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Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes Alejo Rodriguez-Vida1, Jose Luis Perez-Gracia2, and Joaquim Bellmunt1,3

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Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes Alejo Rodriguez-Vida1, Jose Luis Perez-Gracia2, and Joaquim Bellmunt1,3 Published OnlineFirst July 10, 2018; DOI: 10.1158/1078-0432.CCR-17-3108 Review Clinical Cancer Research Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes Alejo Rodriguez-Vida1, Jose Luis Perez-Gracia2, and Joaquim Bellmunt1,3 Abstract Immune checkpoint inhibitors (ICI) have emerged as a maintained remissions. Active research is ongoing in sev- novel therapeutic strategy that achieves significant clinical eral fields, aiming to increase the number of patients that benefit in several tumor types, including urothelial cancer. benefit from ICI, and this research is largely based on the Overall, these agents have shown objective response rates development of biomarkers for personalized immunother- of around 20% to 23%, which indicates that a significant apy and novel combinations of ICI with other agents. proportion of patients do not benefit from immunother- This article will review ongoing efforts to develop combi- apy when given as monotherapy. Moreover, despite an nations of ICI with other therapeutic strategies in patients initial response to therapy and an improvement in the with urothelial cancer, including chemotherapy, targeted median duration of response compared with chemother- agents, other immunotherapy strategies, and radiotherapy. apy, still only half of the patients develop long-term Clin Cancer Res; 24(24); 6115–24. Ó2018 AACR. Introduction urothelial cancer who are ineligible for cisplatin (8, 9), thus leading to ongoing randomized phase III trials in this setting. Immune checkpoint inhibitors (ICI) have become a major step Overall, these studies have shown objective response rates forward in the treatment of urothelial cancer. Indeed, significant (ORR) of around 20%–23%, which indicates that a significant clinical activity has been demonstrated since the first studies were proportion of patient does not benefit from immunotherapy reported in this tumor type, which also highlighted for the first when given as monotherapy. Moreover, despite an initial time the potential relevance of PD-L1 expression in tumor-infil- response to therapy and an improvement in the median duration trating immune cells (1). Subsequent phase II studies have of response compared with chemotherapy, still the majority of demonstrated significant activity and durable responses for ate- patients ultimately experience disease progression. Therefore, zolizumab, pembrolizumab, nivolumab, avelumab, and durva- additional strategies for improving the outcome of patients with lumab in patients with advanced urothelial cancer previously advanced urothelial cancer are urgently needed. In addition to treated with chemotherapy (2–5), and consequently all these personalized immunotherapy based on predictive biomarkers, agents have been approved for the treatment of this patient immunotherapy-based combinations (10) have emerged as one population by the FDA. Furthermore, pembrolizumab has shown of the most promising hopes to improve the outcomes of these increased overall survival (OS) in comparison with second-line patients, and great efforts are being undertaken in this regard. This chemotherapy in a randomized phase III trial in patients with review will focus on immunotherapy-based combinations under advanced urothelial cancer (6). However, with a similar phase III development for patients with advanced urothelial cancer. trial design, atezolizumab was not associated with significantly longer OS than chemotherapy, in patients with platinum-refrac- tory metastatic urothelial cancer overexpressing PD-L1 (IC2/3), Combinations of ICIs and Chemotherapy although in an exploratory analysis, OS in the intention-to-treat Cisplatinum-based combination chemotherapy remains the population was numerically improved in the atezolizumab arm standard first-line treatment for patients with advanced urothelial (7). Finally, when exploring earlier stages of the disease in phase II cancer who are fit to tolerate cisplatin (11). Vinflunine is approved trials, both atezolizumab and pembrolizumab have shown prom- by the European Medicines Agency (EMEA) as second-line treat- ising activity in the first-line setting in patients with metastatic ment based on a limited survival benefit (12), and may have a role as maintenance treatment in the first-line setting (13). Therefore, it is not surprising that combinations of immunotherapy and 1Medical Oncology Department, Hospital del Mar, IMIM (Hospital del Mar chemotherapy have been included as experimental arms in several 2 Research Institute), Barcelona, Spain. Medical Oncology Department, Clinica of the ongoing phase III trials that are exploring the efficacy of ICI 3 Universidad de Navarra, Pamplona, Spain. Dana-Farber Cancer Institute, Brig- as first-line treatment of advanced urothelial cancer. The rationale ham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts. for such combinations is 2-fold. First, chemotherapy has shown synergistic activity when combined with ICI, which is based on the fi Note: A. Rodriguez-Vida and J.L. Perez-Gracia share rst authorship. ability of chemotherapy to induce immunogenic cell death, to Corresponding Author: Joaquim Bellmunt, Hospital Del Mar, Paseo Maritimo, attenuate immunosuppression in the tumor microenvironment Barcelona 08003, Spain. Phone: 349-3316-0750; Fax: 349-3316-0410; E-mail: [through the modulation of regulatory T cells, myeloid-derived [email protected] suppressor cells (MDSC), immunosuppressive cytokines, and doi: 10.1158/1078-0432.CCR-17-3108 immunosuppressive enzymes], and to enhance the performance Ó2018 American Association for Cancer Research. of antigen-presenting cells (10). Second, chemotherapy has well- www.aacrjournals.org 6115 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 10, 2018; DOI: 10.1158/1078-0432.CCR-17-3108 Rodriguez-Vida et al. confirmed activity in patients with advanced urothelial cancer, damage response mutations. On exploratory analysis, there was and the subset of patients that benefit from either chemotherapy a significant expansion of circulating CD4 T cells with the addition or ICI may not overlap. Moreover, chemotherapy retains high of ipilimumab and this correlated with an improved survival. The activity following first-line treatment with ICI (14), and the combination was safe with grade 3–4 adverse events (AE) occur- phenomenon of hyperprogression to immunotherapy has also ring in 81% of patients, the majority being hematologic. Despite been described among patients with urothelial cancer, which these promising results, the study did not achieve its primary could be potentially avoided with the combination (15, 16). endpoint of a lower bound of the 90% confidence interval for 1- Consequently, the strategy of delivering chemotherapy and ICI year OS greater than 60% and consequently further studies are to all patients might be able to capture all the clinical benefit that is needed to define optimal combinations and how to identify attainable with both treatment modalities. Hence, chemotherapy, patients most likely to benefit (18). with a quicker mechanism of action, could potentially counteract Several other trials combining chemotherapy and ICIs are still the deleterious delayed appearance of the response seen with ongoing. Table 1 lists the most relevant ongoing ICI–chemother- immunotherapy. Nevertheless, the potential disadvantages of apy combination studies. Three trials include an experimental combining ICI with chemotherapy might be increased toxicity arm that combines ICI and chemotherapy: IMVIGOR-130, which and potential unknown negative interactions of both therapeutic randomizes 1,200 patients to gemcitabine and platinum versus alternatives. Given the different toxicity profile of chemotherapy gemcitabine, platinum, and atezolizumab versus single-agent agents, the viability of combining new immunotherapy agents atezolizumab; Keynote 361, which is randomizing 990 patients and chemotherapy will depend greatly on the absence of to gemcitabine and platinum versus gemcitabine, platinum, and enhanced toxicity. Consequently, sequential administration of pembrolizumab versus single-agent pembrolizumab; and Check- both treatment modalities might also be a valid alternative to mate 901, which is randomizing 897 patients to gemcitabine and further explore, potentially limiting the risk of increased tox- platinum versus gemcitabine, platinum, and nivolumab versus icity. Despite the limitations of a retrospective data collection, nivolumab and ipilimumab (Table 1). Szabados and colleagues reported a 68% ORR to chemotherapy Another strategy is to compare treatment exclusively based on in patients with urothelial cancer previously treated with ICI, ICI with platinum-based chemotherapy. Such a strategy is also thus indicating a lack of cross resistance between both alter- being explored by the latter three studies, which include an arm in natives, and even suggesting increased efficacy of chemotherapy which patients are treated exclusively with ICI, either as single following ICI (14). Activity of single-agent ICI in urothelial agent (atezolizumab or pembrolizumab) or in combination cancer also seems to be maintained regardless of whether it is (nivolumab plus ipilimumab or durvalumab and tremelimumab, administered in the first-line setting or following one or several which will be reviewed in the following section; Table 1). These lines of chemotherapy (17). ICI-based arms should capture the benefit that is observed in Concomitant
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