Immunotherapy Finds a Foothold in Metastatic Bladder Cancer, But Frontline Challenges Remain

The emergence of checkpoint inhibitors has transformed the second-line treatment of patients with metastatic bladder cancer. However, questions regarding the utility of immunotherapy in the frontline setting remain unanswered, leaving chemotherapy as the standard-of-care option.

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The emergence of checkpoint inhibitors has transformed the second-line treatment of patients with metastatic bladder cancer (mBC). However, questions regarding the utility of immunotherapy in the frontline setting remain unanswered, leaving chemotherapy as the standard-of-care option, said Arjun V. Balar, MD.

Although atezolizumab (Tecentriq) and pembrolizumab (Keytruda) have frontline FDA indications for patients with PD-L1–positive, cisplatin-ineligible mBC, ongoing trials are evaluating immunotherapy combinations as well as emerging modalities such as antibody-drug conjugates (ADCs).

Additionally, immunotherapy is being brought into muscle-invasive bladder cancer (MIBC) and non–MIBC, and the modality may have utility in combination with chemoradiation in MIBC.

During the 5th Annual International Congress on Immunotherapies in Cancer®, a program run by Physicians’ Education Resource®, Balar discussed key nuances to consider when utilizing immunotherapy in mBC, as well as emerging strategies in muscle-invasive and non–muscle-invasive disease. He is an associate professor within the Department of Medicine at NYU Grossman School of Medicine and director of the Genitourinary Medical Oncology Program and medical director of the Clinical Trials Office at NYU Langone Health’s Perlmutter Cancer Center.

Chemotherapy Gives Way to Checkpoint Inhibition in Second-Line mBC

Five PD-1/PD-L1 inhibitors have been FDA approved for the second-line treatment of patients with mBC, showing improved responses compared with single-agent chemotherapy.

In the frontline setting, cisplatin has demonstrated improved survival rates with some curative benefit. However, up to two-thirds of patients with mBC are cisplatin ineligible because of comorbidities; they cannot derive benefit from cisplatin and generally have poor outcomes.

In April and May 2017, respectively, the FDA approved atezolizumab and pembrolizumab for the first-line treatment of previously untreated patients with cisplatin-ineligible disease based on findings from cohort 1 of the phase 2 IMvigor210 (NCT02108652) and phase 2 KEYNOTE-052 (NCT02335424) trials, respectively. The objective response rate was 24% with atezolizumab and 28.6% with pembrolizumab.1,2

However, in May 2018, the FDA issued a safety alert of decreased survival with single-agent atezolizumab or pembrolizumab among patients with mBC who have not received prior therapy and who have low PD-L1 expression; the alert was based on findings from the ongoing phase 3 IMvigor130 (NCT02807636) and KEYNOTE-361 (NCT02853305) trials.3,4 As such, updates to the agents’ labels require the use of an FDA-approved companion diagnostic to determine PD-L1 expression for patients with advanced cisplatin-ineligible bladder cancer.

“Systematically, we had to roll back some of the excitement [generated with first-line checkpoint inhibitors] when the label was restricted to those who are PD-L1 positive or chemotherapy ineligible. Now, there is some controversy about [checkpoint inhibitors’] continued use at all in the first-line setting,” said Balar.

Chemotherapy Combos Yield Underwhelming Data in the Metastatic Setting

In the IMvigor130 trial, the progression-free survival (PFS) in the intention-to-treat population was 8.2 months (95% CI, 6.5-8.3) with atezolizumab plus chemotherapy versus 6.3 months (95% CI, 6.2-7.0) with placebo plus chemotherapy (stratified HR, 0.82; 95% CI, 0.70-0.96; 1-sided P = .007), meeting the coprimary end point of the study.3

“Anytime we look at a curve like this, we think: Yes, it is statistically significant, but is it clinically meaningful?” said Balar. “The curves separate, and they maintain separation, but in terms of what we were hoping to see, it certainly didn’t mirror what we saw in advanced lung cancer.”

However, subgroup analyses of overall survival (OS) showed that patients with PD-L1–negative disease have an increased risk of death within the first year of single-agent atezolizumab compared with chemotherapy, which led to the FDA label change.

The KEYNOTE-361 trial (NCT02853305) yielded similar findings, and the PFS results did not meet statistical significance.4

Results of the pivotal phase 3 JAVELIN Bladder 100 trial (NCT02603432) have called the use of immunotherapy into question, although it was a maintenance therapy–powered trial. The results demonstrated a 31% reduction in the risk of death with avelumab (Bavencio) maintenance versus best supportive care (BSC) in the overall population of patients with unresectable locally advanced or mBC who derived a complete response (CR) or partial response or stable disease with standard first-line chemotherapy (95% CI, 0.56-0.86; P < .001).5 In the PD-L1–positive population, the risk of death was reduced by 44% (95% CI, 0.40- 0.79; P < .001).

Notably, 6.3% of patients who received avelumab plus BSC and 43.7% of patients who received BSC alone discontinued maintenance therapy and received a PD-1/PD-L1 inhibitor as subsequent therapy.

In June 2020, the FDA approved avelumab for the frontline maintenance treatment of patients with locally advanced or mBC that has not progressed with first-line platinum-containing chemotherapy.6

“Along with some of the data from [KEYNOTE-361], this is saying that maybe we should give everyone platinum-based chemotherapy up front and really reserve immunotherapy for the second-line setting,” said Balar.

Other ongoing trials are continuing to parse out the role of immunotherapy, particularly by evaluating CTLA-4 inhibitors in the metastatic setting. However, the phase 3 DANUBE trial (NCT02516241), which evaluated durvalumab (Imfinzi) alone versus in combination with tremelimumab versus chemotherapy, did not meet either coprimary end point.7

“High-volume, symptomatic disease [should] be treated with chemotherapy, irrespective of PD-L1 status,” stated Balar. “Small-volume, asymptomatic disease can be treated effectively with immunotherapy, also irrespective of PD-L1 status. PD-L1 expression is a dubious value in metastatic disease. Perhaps [PD-L1 status is useful] in equivocal cases where we are not sure what direction to go in. For chemotherapy-ineligible patients, immunotherapy remains the only viable option.”

Emerging Options

Antibody-drug conjugates, such as enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan-hziy (Trodelvy), could reshape the third-line treatment of patients with mBC, said Balar.

In December 2019, enfortumab vedotin received an accelerated approval from the FDA for the treatment of patients with locally advanced or mBC after prior PD-1/ PD-L1 therapy and platinum-containing chemotherapy. Long-term follow-up of the EV-201 trial (NCT03219333), findings of which served as the basis for the approval, demonstrated a 50.4% OS rate at 12 months and a 34.2% OS rate at 18 months with enfortumab vedotin in this patient population.8

Additionally, combinations with ADCs and checkpoint inhibitors, such as enfortumab vedotin and pembrolizumab in the ongoing phase 2 EV-103 trial (NCT03288545), are under investigation to potentially introduce chemotherapy-free options for patients with advanced disease. 

Making Way for Immunotherapy in Non-MIBC

Traditionally, patients with MIBC are treated with radical cystectomy; however, a significant portion of patients relapse after surgery. Notably, singleagent immunotherapy has demonstrated pathologic CR rates in the range of 30% to 40% in the neoadjuvant setting. Additionally, checkpoint inhibitors have shown some responses in the adjuvant setting, explained Balar.

The trimodality of chemoradiation plus immunotherapy is being evaluated for this patient population in the ongoing KEYNOTE-992 (NCT04241185) and SWOG 1806 (NCT03775265) trials and could offer a potential option for patients who want to avoid radical cystectomy.

Finally, initial findings from the ongoing KEYNOTE-057 trial (NCT03711032) demonstrated encouraging early efficacy and CR rates with seemingly durable responses with pembrolizumab monotherapy in patients with high-risk non-MIBC who are unresponsive to BCG and who decline to undergo or are ineligible for cystectomy, according Balar, lead author of the study.

“The benefit of immunotherapy is still evolving, especially in the case of bladder preservation in non-MIBC and also, in particular, when we combine it with trimodality bladder preservation,” concluded Balar.


  1. Balar AV, Dreicer R, Loriot Y, et al. Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): long-term efficacy from phase 2 study IMvigor210. J Clin Oncol. 2018;36(suppl 15):4523-4523. doi:10.1200/JCO.2018.36.15_suppl.4523
  2. Vuky J, Balar AV, Castellano D, et al. Long-term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol. 2020;38(23):2658-2666. doi:10.1200/JCO.19.01213
  3. Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0
  4. 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
  5. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. New Eng J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788
  6. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed December 14, 2020.
  7. Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588. doi:10.1016/S1470-2045(20)30541-6
  8. O’Donnell P, Galsky M, Rosenberg JE, et al. EV-201: long-term results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and PD-1/PD-L1 inhibitors. Ann Oncol. 2020;31(suppl 4):579-580. doi:10.1016/j.annonc.2020.08.818