Bladder Cancer Awareness Month: New Advances in Therapies for Urothelial Carcinoma

Shifeng S. Mao, MD, PhD

Bladder cancer, most commonly in the form of urothelial carcinoma, is the sixth most common cancer overall and fourth most common cancer for men in the United States.¹ For advanced bladder cancer, treatment can involve difficult regimens such as removal of the bladder and significant levels of toxic chemotherapy. Many patients have refractory or relapsed disease following the standard of care, which is platinum-based chemotherapy. For this reason, finding effective therapies with less toxicity is a key area of cancer research.

Clinical studies have shown superior efficacy and tolerability from treatment with several types of systemic therapy including immunotherapy, targeted inhibitors, and antibody-drug conjugates. Adjuvant and neoadjuvant therapy with new classes of drugs can also improve the outcomes of surgery.

“We are in the exciting era of a changing treatment landscape. Over the last 5 years, there have been several new, exciting treatments being developed,” Shifeng S. Mao, MD, PhD, said in an interview with Targeted Oncology^TM.

Mao is the chair of the Allegheny Health Network (AHN) Cancer Institute urological oncology team and associate professor of medicine at Drexel University College of Medicine. During the interview, Mao discussed what current and upcoming clinical studies have led to improvements in how physicians treat urothelial cancer.

Targeted Oncology^TM: How would you say that the field of bladder cancer has changed compared with 10 years ago?

MAO: The field has been revolutionized completely thanks to the development of immune checkpoint inhibitors [ICIs], since 2016, then the development of antibody-drug conjugates since 2019, and also the FGFR inhibitor erdafitinib [Balversa], which also presented data in 2019. The field is still evolving, [but] about 10 years ago, the only thing we had was chemotherapy in the metastatic setting or in localized muscle-invasive disease.

What recent trials have been most practice-changing in the metastatic bladder cancer setting?

In the metastatic setting, patients are divided into 2 categories based on cisplatin eligibility. Cisplatin is a very effective agent in bladder cancer, and cisplatin-based regimens, [such as] gemcitabine plus cisplatin or MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), cisplatin] have provided very significant response rates in bladder cancer, so that is a standard first-line treatment in patients who are eligible for cisplatin.

For the cisplatin-ineligible population, the historic survival in the metastatic setting was only 8 to 9 months with conventional chemotherapy. This has changed with the development of ICIs. There are 2 studies designed in the cisplatin-ineligible setting with ICIs: pembrolizumab [Keytruda] in KEYNOTE-052 [NCT02335424] and atezolizumab [Tecentriq] in IMvigor 210 [NCT02108652]. Both have shown significantly improved median OS.^2,3 Therefore, ICIs are a good option for a patient in the cisplatin-ineligible population.

There have been several ICIs approved in the [second-line] setting. Pembrolizumab was tested in the phase 3 KEYNOTE-045 trial. That is a study [where pembrolizumab] was shown to improve overall survival [OS] with a median 10.3 months versus 7.4 months with chemotherapy. That was published back in 2017.⁴

What about patients who did not progress, but still achieved partial response or stable disease after 4 to 6 cycles of chemotherapy? The problem with chemotherapy compared [with] immunotherapy is you will hit that limit of the patient’s tolerance even if the patient responds.

For those who benefit from the treatment, can we maintain the response to achieve further treatment benefit? That is the switch maintenance approach. In the JAVELIN Bladder 100 trial [NCT02603432], which was published in 2020, patients would receive platinum-based chemotherapy. If they responded, or had stabilization of disease, those patients were randomized to an anti–PD-L1 inhibitor, avelumab [Bavencio]. The study shows an improvement in the median OS, and the benefit holds up even with longer follow-up.⁵

Which treatments are available for metastatic bladder cancer after the first and second line?

Beyond immunotherapy and platinum-based chemotherapy or for those cannot receive chemotherapy but have received immunotherapy in the frontline setting, there is a drug called enfortumab vedotin-ejfv [Padcev] developed by Seagen [and Astellas]. That is an antibody-drug conjugate using a monoclonal antibody targeting Nectin-4 with a payload called MMAE. Nectin-4 is preferentially expressed in the majority of bladder cancer cases. This approach would allow the highly toxic MMAE to concentrate in the area when the Nectin-4-expressing bladder cancer is located and minimize systemic adverse events.

In the phase 3 EV-301 study [NCT03474107] in the third-line setting, published in the New England Journal of Medicine in 2021, both median OS and progression-free survival [PFS] were improved, the overall response rate [ORR] was close to 41%, and the hazard ratio was 0.7, so the risk of reduction of death was 30%.⁶

There is another antibody-drug conjugate, sacituzumab govitecan [Trodelvy], being developed. It utilizes a monoclonal antibody targeting Trop-2—[which is] highly expressed in urothelial cancer—with a different toxic payload, SN-38. In the TROPHY-U-01 trial [NCT03547973], presented in the European Society for Medical Oncology Congress in 2020, the ORR of sacituzumab govitecan was about 27%.⁷ The drug has received a fast-track designation by the FDA for bladder cancer in the third-line setting and a larger-scale clinical trial using sacituzumab govitecan is being planned and underway.

Targeted therapy plays a role if a patient carries an actionable mutation, and 1 particular [mutation] involved FGFR, which is fairly prevalent in localized disease, but also found in about 15% of patients with metastatic bladder cancer. Erdafitinib is a pan-FGFR inhibitor [which was explored] in a phase 2 study that was presented by Arlene Siefker-Radtke, MD, at the 2018 American Society for Clinical Oncology [ASCO] Annual Meeting, among patients who have progressed on platinum-based chemotherapy with or without [receiving] immunotherapy in the second- or third-line setting.

The ORR for those who had FGFR mutations was 40%.⁸ The [median] PFS was about 5.5 months. The OS in the second- or third-line setting was 13.8 months, which is a significant in a population that has progressed [after] platinum-based chemotherapy. So for that reason, erdafitinib has been approved for urothelial carcinoma harboring FGFR mutations.⁹

How has treatment for localized bladder cancer evolved over time?

Within localized bladder cancer, there are 2 categories: non-muscle invasive urothelial carcinoma and muscle-invasive urothelial carcinoma. For patients with muscle-invasive urothelial carcinoma, the standard of care for years would be neoadjuvant chemotherapy followed by radical cystectomy in cisplatin-eligible patients. This is based on 2 landmark phase 3 clinical trials, the SWOG 8710 and EORTC 30894 [BA06] studies. Both studies demonstrated survival [benefit with] neoadjuvant chemotherapy using MVAC followed by radical cystectomy in the SWOG trial or a modified regimen called MCV [methotrexate, cisplatin, vinblastine] followed by either radical cystectomy or radiotherapy in the EORTC trial.^10,11 Both studies showed improvement of OS, so that has been the standard of care.

In the modern immunotherapy era, the question is if the ICIs that work in the metastatic setting would work for disease that is localized in the perioperative setting.

The CheckMate 274 study [NCT02632409], which was presented at the 2021 ASCO Genitourinary Cancers Symposium and published in the New England Journal of Medicine last year, was designed for patients with high-risk urothelial carcinoma who had surgery and either still had [residual] T2 disease after neoadjuvant chemotherapy or those who have never had a neoadjuvant chemotherapy but had more advanced T3 disease or nodal-positive disease. This patient population was randomized to ICI using nivolumab [Opdivo], which is anti–PD-1, or placebo. The primary end point of disease-free survival was positive favoring nivolumab.¹² Therefore, nivolumab has been approved in the adjuvant setting for high-risk invasive urothelial cancer after surgery.¹³

Now, the controversy is, there‘s another study that was designed using another ICI, atezolizumab, but that study [IMvigor 010; NCT02450331] was a negative study. The question is why nivolumab worked but atezolizumab did not work in the adjuvant setting even though the designs were similar.¹⁴ There are different speculative explanations, such as the proportion of patients with upper urinary tract disease. The trial using atezolizumab included more patients with upper tract disease, but for some reason, the upper tract disease does not respond to ICIs as much. One of the follow-up studies indicated those who had positive circulating cell-free tumor DNA [ctDNA] seem to benefit more from adjuvant ICI. There is another adjuvant trial being developed using atezolizumab in ctDNA-positive patients after surgery; we will participate in the study at our site.

There is an [upcoming] study called AMBASSADOR [NCT03244384] using pembrolizumab, which is an anti–PD-1 inhibitor, in the adjuvant setting. That study could be a tiebreaker [for the efficacy of ICIs in this setting].

The ICIs are also being tested in the neoadjuvant setting or peri-surgical setting. For example, pembrolizumab combined with chemotherapy in the perioperative setting, are being studied in the KEYNOTE-866 [NCT03924856] in cisplatin-eligible patients and upfront surgery versus pembrolizumab in KEYNOTE-905 [NCT03924895] trial for the cisplatin-ineligible population. We‘re still waiting for the readout for those studies. So far, ICIs, specifically nivolumab, are only approved in the adjuvant setting.

What is the role of the Bacillus Calmette–Guérin (BCG) vaccine in bladder cancer, and how are BCG-refractory patients treated?

Intravesical BCG has been the standard in high-grade, non-muscle-invasive urothelial carcinoma of the bladder. It is highly effective. With induction followed by maintenance BCG, the response rate reaches up to 70% to 80%.¹⁵

However, there is a significant proportion of patients who don’t response to BCG [BCG-refractory]. The standard of care for this patient population would be radical cystectomy, which is a very aggressive surgery. What about those who are unwilling to go through radical cystectomy? This is addressed by the KEYNOTE-057 trial [NCT02625961]. Patients that are BCG-refractory and are unwilling to go through radical cystectomy were enrolled in this single-arm study using pembrolizumab. The response rate was about 40%.¹⁶ So, pembrolizumab was approved for [patients with] high-risk, non-muscle invasive urothelial carcinoma, specifically those with carcinoma-in situ, which is a high-risk, high-grade condition.

What areas of research are now showing potential?

Besides expanding the indications for ICI, antibody-drug conjugates have been an active area of research. For example, enfortumab vedotin is a very promising agent. It demonstrated a very impressive ORR as a single agent, 41% in the third line in the EV-301 trial and 52% in the second-line setting for cisplatin-ineligible patient in the EV-201 trial [NCT03219333].^6,17 

What about if we used this drug in the first-line setting? There‘s a study called EV-103 [NCT03288545], which used enfortumab vedotin plus pembrolizumab in cohort A, that was originally presented in 2019 and updated several times by now. The response rate was very promising, in the range of the 70% to 80%.¹⁸ So we need to expand that study on a larger scale. Also, there‘s an [ongoing] study [NCT04700124] using enfortumab vedotin in the perioperative setting for cisplatin-ineligible patients; we can use enfortumab vedotin [alone] or enfortumab vedotin plus immunotherapy to induce a good response before surgery.

There are some patients with bladder cancer known to express HER2. There are studies designed to target HER2-expressing bladder cancer, using an antibody-drug conjugate approach.

What questions remain in the field of bladder cancer research?

Bladder cancer in the metastatic setting remains a fatal disease even though we have made so much progress. There‘s certainly a lot of work to be done. Now that we have chemotherapy, immunotherapy, antibody-drug conjugates, and FGFR-targeted therapy in our armamentarium against bladder cancer, how do we incorporate all these agents in a comprehensive and intelligent manner and how do we sequence those agents to maximize the benefit?

We need develop better biomarkers to predict which patients would benefit most from ICI as opposed to chemotherapy or combining both ICI and chemotherapy. The biomarkers such as PD-L1 expression or tumor mutation burden are far from perfect. There have been studies designed to shed light in understanding different subtypes of bladder cancer based on their molecular profiles. Hopefully, we will be able to predict treatment response based on both clinical and molecular tools, and clinical trial and treatment development will not be a “one-size-fits-all” approach but rather more smartly based on the “immune-response” or “chemo-response molecular signature”. That is ongoing, [using] next-generation sequencing on a large scale in a collaborative manner nationwide. Hopefully in the future, we can use artificial intelligence to help us to analyze the data and try to help us to accomplish something beyond our human capacity, using big data and computational biology.

We also need to perfect immunotherapy; the response rate for anti–PD-1/PD-L1 as single agent at best is about 20% to 30%. Can we improve the response rate by combining anti–CTLA-4 with anti–PD-1, as in renal cell carcinoma, melanoma, or non–small cell lung cancer? There would certainly be a price to pay for any combination—ie, treatment toxicity. What would be the risk/benefit ratio? There are also other ICIs, such as LAG-3 inhibitors, which are being developed. Can they be safely combined with existing ICIs or chemotherapy or antibody-drug conjugates? Those are the questions the field is trying to answer.

_References:

_{1. Key Statistics for Bladder Cancer. American Cancer Society. Accessed May 19, 2022. https://bit.ly/39ZVHSY}

_{2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2}

_{3. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial [published correction appears in Lancet. 2017 Aug 26;390(10097):848]. Lancet. 2017;389(10064):67-76. doi:10.1016/S0140-6736(16)32455-2}

_{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 first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022; 40(6_suppl):487:487. doi: 10.1200/JCO.2022.40.6_suppl.487}

_{6. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807}

_{7. 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(22):2474-2485. doi:10.1200/JCO.20.03489}

_{8. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-348. doi: 10.1056/NEJMoa1817323}

_{9. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. FDA. Published April 12, 2019. Accessed May 24, 2022. https://bit.ly/3lEyxUR}

_{10. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi:10.1056/nejm200311063491928}

_{11. International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177. doi:10.1200/JCO.2010.32.3139}

_{12. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442}

_{13. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. FDA. Published August 19, 2021. Accessed May 19, 2022. https://bit.ly/3G2PEJa}

_{14. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525-537. doi:10.1016/S1470-2045(21)00004-8}

_{15. Lamm, DL. Efficacy and safety of Bacille Calmette-Guerin immunotherapy in superficial bladder cancer. Clin Infect Dis. 2000;31(Suppl­­_3):S86-90. doi:10.1086/314064}

_{16. 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(7):919-930. doi:10.1016/S1470-2045(21)00147-9}

_{17. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600. doi:10.1200/JCO.19.01140}

_{18. Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2022;38(6_suppl):441:441. doi:10.1200/JCO.2020.38.6_suppl.441}