Although metastatic urothelial carcinoma (mUC) remains generally incurable, management of bladder cancer has witnessed several multidisciplinary advances in the past few years (

). Cisplatin-based combination chemotherapy employing gemcitabine plus cisplatin; methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) or dose-dense MVAC yields a median survival of 14 to 15 months and a 5-year overall survival (OS) of 5% to 15%, suggesting some potential cures.

Figure. Multidisciplinary Advances Have Expanded Treatment and Staging Options for mUC

Informed by tumor biology, the therapeutic landscape for mUC has been transformed with the advent of the PD-1/ PD-L1 inhibitors pembrolizumab (Keytruda), atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), and avelumab (Bavencio) for the treatment of patients with progressive disease who have previously received platinum-containing regimens.

In results from the KEYNOTE-045 trial (NCT02256436), pembrolizumab induced an impressive 2-year OS rate of 26.9% compared with 14.3% with taxane or vinflunine chemotherapy in the intention-to-treat (ITT) population regardless of PD-L1 expression.

 While the objective response rate (ORR) was higher with pembrolizumab (21.1% vs 11.0%), the most impressive aspect of outcomes may be the prolonged median duration of response greater than 2 years compared with just 4.4 months with chemotherapy. 

Pembrolizumab and atezolizumab are also approved as first-line therapy for platinum-ineligible patients and cisplatin-ineligible patients with high tumor PD-L1 expression, although phase 3 trials have not demonstrated improved survival with this approach.

 Indeed, findings from the phase 3 DANUBE trial (NCT02516241) did not demonstrate improved OS for durvalumab in patients with PD-L1–high tumors or for durvalumab plus tremelimumab versus gemcitabine-platinum in unselected patients.

Furthermore, the combination of PD-1/PD-L1 inhibitors with platinum-based chemotherapy in the KEYNOTE-361 and IMvigor130 trials for metastatic disease was not successful in improving survival.

 The combination of atezolizumab with gemcitabine-platinum in IMvigor130 (NCT02807636) demonstrated modestly improved progression-free survival (PFS; 8.2 vs 6.3 months; HR, 0.82; 95% CI 0.70-0.96; 1-sided 

 = .007). Similarly, investigators in KEYNOTE-361 (NCT02853305) did not observe an improvement in OS with the combination of either atezolizumab or pembrolizumab with gemcitabine-platinum. 

The ongoing CheckMate-901 trial (NCT03036098) is comparing the combination of ipilimumab (Yervoy) plus nivolumab versus gemcitabine-platinum with coprimary end points of survival in cisplatin-ineligible patients and patients with PD-L1–high expressing tumors. Moreover, this trial is devoting a large substudy to examining the impact of combining nivolumab with cisplatin-gemcitabine specifically in cisplatin-eligible patients.

More recently, the landmark JAVELIN Bladder 100 phase 3 trial (NCT02603432) demonstrated that first-line switch maintenance with avelumab in patients who demonstrated a response or stable disease on 4 to 6 cycles of platinum-based chemotherapy significantly improved survival compared with best supportive care (BSC) in the overall ITT population regardless of tumor PD-L1 expression (median OS 21.4 vs 14.3 months; HR, 0.69; 95% CI, 0.56-0.86; 1-sided 

Additionally, investigators reported prolonged OS in patients with PD–L1-positive tumors (HR, 0.56; 95% CI 0.40-0.79; 1-sided 

 = .0003). Avelumab plus BSC also extended PFS compared with BSC alone in the ITT population (HR, 0.62; 95% CI, 0.52-0.75) as well as the PD-L1–high population (HR, 0.56; 95% CI, 0.43-0.73). These data are considered practice-changing. 

Advances have occurred for the therapy of postplatinum patients with progressive metastatic disease, with FDA approvals of enfortumab vedotin-ejfv (Padcev), an antibody-drug conjugate (ADC), and the first targeted agent, erdafitinib (Balversa). In the phase 2 EV-201 trial (NCT03219333), investigators administered enfortumab vedotin, the first FDA-approved Nectin–4 targeting ADC, to 125 patients who previously received platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

Enfortumab vedotin induced an ORR of 44% (95% CI, 35.1%-53.2%) including 12% complete responses (CRs).

 The median PFS and OS were 5.8 and 11.7 months, respectively. Investigators observed encouraging responses even in patients with liver metastases and those with no response to prior PD1/PD-L1 inhibitor therapy. In TROPHY-U01 (NCT03547973), the ADC sacituzumab govitecan, which targets trophoblast cell–surface antigen 2, showed preliminary promise in the same setting.

Erdafitinib, an oral FGFR inhibitor, is applicable to approximately 15% of post-platinum patients with activating genomic alterations in 

 and has provided advances in the salvage setting. In a phase 2 trial (N = 99) patients, ORR with erdafitinib was 40%. The median PFS was 5.5 months, and the median OS was 13.8 months.

 Ongoing phase 3 trials are attempting to validate the activity of the 2 agents. 

Targeted agents for HER2-driven tumors have shown preliminary promise, which has led to early trials evaluating potent HER2 inhibitors such as fam-trastuzumab deruxtecan-nxki (Enhertu).12 PARP inhibitors and epigenetic modifiers have been preliminarily disappointing in unselected or selected patients.

Moreover, combinations of active agents are undergoing evaluation. The combination of enfortumab vedotin plus pembrolizumab exhibited promising activity as first-line therapy for patients with cisplatin-ineligible advanced or metastatic UC.

 The ongoing phase 3 EV-302 trial (NCT04223856) is evaluating the novel combination of enfortumab vedotin plus pembrolizumab versus gemcitabine-platinum in the first-line setting. 

The combination of VEGF/FGFR inhibitors and PD-1/PD-L1 inhibitors has also shown preliminary promise. The phase 3 LEAP-011 trial (NCT03898180) is evaluating the combination of lenvatinib (Lenvima) and pembrolizumab as first-line therapy for cisplatin-ineligible mUC. The optimal sequencing of active agents needs investigation, although these efforts may have to rely on retrospective and real-world datasets. 

Unfortunately, applying atezolizumab to the adjuvant setting following radical cystectomy for high-risk muscle invasive disease did not improve outcomes in the phase 3 IMvigor010 trial (NCT02450331).

 Similar efforts to evaluate pembrolizumab and nivolumab in the adjuvant setting are ongoing. 

Interestingly, the phase 3 CheckMate 274 (NCT02632409) trial was reported in a news release to have met its co-primary end points of improving disease-free survival versus placebo in all randomized patients as well as in patients with tumor PD-L1 expression of 1% or higher. If these data prove practice-changing, the therapeutic landscape of first-line therapy of metastatic disease may be impacted for patients who relapse.

Neoadjuvant PD-1/ PD-L1 inhibitors alone for cisplatin-ineligible or cisplatin-refusing patients or combined with cisplatin-based chemotherapy preceding radical cystectomy have exhibited promising activity, and phase 3 trials are attempting to confirm a role for these approaches.

 The incorporation of PD-1/PD-L1 inhibitors in bladder-preserving trimodal chemoradiation approaches is being evaluated in ongoing phase 3 trials.

Therapy for non–muscle-invasive bladder cancer (NMIBC) has also enjoyed advances with the approval of systemic pembrolizumab for rigorously defined bacillus CalmetteGuérin (BCG)–unresponsive high-risk disease. Among 96 patients in the KEYNOTE-057 trial (NCT02625961) with high-risk BCG-unresponsive NMIBC with carcinoma in situ, the CR rate was 41% and the median duration of response was 16.2 months.

In April 2020, the FDA approved mitomycin gel (Jelmyto) as the first therapy indicated for low-grade upper tract UC based data from the pivotal phase 3 OLYMPUS trial (NCT02793128). Forty–one of 71 patients (58%) had CR. Of those patients, 19 (46%) had durable CR at 12 months.

 Moreover, other promising intraluminally delivered agents are emerging for high-risk BCG-unresponsive NMIBC including nadofaragene firadenovec (rAd-IFN/Syn3), a non-replicating adenovirus vector harboring the human 

 gene, and vicinium, a recombinant fusion protein of an anti-EpCAM antibody linked to a variant of 

Blue light cystoscopy has improved the sensitivity of detection of malignancy, although further studies are ongoing to evaluate efficacy and cost effectiveness to justify universal adoption.

 Multiparametric MRI and fluorodeoxyglucose positron emission tomography imaging may warrant further evaluation to enhance clinical staging of muscle-invasive disease.

Enhanced recovery after surgery (ERAS) protocols in the setting of radical cystectomy may improve the quality of life for patients.

 Robotic cystectomy was noninferior to open cystectomy for 2-year PFS and quality of life in the phase 3 RAZOR trial (NCT01157676).

Finally, the emergence of intensity-modulated radiation therapy and use of MRI to plan radiotherapy may improve the therapeutic index of radiotherapy for muscle-invasive bladder cancer.

Despite these advances in therapy, it is important to not lose sight that metastatic disease is generally incurable and that clinical trials should be considered a standard of care for all settings of the disease. The critically important first step that engenders advances is the understanding of tumor biology. Novel clinical prognostic factors have been presented in the setting of PD-L1 inhibitors following platinum-based chemotherapy.

The Cancer Genome Atlas program has shed light on the enormous heterogeneity of tumor biology, high mutation burden, and multiple potential driver alterations in subsets of patients.

 However, we must better understand the dynamic changes in tumor and microenvironment following therapy to develop insights into resistance and new therapeutic targets. Noninvasive molecular monitoring employing cell-free DNA profiling studies of plasma and urine may provide avenues to better understand mechanisms of resistance, new therapeutic targets, and minimal residual disease.

Precision medicine that leverages molecular information from multiple platforms may be necessary for optimal patient selection. In this context, DNA damage repair alterations and gene expression subtypes of tumor are a step in this direction and are associated with pathologic CR to neoadjuvant cisplatin-based chemotherapy.

 The combination of molecular and clinical factors may also warrant exploration to develop precision medicine.

von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. 

. 2005;23(21):4602-4608. doi:10.1200/JCO.2005.07.757

Fradet Y, Bellmunt J, Vaughn DJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. 

. 2019;30(6):970-976. doi:10.1093/annonc/mdz127

Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. 

. 2017;389(10064):67-76. Published correction appears in 

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. 

. 2020;38(23):2658-2666. doi:10.1200/JCO.19.01213

Update on phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, stage IV bladder cancer. News release. AstraZeneca. March 6, 2020. Accessed November 12, 2020. https://bit.ly/2J4bra3

Galsky MD, Arija JÁA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. 

. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0

Merck provides update on phase 3 KEYNOTE-361 trial evaluating KEYTRUDA (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. News release. Merck. June 09, 2020. Accessed November 12, 2020. https://bwnews.pr/2HJj59f

Powles T, Park SH, Voog E, et al: Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. 

. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

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. 

. 2019;37(29):2592-2600. doi:10.1200/JCO.19.01140

Tagawa ST, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients (pts) with metastatic urothelial cancer (muc) after failure of platinum-based regimens (plt) or immunotherapy. 

 2019;30(suppl 5):V890-V891. 10.1093/annonc/mdz394.049

Loriot Y, Necchi A, Park SH, et al; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. 

 2019;381(4):338-348. doi:10.1056/NEJMoa1817323

Choudhury NJ, Campanile A, Antic T, et al. Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. 

. 2016;34(18):2165-2171. doi:10.1200/JCO.2015.66.3047

Grivas P, Loriot Y, Feyerabend S, et al. Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): results from ATLAS, a phase II open-label trial. 

. 2020;38(suppl 6):440. doi:10.1200/JCO.2020.38.6_suppl.440

Grivas P, Mortazavi A, Picus J, et al. Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes. 

. 2019;125(4):533-540. doi:10.1002/cncr.31817

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. 

. 2020;38(suppl 6):441. doi:10.1200/JCO.2020.38.6_suppl.441

Hussain SA, Lester JF, Jackson R, et al. Phase II randomized placebo-controlled neoadjuvant trial of nintedanib or placebo with gemcitabine and cisplatin in locally advanced muscle invasive bladder cancer (NEO-BLADE). 

 2020;38(suppl 6):438. doi:10.1200/JCO.2020.38.6_suppl.438

Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. 

. 2019;25(11):1706-1714. doi:10.1038/s41591-019-0628-7

Necchi A, Raggi D, Gallina A, et al. Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies. 

. 2020;77(4):439-446. doi:10.1016/j.eururo.2019.10.026

Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). 

. 2019;37(suppl 7):350. doi:10.1200/JCO.2019.37.7_suppl.350

Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. 

. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9

Boorjian SA, Dinney CPN, SUO Clinical Trials Consortium. Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): results from a phase III trial. 

2020;38(suppl 6):442. doi: 0.1200/JCO.2020.38.6_suppl.442

Shore N, O’Donnel M, Keane T, et al. Phase 3 results of vicinium in BCG-unresponsive non-muscle invasive bladder cancer. 

. 2020;203(suppl 4):e72. doi:10.1097/JU.0000000000000823.02

Lotan Y, Chaplin I, Ahmadi H, et al. Prospective evaluation of blue-light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. 

. Published online July 10, 2020. doi:10.1111/bju.15166

Necchi A, Bandini M, Calareso G, et al. Multiparametric magnetic resonance imaging as a noninvasive assessment of tumor response to neoadjuvant pembrolizumab in muscle-invasive bladder cancer: preliminary findings from the PURE-01 study. 

. 2020;77(5):636-643. doi:10.1016/j.eururo.2019.12.016

Einerhand SMH, van Gennep EJ, Mertens LS, et al. 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in muscle-invasive bladder cancer. 

. 2020;30(5):654-664. doi:10.1097/MOU.0000000000000798

Vlad O, Catalin B, Mihai H, et al. Enhanced recovery after surgery (ERAS) protocols in patients undergoing radical cystectomy with ileal urinary diversions: a randomized controlled trial. 

. 2020;99(27):e20902. doi:10.1097/MD.0000000000020902

Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. 

. 2018;391(10139):2525-2536. doi:10.1016/S0140-6736(18)30996-6

Sonpavde G, Manitz J, Gao C, et al. Five-factor prognostic model for survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-L1 inhibitors. 

. 2020;204(6):1173-1179. doi: 10.1097/JU.0000000000001199

Robertson AG, Kim J, Al-Ahmadie H, et al; TCGA Research Network. Comprehensive molecular characterization of muscle-invasive bladder cancer. 

. 2017;171(3):540-556.e25. doi:10.1016/j.cell.2017.09.007

Agarwal N, Pal SK, Hahn AW, et al. Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. 

. 2018;124(10):2115-2124. doi:10.1002/cncr.31314

Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. 

. 2017;72(4):544-554. doi:10.1016/j.eururo.2017.03.030

Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. 

. 2016;2(8):1094-1096. doi:10.1001/jamaoncol.2016.1056

Nassar AH, Mouw KW, Jegede O, et al. A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma. 

. 2020;122(4):555-563. doi: 10.1038/s41416-019-0686-0

Galsky MD, Saci A, Szabo PM, et al. Nivolumab in patients with advanced platinum-resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended follow-up from CheckMate 275. 

. 2020;26(19):5120-5128. doi:10.1158/1078-0432.CCR-19-4162

Articles

November 25, 2020 — Although metastatic urothelial carcinoma remains generally incurable, management of bladder cancer has witnessed several multidisciplinary advances in the past few years. 

New Strategies Enhance Care in mUC

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the need for phase 3 data evaluating frontline pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in bladder cancer.

​In 2017, the FDA granted single-agent pembrolizumab and atezolizumab accelerated approvals for the frontline treatment of patients with locally advanced or metastatic bladder cancer who are ineligible for cisplatin-containing chemotherapy. The approvals were based off findings from the phase 2 KEYNOTE-052 (pembrolizumab) and IMvigor210 (atezolizumab) trials.

The agents appear feasible in ​patients with PD-L1–high disease, says Sonpavde. However, phase 3 clinical trials are needed to determine whether the agents are superior to the switch maintenance regimen of gemcitabine/platinum followed by avelumab (Bavencio) maintenance, says Sonpavde.

​The switch maintenance approach is backed by positive phase 3 data from the JAVELIN Bladder 100 trial, concludes Sonpavde.

Videos

Guru P. Sonpavde, MD, discusses the need for phase 3 data evaluating frontline pembrolizumab or atezolizumab in bladder cancer.

Dr. Sonpavde on the Need for Phase 3 Data With Pembrolizumab or Atezolizumab in Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the utility of combining anti-VEGF and anti–PD-1 agents in metastatic urothelial carcinoma.

The combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) with or without ipilimumab (Yervoy) has elicited intriguing data in metastatic urothelial carcinoma, Sonpavde says. Moreover, the triplet is being evaluated in an ongoing phase 2 trial to further evaluate its efficacy.

Another combination, lenvatinib (Lenvima) and pembrolizumab (Keytruda), is being investigated in the ongoing phase 3 LEAP-011 trial in patients with PD-L1–positive, cisplatin-ineligible or platinum-ineligible disease, explains Sonpavde.

Finally, the investigational TYRO3, AXL and MER (TAM) inhibitor sitravatinib (MGCD516), which also inhibits VEGF, in combination with nivolumab has demonstrated early efficacy in patients who progress on checkpoint inhibitors, Sonpavde says.

Dual inhibition of VEGF and PD-1/PD-L1 could lead to regulatory approvals in the future pending positive findings from larger phase 3 trials, Sonpavde concludes.

Guru P. Sonpavde, MD, discusses the utility of combining anti-VEGF and anti–PD-1 agents in metastatic urothelial carcinoma.

Dr. Sonpavde on Combining VEGF/PD-1 Inhibitors in Metastatic Urothelial Carcinoma 

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the safety profile of erdafitinib (Balversa), which was 

 in April 2019 to treat adult patients with locally advanced or metastatic bladder cancer with an 

 alteration that has progressed on platinum-containing chemotherapy.

Erdafitinib was shown to be active in a phase II trial at the 2019 ASCO Annual Meeting with an overall response rate of higher than 36% and a median duration of response of around 6 months, explains Sonpadve. However, there are some unique toxicities with this agent, including hypophosphatemia and hand-foot syndrome, both of which were grade 1/2 and manageable.

Eye toxicity involving central serous retinopathy (CSR) and central visual defect were also common in patients who received erdafitinib, says Sonpavde. Many oncologists do not have experience with eye toxicity. Sonpavde recommends enlisting the help of an ophthalmologist to monitor patients at the start of treatment. There should also be testing in the oncology clinic to look for CSR.

Although common, CSR was usually grade 1/2 and was reversed when erdafitinib was stopped, according to Sonpavde. Some patients resumed therapy after the toxicity was resolved. Overall, erdafitinib had manageable toxicity and is a significant advance as the first targeted agent in the urothelial space, concludes Sonpavde.

Guru P. Sonpavde, MD, discusses the safety profile of erdafitinib, which was approved by the FDA in April 2019 to treat adult patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration that has progressed on platinum-containing chemotherapy.

Dr. Sonpavde on the Safety Profile of Erdafitinib in Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses current neoadjuvant immunotherapy options in bladder cancer based on cisplatin-eligibility status. 

Checkpoint inhibitors pembrolizumab (Keytruda) and atezolizumab (Tecentriq), as single agents, have demonstrated activity in the neoadjuvant setting with pathologic complete response (pCR) rates of 30% to 40%. 

For cisplatin-eligible patients, phase III trials are underway exploring these agents in combination with platinum-based chemotherapy. Pembrolizumab in combination with gemcitabine, for example, reported a pCR rate of approximately 45%, says Sonpavde.

Conversely, immunotherapy alone is being explored for cisplatin-ineligible patients compared with standard cystectomy, says Sonpavde. 

Guru P. Sonpavde, MD, discusses current neoadjuvant immunotherapy options in bladder cancer based on cisplatin eligibility status. 
 

Dr. Sonpavde on Neoadjuvant Immunotherapy in Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the results of the phase II EV-201 trial in patients with locally advanced or metastatic urothelial cancer. 

In the trial, patients who were previously treated with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor and those who had not received platinum-containing chemotherapy or who are ineligible for cisplatin received enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4, explains Sonpavde. 

Results from the trial showed a high objective response rate of 44%. Moreover, responses were reported irrespective of prior treatment with platinum-based chemotherapy or PD-1/PD-L1 inhibitors. Additionally, the median duration of response was 7.6 months. 

Encouragingly, investigators also reported complete responses in 12% of patients and robust responses in patients with liver metastases. Going forward, Sonpavde hopes enfortumab vedotin will be approved for clinical use in this patient population.  

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the results of the phase II EV-201 trial in patients with locally advanced or metastatic urothelial cancer. 
 

Dr. Sonpavde on Enfortumab Vedotin Data in Urothelial Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the use of immunotherapy after progression on platinum-based therapy in advanced bladder cancer.

There are 5 FDA-approved checkpoint inhibitors for patients who progress on platinum-based chemotherapy. Pembrolizumab (Keytruda) is the only agent among them that has level 1 data to support its use in this setting. However, there are 4 additional agents that can be used, and durvalumab (Imfinzi) is one of them, says Sonpavde. It is difficult to compare these agents across trials, especially since durvalumab was approved based on data from a large nonrandomized phase II trial. However, in that trial, the agent showed a similar incidence of grade ≥3 toxicities, ranging from 10% to 15%.  

In terms of patient selection, pembrolizumab has the most robust data to support its use. Its approval was based on data from the phase III KEYNOTE-045 trial, in which the PD-1 inhibitor was superior to chemotherapy regardless of PD-L1 expression. All the other agents are approved based on nonrandomized phase II data, showing responses in the 15% to 25% range, with durable responses, says Sonpavde. Notably, atezolizumab (Tecentriq) was not found to be superior to chemotherapy in the phase III trial.

Dr. Sonpavde on Immunotherapy After Progression in Advanced Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses emerging immunotherapy approaches in bladder cancer.

Data from several confirmatory phase III trials with FGFR inhibitors are eagerly anticipated in the bladder cancer space. Furthermore, immunotherapy is under investigation—specifically, looking at PD-1/PD-L1 inhibitors as adjuvant therapy after radical cystectomy to improve cure rates. Perhaps more exciting, says Sonpavde, is neoadjuvant therapy. Phase III trials combining platinum-based chemotherapy plus PD-1/PD-L1 inhibition are ongoing. There are also trials that are being planned in the setting of cisplatin ineligibility in the neoadjuvant space, an area of great unmet need. Right now, the standard of care in this setting is radical cystectomy.

In the neoadjuvant space, several phase II trials evaluating pembrolizumab (Keytruda) or atezolizumab (Tecentriq) alone look promising. Data from those trials showed pathologic complete responses ranging from 30% to 40%, says Sonpavde. Based on these data, phase III trials are being planned to assess the activity of these agents in a larger cohort of patients.

Dr. Sonpavde on Emerging Immunotherapy Approaches in Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses the biggest challenges in the field of bladder cancer.

Bladder cancer is a heterogeneous disease driven by many pathways and molecules, explains Sonpavde. As such, there is no predominant target. This has been an impediment to improving cure rates. However, these challenges have, in part, been addressed with immunotherapy. Bladder cancer has a high mutation burden, which has enabled advances with this approach.

Combinations of immunotherapy drugs might further enhance the benefit that has been observed to date. There are many ongoing phase I trials looking at these combinations, many of which are open at Dana-Farber Cancer Institute. Sonpavde is hopeful that these combinations will take treatment of the disease to the next level.

Dr. Sonpavde on the Biggest Challenges in Bladder Cancer

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses therapeutic agents under investigation for patients with PD-L1—low bladder cancer.

There are trials being planned in that patient population, says Sonpavde, and time will tell whether or not the combination of chemotherapy and PD-1/PD-L1 inhibitors will be valuable in this setting. This approach also being looked at in ongoing phase III trials enrolling both cisplatin-eligible and -ineligible patients.

In addition, there is an Intergroup trial for cisplatin-ineligible patients that is comparing the combination of cisplatin and gemcitabine with or without bevacizumab (Avastin) or placebo. Those results are pending, adds Sonpavde. Finally, investigators are also looking into a “kitchen sink” approach in which several agents are being combined together, including durvalumab (Imfinzi) and tremelimumab—a PD-L1 inhibitor and a CLTA-4 inhibitor&mdash;plus platinum-based chemotherapy, compared with chemotherapy, or chemotherapy plus PD-L1 inhibition alone.

Guru P. Sonpavde, MD, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discusses therapeutic agents under investigation for patients with PD-L1–low bladder cancer.

Guru P. Sonpavde, MD