims to detect an absolute increase in response rate of at least 15% for the combination arm at 9 weeks, compared with the control arm (assuming 15% response in control, 1:1 randomisation, 80% power, one-sided 0.2 significance level). Randomised reports of abscopal responses to radiotherapy plus ICI are currently lacking in metastatic urothelial cancer, whereas reports in other tumour types show diverse results. A recent combined analysis of two phase I/II randomised studies of pembrolizumab, with or without radiotherapy, in metastatic non-small cell lung cancer showed a best out-of-field (abscopal) response rate of 41.7% (30/72) when radiotherapy was added, versus a response rate of 19.7% (15/76) with pembrolizumab alone (odds ratio 2.96, 95% confidence interval 1.42–6.20; P = 0.0039) [[8]Theelen W. Chen D. Verma V. Hobbs B.P. Peulen H.M.U. Aerts J. et al.Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.Lancet Respir Med. 2021; 9: 467-475https://doi.org/10.1016/S2213-2600(20)30391-XAbstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. The median overall survival was extended from 8.7 months (6.4–11.0) with pembrolizumab alone to 19.2 months (14.6–23.8) with pembrolizumab plus radiotherapy (0.67, 0.54–0.84; P = 0.0004) [[8]Theelen W. Chen D. Verma V. Hobbs B.P. Peulen H.M.U. Aerts J. et al.Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.Lancet Respir Med. 2021; 9: 467-475https://doi.org/10.1016/S2213-2600(20)30391-XAbstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. In contrast, a recently reported randomised phase II study of nivolumab plus or minus stereotactic body radiotherapy (8 × 3 Gy) in metastatic head and neck cancer showed no improvement in the rates of out-of-field abscopal responses, progression-free or overall survival with stereotactic body radiotherapy [[9]McBride S. Sherman E. Tsai C.J. Baxi S. Aghalar J. Eng J. et al.Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.J Clin Oncol. 2021; 39: 30-37https://doi.org/10.1200/JCO.20.00290Crossref PubMed Scopus (94) Google Scholar]. The UK PERM trial randomised patients with metastatic melanoma to pembrolizumab with or without radiotherapy (8 Gy × 3 to up to three tumour sites) [[10]Yip K. Melcher A. Harrington K. Illidge T. Nobes J. Webster A. et al.Pembrolizumab in combination with radiotherapy for metastatic melanoma - introducing the PERM trial.Clin Oncol. 2018; 30: 201-203https://doi.org/10.1016/j.clon.2018.01.001Abstract Full Text Full Text PDF Scopus (6) Google Scholar], but was halted due to poor recruitment. The above varying results have led some to advocate for more aggressive strategies, including ablation of all radiologically visible disease, high doses per fraction and/or addition of other ICIs beyond the PD1/PD-L1 axis, such as anti-TIGIT agents. The limited reports to date of ICI plus radiotherapy in urothelial cancer suggest, firstly, that radiotherapy might be best given during ICI, rather than beforehand [[11]Sundahl N. Vandekerkhove G. Decaestecker K. Meireson A. De Visschere P. Fonteyne V. et al.Randomized phase 1 trial of pembrolizumab with sequential versus concomitant stereotactic body radiotherapy in metastatic urothelial carcinoma.Eur Urol. 2019; 75: 707-711https://doi.org/10.1016/j.eururo.2019.01.009Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar] – an approach that is also supported by preclinical data [[12]Dovedi S.J. Adlard A.L. Lipowska-Bhalla G. McKenna C. Jones S. Cheadle E.J. et al.Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.Cancer Res. 2014; 74: 5458-5468https://doi.org/10.1158/0008-5472.CAN-14-1258Crossref PubMed Scopus (718) Google Scholar]. In a small phase I study, concomitant irradiation of 3 × 8 Gy to a single site, prior to cycle 3 of pembrolizumab, resulted in RECIST v1.1 response in non-irradiated lesions in four of nine patients (44%). Second, the high rates of bowel and urinary toxicity seen in the PLUMMB trial of pembrolizumab plus hypofractionated radiotherapy [[13]Tree A.C. Jones K. Hafeez S. Sharabiani M.T.A. Harrington K.J. Lalondrelle S. et al.Dose-limiting urinary toxicity with pembrolizumab combined with weekly hypofractionated radiation therapy in bladder cancer.Int J Radiat Oncol Biol Phys. 2018; 101: 1168-1171https://doi.org/10.1016/j.ijrobp.2018.04.070Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar] and a second phase I trial incorporating pelvic radiotherapy [[14]Marcq G. Souhami L. Cury F.L. Salimi A. Aprikian A. Tanguay S. et al.Phase 1 trial of atezolizumab plus trimodal therapy in patients with localized muscle-invasive bladder cancer.Int J Radiat Oncol Biol Phys. 2021; 110: 738-741https://doi.org/10.1016/j.ijrobp.2020.12.033Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], indicate that an ICI/radiotherapy interaction may be present, but that caution is warranted with high radiotherapy doses to the pelvis. RE-ARM incorporates both of these factors in an adaptive randomised design and is an exciting opportunity for the UK to systematically address the role of radiotherapy plus ICI in the control of metastatic urothelial cancer. Specific aspects of trial design that differ from the randomised studies above include the preselection for non-responders to ICI, which means the RE-ARM trial population is likely to be enriched for patients with immune cold or immune-excluded tumour phenotypes. The radiotherapy dose schedule of 20 Gy in five fractions has been in part pragmatically selected based on ease of delivery across different UK radiotherapy centres; however, it is also fairly similar to the 30 Gy in six fractions that has been shown to optimally induce type I interferon and abscopal responses in a preclinical context [[15]Vanpouille-Box C. Alard A. Aryankalayil M.J. Sarfraz Y. Diamond J.M. Schneider R.J. et al.DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.Nat Commun. 2017; 8: 15618https://doi.org/10.1038/ncomms15618Crossref PubMed Scopus (806) Google Scholar]. A further strategy to optimise response includes guidance to centres to preferentially irradiate larger lesions in locations considered more immunogenic, such as visceral and nodal metastases, as opposed to bone metastases. The outcomes following irradiation of liver metastases in RE-ARM will be particularly intriguing in view of recent preclinical findings that a single 8 Gy radiotherapy treatment to the liver can reprogramme the tumour microenvironment, thus enhancing systemic responses to ICI [[16]Yu J. Green M.D. Li S. Sun Y. Journey S.N. Choi J.E. et al.Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.Nat Med. 2021; 27: 152-164https://doi.org/10.1038/s41591-020-1131-xCrossref PubMed Scopus (133) Google Scholar]. This is particularly relevant as we know that liver metastases predict for inferior responses to ICI across different tumour sites [[16]Yu J. Green M.D. Li S. Sun Y. Journey S.N. Choi J.E. et al.Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.Nat Med. 2021; 27: 152-164https://doi.org/10.1038/s41591-020-1131-xCrossref PubMed Scopus (133) Google Scholar,[17]Tumeh P.C. Hellmann M.D. Hamid O. Tsai K.K. Loo K.L. Gubens M.A. et al.Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC.Cancer Immunol Res. 2017; 5: 417-424https://doi.org/10.1158/2326-6066.CIR-16-0325Crossref PubMed Scopus (248) Google Scholar]. Patients who fail to show an initial response to ICI will exhibit considerable biological heterogeneity. Recent unbiased integrative analyses of baseline tumours in IMvigor 210 and Checkmate 275 have combined bulk RNA sequencing and single cell sequencing. Here, the ratio between an adaptive immune response signature and a pro-tumourigenic inflammation signature best predicted response to ICI [[18]Wang L. Sfakianos J.P. Beaumont K.G. Akturk G. Horowitz A. Sebra R.P. et al.Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing.Clin Cancer Res. 2021; 27: 4287-4300https://doi.org/10.1158/1078-0432.CCR-20-4574Crossref PubMed Scopus (10) Google Scholar]; such signatures were predominantly derived from diverse myeloid populations [[18]Wang L. Sfakianos J.P. Beaumont K.G. Akturk G. Horowitz A. Sebra R.P. et al.Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing.Clin Cancer Res. 2021; 27: 4287-4300https://doi.org/10.1158/1078-0432.CCR-20-4574Crossref PubMed Scopus (10) Google Scholar]. This builds on previous insights into ICI response in urothelial cancer; these include the relevance of tumour mutational burden as a positive predictor of response [[19]Galsky M.D. Saci A. Szabo P.M. Han G.C. Grossfeld G. Collette S. et al.Nivolumab in patients with advanced platinum-resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended follow-up from CheckMate 275.Clin Cancer Res. 2020; 26: 5120-5128https://doi.org/10.1158/1078-0432.CCR-19-4162Crossref PubMed Scopus (39) Google Scholar], as well as the association between enrichment with cancer-associated fibroblasts, increased transforming growth factor-beta signalling and ICI resistance [[20]Mariathasan S. Turley S.J. Nickles D. Castiglioni A. Yuen K. Wang Y. et al.TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.Nature. 2018; 554: 544-548https://doi.org/10.1038/nature25501Crossref PubMed Scopus (1795) Google Scholar]. Additionally, antibiotic use within 30 days of starting ICI in IMvigor 210 and 211 was associated with inferior responses, which intriguingly was not seen in patients receiving chemotherapy in IMvigor 211 [[21]Hopkins A.M. Kichenadasse G. Karapetis C.S. Rowland A. Sorich M.J. Concomitant antibiotic use and survival in urothelial carcinoma treated with atezolizumab.Eur Urol. 2020; 78: 540-543https://doi.org/10.1016/j.eururo.2020.06.061Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The balance of bacterial versus fungal strains is known to be relevant to radioresponsiveness [[22]Shiao S.L. Kershaw K.M. Limon J.J. You S. Yoon J. Ko E.Y. et al.Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.Cancer Cell. 2021; 39 (e6): 1202-1213https://doi.org/10.1016/j.ccell.2021.07.002Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], and both these finding show the likely relevance of the microbiome to clinical responses in RE-ARM. The biological heterogeneity described above probably means there will be some patients who just need an immunological ‘nudge’ to enable a response to combined ICI/radiotherapy, whereas, sadly, other patients will show rapid progression despite combination treatment. Going forward, the field needs to prospectively identify patients with such divergent responses and better understand the biological hallmarks of differential response. For this reason, comprehensive integrative translational profiling is embedded in the design of RE-ARM. We are enormously grateful to the participating National Health Service hospitals for their support for the collection of baseline tumour biopsies, longitudinal bloods and planned microbiome samples. Where sites have the relevant interventional radiology support available, we are also planning to incorporate paired biopsies pre- and post-radiotherapy. Here, single cell sequencing should provide high resolution understanding of intra-tumoural tumour microenvironment changes in a small cohort of patients. Patients who present with metastatic bladder cancer have a 1-year survival of only 33% [[23]Cancer Research UK Bladder Cancer Statistics.2018https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer/survival#heading-ThreeGoogle Scholar]. These dismal survival statistics relate in part to a historical lack of funding for bladder cancer, relative to other tumour sites [[24]Van Hemelrijck M. Patel P. Mouw K.W. Editorial: Bladder cancer - a Cinderella cancer: advances and remaining research questions.Front Oncol. 2020; 10: 1749https://doi.org/10.3389/fonc.2020.01749Crossref PubMed Scopus (1) Google Scholar]. RE-ARM is an exciting opportunity to systematically evaluate whether an affordable and readily available experimental treatment (radiotherapy) can augment responses to immune checkpoint blockade. We are grateful to the many UK centres taking part in RE-ARM and for their help with recruiting patients to this important study. Other UK sites interested in participating are invited to contact the trial coordination team ( [email protected] ). R. Huddart declares receipt of honoraria for advisory board and educational sessions and conference expenses from Roche Products Ltd. E. Hall declares the following: grants received by institution as contribution to the central trial management of a non-commercial radiotherapy trial in prostate cancer (Accuray Inc and Varian Medical Systems Inc.); grant received by institution as contribution to support central trial costs at ICR-CTSU for a non-commercial trial in prostate cancer (Merck Sharp and Dohm); grant received by institution as contribution to support central trial costs at ICR-CTSU for non-commercial trials in prostate cancer – provision of study drug and placebo (AstraZeneca); grant received by institution as contribution to support trial health economic evaluation in a non-commercial trial in prostate cancer (Janssen-Cilag); grant received by institution as contribution to support central trial costs at ICR-CTSU for an non-commercial trial in prostate cancer – provision of study drug (Bayer); grant received by institution as contribution to support central trial costs at ICR-CTSU for an academic trial in penis cancer trial (Aventis Pharma Limited (Sanofi)); grant received by institution as contribution to support central trial costs at ICR-CTSU for an non-commercial bladder cancer trial (Roche Products Ltd). RE-ARM is an investigator-initiated study supported by Roche Products Ltd and endorsed by Cancer Research UK ( CRUKE/19/009 ). RE-ARM is sponsored by The Institute of Cancer Research and coordinated by the Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU) which receives core funding from Cancer Research UK ( C1491/A25351 ). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research .