New Strategies Enhance Care in mUC

Although metastatic urothelial carcinoma (mUC) remains generally incurable, management of bladder cancer has witnessed several multidisciplinary advances in the past few years (Figure). 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.¹

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.² 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.^3,4 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.⁵

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.^6,7 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 P = .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 P = .0005).⁸

Additionally, investigators reported prolonged OS in patients with PD–L1-positive tumors (HR, 0.56; 95% CI 0.40-0.79; 1-sided P = .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).⁹ 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.¹⁰

Erdafitinib, an oral FGFR inhibitor, is applicable to approximately 15% of post-platinum patients with activating genomic alterations in FGFR2 or FGFR3 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.¹¹ 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.^13,14

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.¹⁵ 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).¹⁶ 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.^17,18 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.¹⁹

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.²⁰ 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 IFNA2B gene, and vicinium, a recombinant fusion protein of an anti-EpCAM antibody linked to a variant of Pseudomonas exotoxin A.^21,22

Innovations Across Modalities

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.²³ Multiparametric MRI and fluorodeoxyglucose positron emission tomography imaging may warrant further evaluation to enhance clinical staging of muscle-invasive disease.^24,25

Enhanced recovery after surgery (ERAS) protocols in the setting of radical cystectomy may improve the quality of life for patients.²⁶ Robotic cystectomy was noninferior to open cystectomy for 2-year PFS and quality of life in the phase 3 RAZOR trial (NCT01157676).²⁷

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.²⁸

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.²⁹ 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.³⁰

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.^31,32 The combination of molecular and clinical factors may also warrant exploration to develop precision medicine.^33,34

References

1. 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. J Clin Oncol. 2005;23(21):4602-4608. doi:10.1200/JCO.2005.07.757
2. 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. Ann Oncol. 2019;30(6):970-976. doi:10.1093/annonc/mdz127
3. 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. Lancet. 2017;389(10064):67-76. Published correction appears in Lancet. 2017;390(10097):848.
4. 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
5. 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
6. 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. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0
7. 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
8. 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. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1
9. 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
10. 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. Ann Oncol. 2019;30(suppl 5):V890-V891. 10.1093/annonc/mdz394.049
11. Loriot Y, Necchi A, Park SH, et al; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-348. doi:10.1056/NEJMoa1817323
12. Choudhury NJ, Campanile A, Antic T, et al. Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. J Clin Oncol. 2016;34(18):2165-2171. doi:10.1200/JCO.2015.66.3047
13. 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. J Clin Oncol. 2020;38(suppl 6):440. doi:10.1200/JCO.2020.38.6_suppl.440
14. 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. Cancer. 2019;125(4):533-540. doi:10.1002/cncr.31817
15. 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. 2020;38(suppl 6):441. doi:10.1200/JCO.2020.38.6_suppl.441
16. 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). J Clin Oncol. 2020;38(suppl 6):438. doi:10.1200/JCO.2020.38.6_suppl.438
17. 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. Nat Med. 2019;25(11):1706-1714. doi:10.1038/s41591-019-0628-7
18. 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. Eur Urol. 2020;77(4):439-446. doi:10.1016/j.eururo.2019.10.026
19. 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). J Clin Oncol. 2019;37(suppl 7):350. doi:10.1200/JCO.2019.37.7_suppl.350
20. 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. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9
21. 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. J Clin Oncol. 2020;38(suppl 6):442. doi: 0.1200/JCO.2020.38.6_suppl.442
22. Shore N, O’Donnel M, Keane T, et al. Phase 3 results of vicinium in BCG-unresponsive non-muscle invasive bladder cancer. J Urol. 2020;203(suppl 4):e72. doi:10.1097/JU.0000000000000823.02
23. Lotan Y, Chaplin I, Ahmadi H, et al. Prospective evaluation of blue-light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. BJU Int. Published online July 10, 2020. doi:10.1111/bju.15166
24. 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. Eur Urol. 2020;77(5):636-643. doi:10.1016/j.eururo.2019.12.016
25. 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. Curr Opin Urol. 2020;30(5):654-664. doi:10.1097/MOU.0000000000000798
26. 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. Medicine (Baltimore). 2020;99(27):e20902. doi:10.1097/MD.0000000000020902
27. 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. Lancet. 2018;391(10139):2525-2536. doi:10.1016/S0140-6736(18)30996-6
28. 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. J Urol. 2020;204(6):1173-1179. doi: 10.1097/JU.0000000000001199
29. Robertson AG, Kim J, Al-Ahmadie H, et al; TCGA Research Network. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540-556.e25. doi:10.1016/j.cell.2017.09.007
30. Agarwal N, Pal SK, Hahn AW, et al. Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer. 2018;124(10):2115-2124. doi:10.1002/cncr.31314
31. 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. Eur Urol. 2017;72(4):544-554. doi:10.1016/j.eururo.2017.03.030
32. Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol. 2016;2(8):1094-1096. doi:10.1001/jamaoncol.2016.1056
33. 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. Br J Cancer. 2020;122(4):555-563. doi: 10.1038/s41416-019-0686-0
34. 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. Clin Cancer Res. 2020;26(19):5120-5128. doi:10.1158/1078-0432.CCR-19-4162