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