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Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 603-607

Combinations will lead the way in immunotherapy for bladder cancer

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission27-Jul-2020
Date of Decision11-Aug-2020
Date of Acceptance15-Aug-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Rahul Ravind
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_257_20

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How to cite this article:
Ravind R. Combinations will lead the way in immunotherapy for bladder cancer. Cancer Res Stat Treat 2020;3:603-7

How to cite this URL:
Ravind R. Combinations will lead the way in immunotherapy for bladder cancer. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Sep 21];3:603-7. Available from: https://www.crstonline.com/text.asp?2020/3/3/603/295504

For decades, bladder cancer has existed as a Cinderella disease, with only a few practice-changing advances in systemic therapy. However, with the advent of immunotherapy and the discovery of potential biomarkers, the latter half of this decade witnessed some path-breaking treatments in bladder cancer.[1] Trials were centered on the role of immunotherapy as first-line treatment for cisplatin-eligible patients and improving the cure rates for muscle-invasive bladder cancer (MIBC) with the addition of immunotherapy.

The rapid approval of immunotherapeutic agents by the Food and Drug Administration (FDA) has provided us a wealth of opportunities for the treatment of bladder cancers. Currently, five FDA approved agents are available for patients with bladder cancer that is refractory to platinum agents, with a response rate of 15%–21%.[2] In addition, there are two trials that have changed the standard of care in patients with cisplatin-ineligible advanced bladder cancer.[3] However, yet another challenge faced by oncologists is deciding the optimal sequence and feasible combinations of these agents to obtain the best outcomes.

Recent trials have attempted to combine a chemotherapeutic agent with an immunotherapy drug in the first-line setting. One such phase III trial, IMVIGOR 130, enrolled 1213 patients who were randomly assigned to receive either atezolizumab with platinum-gemcitabine chemotherapy or chemotherapy alone. The primary endpoint of this trial was the response rate, and the co-primary endpoints were overall survival (OS) and progression-free survival (PFS). The trial showed a significant improvement in the PFS for the combination arm compared to the chemotherapy arm; similarly, a trend toward an improved OS was observed at an interim analysis. The median PFS in the intention-to-treat population was 8.2 months (95% confidence interval [CI], 6.5–8.3) for the combination arm and 6.3 months (95% CI, 6.2–7.0) for the chemotherapy arm, with a stratified hazard ratio (HR) of 0.82 (95% CI, 0.70–0.96) (one-sided P = 0.007). The median OS was 16.0 months (95% CI, 13.9–18.9) for the combination arm and 13.4 months (95% CI, 12.0–15.2) for the chemotherapy arm, with a HR of 0.83 (95% CI, 0.69–1.00) (one-sided P = 0.027).[5] These results support the use of an immunotherapy agent with platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial cancer [Table 1].
Table 1: Immunotherapy trials used in first-line advanced or metastatic urothelial cancer, and the potential implications in future practice

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KEYNOTE-361 (NCT02853305), a randomized, ongoing phase III study enrolled 1010 patients with advanced urothelial carcinoma who were randomly assigned to receive either pembrolizumab with or without chemotherapy or chemotherapy alone in the first-line setting. The primary endpoints of this study were OS and PFS. However, as reported by the sponsor drug company, Merck, this trial failed to achieve its dual endpoint [Table 1].[6],[7]

The randomized controlled, open-label, multi-center phase III DANUBE trial explored the efficacy and safety of frontline durvalumab with or without tremelimumab in comparison with chemotherapy (gemcitabine along with a platinum agent) in cisplatin-eligible and ineligible patients with unresectable Stage IV bladder cancer. This trial recruited 1104 patients, and the primary end point was OS. In a web release by AstraZeneca, the sponsor, it was reported that the immunotherapy arm had failed to meet the primary endpoint, where durvalumab alone failed to show an improved OS over the standard of care. The final data are awaited ([Table 1]).[8] Other trials continue to test the use of durvalumab along with chemotherapy (phase III NIAGARA study [NCT03732677]) in patients with MIBC, with both tremelimumab and chemotherapy (phase III NILE trial [NCT03682068]) in patients with unresectable urothelial cancers, and in combination with Bacillus Calmette-Guerin immunotherapy vaccine (phase III POTOMAC trial [NCT03528694]) in patients with non-MIBC.

The Checkmate 901 (NCT03036098) study is a phase III study in 1290 previously untreated patients with unresectable or metastatic urothelial cancer to evaluate whether nivolumab in combination with ipilimumab or standard-of-care chemotherapy is better than standard-of-care chemotherapy alone. The primary endpoints of this trial are OS and PFS. The trial is ongoing, and the results are awaited [Table 1].[9]

Researchers have tried the “switch maintenance” therapy comprising a primary treatment followed by maintenance with another treatment modality. HCRN GU14-182 was an investigator-led phase II study in 107 patients with metastatic urothelial cancer who achieved stable disease after a maximum of 8 cycles of first-line platinum-based chemotherapy to receive 200 mg pembrolizumab intravenously every 3 weeks versus placebo for up to 24 months. The primary endpoint was PFS at 6 months. Galsky et al. reported that at a median follow-up of 14.7 months, the PFS was significantly longer in patients who received pembrolizumab versus those who received the placebo. The 18-month restricted mean PFS was 8.2 months in the pembrolizumab arm and 5.6 months in the placebo arm (P = 0.023) (HR, 0.64; 95% CI, 0.41–0.98) (maximum efficiency robust test P = 0.036; log-rank P = 0.038). The role of switch-maintenance programmed cell death protein 1 (PD-1) blockade will be defined by the ongoing phase III studies [Table 1].[10]

The JAVELIN Bladder 100, a phase III randomized, multi-center trial, defined a new first-line standard of care for patients with advanced urothelial cancer whose disease had not progressed with platinum-based induction chemotherapy by using maintenance therapy with avelumab. The primary endpoint for this trial with 700 patients was OS. It was observed that avelumab with best supportive care (BSC) significantly prolonged the OS compared to BSC alone in all the patients. The median OS for avelumab with BSC was 21.4 months compared to that for BSC alone at 14.3 months (HR, 0.69; 95% CI, 0.56–0.86; P < 0.001). The median OS in the PD-L1-positive population was not reached vs 17.1 months (HR, 0.56; 95% CI, 0.40–0.79; P <.001). This indicates that the survival benefit achieved with maintenance immunotherapy agents cannot be disregarded and that maintenance immunotherapy could become the standard of care in the near future [Table 1].[11]

Currently in the pipeline is the antibody-drug conjugate consisting of the nectin-4 antibody, enfortumab, and the microtubule disrupting agent, monomethylauristatin E (MMAE) added to pembrolizumab in locally advanced or metastatic urothelial bladder cancer. Enfortumab vedotin (EV) is being tested in the ongoing phase Ib/II study with 407 participants (EV-103/KEYNOTE-869 [NCT03288545]). The primary endpoints for this study are toxicity, pathological complete response, and objective response rates (ORR). The results presented at the American Society of Clinical Oncology 2020 virtual meeting revealed that the combination of pembrolizumab and EV led to encouraging and durable activity with an ORR of 73.3%, a median PFS of 12.3 months with 93% of the patients showing a reduction in target lesions, with a favorable safety profile. These results led the FDA to approve this combination therapy [Table 1].[12]

The search for potential biomarkers has helped us to move beyond immunotherapeutic agents, to include targeted therapies against cell surface receptors (such as fibroblast growth factor receptor 3, human epidermal growth factor receptor 2), cell cycle regulators (like cyclin-dependent kinases 4/6), epigenetic regulators (like EZH2, BRD4), and intracellular signaling pathways (like PI3K/AKT/mTOR).[13],[14] The results for these targeted receptor therapies are awaited.

The management of bladder cancer is challenging, and in recent times, we have seen some important advances in its underlying molecular biology. The impressive results with immunotherapy and combination chemotherapy give us a ray of hope for better management of this disease in the future.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.[22]

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