Immunotherapies and Combinations in Advanced Urothelial Cancer

For decades and even to this day, the foundation of metastatic bladder cancer therapy has been cytotoxic chemotherapy. In fact, until recently, the most significant breakthrough in treatment was in the 1980s, when cisplatin-based therapies, specifically MVAC, became the new standard of care.

Arjun V. Balar, MD

For decades and even to this day, the foundation of metastatic bladder (urothelial) cancer therapy has been cytotoxic chemotherapy. In fact, until recently, the most significant breakthrough in treatment was in the 1980s, when cisplatin-based therapies, specifically MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), became the new standard of care. A major step toward improved tolerability of cisplatin-based therapy came in the early 2000s with the advent of the modern regimen of gemcitabine and cisplatin.1However, the proportion of individuals who respond to this type of chemotherapy and the average survival rate of 12 to 15 months has not significantly changed. Moreover, we are increasingly realizing that a large proportion of patients is not eligible for cisplatin-based chemotherapy because of performance status and other medical conditions such as chronic kidney disease, cardiovascular disease, hearing loss, and peripheral neuropathy—conditions that are very common in the population with bladder cancer.2In fact, many patients are not receiving any form of cancer-directed therapy. More-effective and better-tolerated treatments have been a critical need for nearly 30 years.

Immunomodulatory agents targeting specific immune checkpoints, namely the PD-1 pathway, have revolutionized cancer care, beginning first with advanced melanoma, and now have a major impact on a number of solid tumors including non—small cell lung cancer, kidney cancer, headand- neck cancer, and bladder cancer. It turns out that bladder cancer, because of a high rate of somatic mutations leading to the generation of neoantigens, is highly immunogenic. The fact that bladder cancer is responsive to immunotherapy should not be surprising considering that bacille Calmette-Guérin, a form of intravesical immunotherapy, has been an effective tool in managing high-risk nonmuscle invasive bladder cancer since the 1970s.

In metastatic bladder cancer, the first phase I studies of agents targeting the PD-1 pathway were reported in 2014, including agents such as atezolizumab (a PD-L1 antibody) and pembrolizumab (a PD-1 antibody), and showed treatment to be extremely well tolerated, with promising response rates and few significant toxicities. Responses to treatment were durable and were sustained well after therapy was discontinued— outcomes that are unique to immunotherapies. These findings unleashed a slew of large phase I, II, and III studies, leading to approvals of 5 agents targeting the PD-1 pathway (atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab) in the second-line setting after failure of platinum-based chemotherapy, as well as the approval of 2 agents (atezolizumab and pembrolizumab) in the first-line cisplatin-ineligible setting—all of which happened within a year. Notably, in the second-line setting, we recently saw definitive evidence from the phase III KEYNOTE-045 trial that immunotherapy with pembrolizumab improves survival over standard chemotherapy after failure of platinum-based chemotherapy in metastatic bladder cancer.3This was the first study to demonstrate an improvement in survival against an active comparator in second-line metastatic bladder cancer.

What is perplexing is that a similar phase III study (IMVigor 211) of atezolizumab versus standard chemotherapy in a similar patient population failed to meet the primary endpoint of improving survival. It is not entirely clear what led to these conflicting outcomes. However, the statistical design of IMVigor 211, which tested survival in PD-L1—overexpressing patients (using the SP142 Ventana assay), in the primary analysis, may have been a major factor. Regardless, this level of activity in drug development was unprecedented and signaled a sea change in how we managed this disease moving forward.

Unfortunately, while treatment is very well tolerated and can lead to durable responses, only 15% to 29% of patients, depending on the line of therapy, will respond to single-agent PD-1 pathway inhibition, and up to a third of patients who achieve a response will ultimately progress. The challenge that lies ahead is how to build on the initial successes of single- agent PD-1 pathway inhibition and discover new ways to engage the immune system in patients who do not respond.

There may be several ways to address the problem. Combination therapies using conventional cancer therapies such as radiation and/or chemotherapy or molecularly targeted therapy focused on specific bladder cancer subsets (identification made possible by recent advancement in the molecular characterization of bladder cancer) may be able to convert a “cold” tumor (devoid of immune inflammation) into a “hot” tumor. Other combination strategies with IDO-1 inhibitors, adenosine A2A receptor antagonists, and cytotoxic T-lymphocyte antigen-4 inhibitors may also hold promise but may come at the expense of increased toxicities. Therefore, there is a pressing need to develop predictive biomarkers to improve patient selection. PD-L1 overexpression in the tumor microenvironment has been associated with higher response rates to PD-1 pathway inhibitors; however, patients with low expression may also respond, and thus better biomarkers will be necessary to identify patients who warrant combination therapy and the potential added toxicity. Biomarkers under investigation currently include gamma interferon gene signatures, The Cancer Genome Atlas subgroup classification, and tumor mutational burden.

Countless trials are under way to test these hypotheses and hopefully will lead to better insights into the mechanisms of immune resistance in bladder cancer, as well as important treatment discoveries. Although we are still in the early stages of understanding the therapeutically relevant molecular biology of bladder cancer, recent breakthroughs in molecular characterization efforts, especially in the arena of immunotherapy, provide great promise for the future of bladder cancer treatment.

Our session on immunotherapy advancements in urothelial cancer will provide an up-to-the-minute update on the status of immunotherapies and the ongoing research most likely to affect bladder cancer care. We remain optimistic that further scientific study will lead to the development of better-tolerated and more-effective treatments that improve survival for all patients with bladder cancer.


  1. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068-3077. doi: 10.1200/JCO.2000.18.17.3068.
  2. Sonpavde G, Watson D, Tourtellott M, et al. Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer. 2012;10(1):1-5. doi: 10.1016/j.clgc.2011.11.005.
  3. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.