New Treatment Options for Patients With Bladder Cancer

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Thomas W. Flaig
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Bladder cancer is not rare—in men, it is the fourth most common cancer and the eighth leading cause of cancer-related death. The emergence of new systemic therapies, approval of PD-1 and PD-L1 inhibitors, and progress in the development of biomarkers have revolutionized the treatment of this urologic malignancy. The current NCCN Guidelines, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of bladder cancer, support the incorporation of some of these novel therapeutics into clinical practice.

“The landscape for the treatment of bladder cancer has changed remarkably and rapidly over the past several years,” commented Thomas Flaig, MD, Professor of Medicine, Vice Chancellor for Research, University of Colorado Anschutz Medical Campus, and Chair of the NCCN Guidelines Panel for Bladder Cancer, at the NCCN 2022 Annual Conference. The emergence of new systemic therapies, approval of PD-1 and PD-L1 inhibitors, and progress in the development of biomarkers have revolutionized the management of this urologic malignancy. Dr. Flaig presented data evaluating these new treatment options in bladder cancer, as well as relevant updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer.

Overview of Bladder Cancer

“There are approximately 61,700 cases [of bladder cancer] each year, which makes it the fourth most common cancer [in men],” Dr. Flaig remarked. “It is the eighth leading cause of cancer death in men, as well, with approximately 12,120 deaths per year.”1

The incidences of several cancers, such as prostate, lung, colorectal, liver, and melanoma, have changed over the past 40 years; however, the rates of bladder cancer seem to have remained stable. Although the development of both bladder and lung cancers appears to be associated with smoking, only the incidence rate of lung cancer has demonstrated a downward trend.1

“There have been a remarkable number of approvals and indications for [immunotherapy drugs over the past decade],” Dr. Flaig commented. “[The idea of] an immunotherapy-based regimen has been part of our thinking for bladder cancer for 4 decades.” Because bladder cancers are characterized by a high mutational frequency, there has been a large-scale integration of immune checkpoint inhibitor (ICI) therapies.2

Treatment Advances in Non–Muscle-Invasive Bladder Cancer

For several years, there have been issues and concerns regarding the availability of bacillus Calmette-Guérin (BCG) intravesical therapy. Therefore, per the current NCCN Guidelines, patients with high-risk non–muscle-invasive bladder cancer should be prioritized for BCG induction therapy. Intravesical mitomycin and gemcitabine are currently highlighted as preferable alternatives.3 “Recently, several other intravesical chemotherapies have been added, which include sequential gemcitabine + docetaxel/epirubicin/valrubicin/docetaxel, and sequential gemcitabine + mitomycin,” Dr. Flaig remarked.3 “One of the things we have seen in the midst of the BCG shortage is investigations looking at different approaches.”

The current NCCN Guidelines recommend cystectomy or intravesical chemotherapy for the initial management of high-risk BCG-unresponsive or BCG-intolerant non–muscle-invasive bladder cancer. Pembrolizumab is also an option, though only in a select population.

The multicenter phase II KEYNOTE-057 trial results shed light on the characteristics of the group of patients who may be eligible for monotherapy with this ICI.4 A total of 41% and 19% of patients with high-risk BCG-unresponsive non–muscle-invasive bladder cancer achieved a complete response at 3 and 12 months, respectively.4,5 Based on these data, pembrolizumab was FDA-approved for use in this clinical context.

“This is an important new indication for non–muscle-invasive bladder cancer,” Dr. Flaig commented. “Patient selection is critical here, and there is some complexity regarding which patients would qualify for this treatment.”

One of the many novel intravesical chemotherapy regimens that may have emerged as a result of the BCG shortage—gemcitabine + docetaxel—was evaluated in a retrospective study of patients who underwent previous BCG therapy.6 In this population, the recurrence-free survival rate was 60% and 46% at 1 and 2 years, respectively. The 1- and 2-year cancer-specific mortality rates were 1% and 4%, respectively. “This is, I think, a good example…of how intravesical chemotherapy is being examined in new combinations for this setting,” Dr. Flaig commented. “Just note, however, there are a number of investigational agents being evaluated in this setting that have not yet been integrated into the NCCN Guidelines.”

Immune Checkpoint Inhibitors

“[The investigation of new and emerging systemic therapies] has been an extremely active area over the past few years,” Dr. Flaig remarked. “One key theme of this is the integration of ICIs.”

The FDA approval of second-line pembrolizumab paved the way for the integration of ICI therapy in several new indications for patients with bladder cancer. In a phase III trial, patients with advanced urothelial carcinoma who experienced disease progression after undergoing platinum-based chemotherapy derived a statistically significant overall survival (OS) benefit with pembrolizumab versus investigator-selected chemotherapy (hazard ratio [HR], 0.73; P=.002). Overall response rates with pembrolizumab and chemotherapy were 21% and 11%, respectively.7 According to Dr. Flaig, one of the hallmarks of this therapy is the durability of the responses observed.

The ICI nivolumab has also been integrated into the treatment landscape for bladder cancer. In a phase III trial, adjuvant nivolumab conferred a significant disease-free survival benefit compared with a placebo in the intention-to-treat (HR, 0.70; P<.001) and PD-L1–positive (HR, 0.55; P<.001) groups of patients with muscle-invasive urothelial carcinoma.8

Improvement in OS outcomes was also reported with ICIs in a phase III trial of patients with advanced or metastatic urothelial carcinoma who underwent maintenance therapy with avelumab after chemotherapy, according to Dr. Flaig. Median OS was longer with avelumab compared with best supportive care (21.4 vs 14.3 months; HR, 0.69; P=.001).9

“[ICIs] have had a dramatic impact on the way we treat patients with bladder cancer,” he commented. “It is really important for anybody thinking about this disease to understand.”

Antibody–Drug Conjugates

“Antibody–drug conjugate [ADC] therapies…have also made a significant impact [in bladder cancer],” Dr. Flaig explained. Specifically, in a phase III trial, Powles et al10 demonstrated that enfortumab vedotin-ejfv prolonged median progression-free survival (5.55 vs 3.71 months; HR, 0.62; P<.001) and median OS (12.88 vs 8.97 months; HR, 0.70; P=.001) compared with investigator-selected chemotherapy in previously treated patients with locally advanced or metastatic urothelial carcinoma.

In the phase II TROPHY-U-01 trial, patients with unresectable or metastatic urothelial carcinoma who experienced disease progression after undergoing platinum-based chemotherapy and ICI therapy were administered the anti–Trop-2 ADC sacituzumab govitecan. The overall response rate was 27%, with 5% of patients who experienced a complete response. Median OS was 10.9 months.11

Targeted Therapy

In addition to ICIs and ADCs, Dr. Flaig also discussed the role of targeted therapy in bladder cancer. Erdafitinib, a pan-FGFR tyrosine kinase inhibitor, was evaluated in a trial of patients with FGFR2/3-mutated unresectable or metastatic urothelial carcinoma and who were previously treated with chemotherapy. The confirmed response rate was 40%, which included 3% of patients who experienced a complete response and 37% who achieved a partial response. Median OS with erdafitinib was 13.8 months.12

“Targeted therapy and the need to assess the genetic makeup of patients has become much more important,” Dr. Flaig remarked. “In practice, we are now more commonly using genetic testing to identify patients who are eligible for integration of this drug into their treatment regimens.”

Recent Additions to the NCCN Guidelines

Looking back, in 2015, limited data were available to guide the treatment of metastatic bladder cancer. According to Dr. Flaig, the NCCN Guidelines recommended cisplatin combinations for cisplatin-eligible patients; for those who were ineligible for cisplatin therapy, carboplatin combinations or other regimens were recommended. There were no recommended standard therapies in the second and third lines of treatment.

In 2022, a much more complicated picture has emerged in terms of identifying patients with cisplatin- or platinum-eligible disease.3 “There is a broad use of ICIs now in this setting, which is a big change,” Dr. Flaig commented. “Of course, there is an integration of ADCs and targeted therapy into our thinking.”

First-line treatment with gemcitabine + cisplatin or dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) was recommended in the second version of the 2015 NCCN Guidelines, according to Dr. Flaig. The current guidelines still incorporate these therapies into the treatment options for cisplatin-eligible patients—however, now there is an opportunity to administer maintenance therapy with avelumab. Gemcitabine + carboplatin remains an option for cisplatin-ineligible patients, but ICIs have emerged as an alternative for those with PD-L1–positive or platinum-ineligible disease.3

Second-line pembrolizumab is incorporated into the current NCCN Guidelines as the preferred regimen for patients with locally advanced or metastatic disease who underwent chemotherapy. Alternative preferred regimens in this clinical context include nivolumab, avelumab, erdafitinib, and enfortumab vedotin. The current guidelines also recommend a variety of agents, such as enfortumab vedotin and gemcitabine + carboplatin, for the second-line treatment of patients with a history of receiving ICIs.3

“Just think back to 2015, when nothing existed in the second line,” Dr. Flaig commented. “We really have become quite sophisticated here.”

Recommendations regarding subsequent-line systemic therapy for locally advanced or metastatic disease are also included. In the current NCCN Guidelines, preferred regimens in this setting are enfortumab vedotin and erdafitinib.3

According to Dr. Flaig, the NCCN Guidelines also provide recommendations for adjuvant therapy. “In the past, we have simply [considered] chemotherapy if patients had not received it and have significant disease observed at the time of surgery,” he commented. “Now, we have the option of including nivolumab in patients who have a certain level of residual disease after receiving cisplatin-based chemotherapy [or in those who] have not received chemotherapy.”

In terms of neoadjuvant chemotherapy, the current NCCN Guidelines recommend dose-dense MVAC with growth factor support. Alternately, gemcitabine + cisplatin may be used as an alternative regimen in this clinical context.3

References

  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:733.

  • 2.

    Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214218.

  • 3.

    Flaig TW, Spiess PE, Abern M, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder Cancer. Version 1.2022. Accessed March 31, 2022. Available at NCCN.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:919930.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Gill J, Prasad V. Pembrolizumab for non–muscle-invasive bladder cancer—a costly therapy in search of evidence. JAMA Oncol 2021;7:501502.

  • 6.

    Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol 2020;203:902909.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:10151026.

  • 8.

    Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021;384:21022114.

  • 9.

    Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383:12181230.

  • 10.

    Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384:11251135.

  • 11.

    Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39:24742485.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338348.

Disclosures: Dr. Flaig has disclosed receiving grant/research support from Agensys, Inc., Astellas Pharma US, Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech, Inc., Janssen Pharmaceutica Products, LP, Merck & Co., Inc., sanofi-aventis U.S., and Seattle Genetics, Inc; serving as a scientific advisor for Janssen Pharmaceutica Products, LP, and Seattle Genetics, Inc.; and receiving equity interest/stock options in and intellectual property rights for Aurora Oncology.

Correspondence: Thomas W. Flaig, MD, University of Colorado, Mail Stop F520, 13001 East 17th Place, Aurora, CO 80045. Email: thomas.flaig@cuanschutz.edu
  • Collapse
  • Expand
  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:733.

  • 2.

    Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214218.

  • 3.

    Flaig TW, Spiess PE, Abern M, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder Cancer. Version 1.2022. Accessed March 31, 2022. Available at NCCN.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:919930.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Gill J, Prasad V. Pembrolizumab for non–muscle-invasive bladder cancer—a costly therapy in search of evidence. JAMA Oncol 2021;7:501502.

  • 6.

    Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol 2020;203:902909.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:10151026.

  • 8.

    Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021;384:21022114.

  • 9.

    Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383:12181230.

  • 10.

    Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384:11251135.

  • 11.

    Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39:24742485.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338348.

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