- Published in Everyday Urology - Oncology Insights: Volume 5, Issue 1
In 2015, cisplatin-ineligible patients with metastatic urothelial carcinoma could not be offered a first-line treatment option capable of prolonging their survival. Also, a paucity of second-line treatments resulted in these same patients usually surviving for only 3 to 6 months after progressing on platinum-treatment. Recent successful registrational trials and U.S. Food and Drug Administration (FDA) approvals have revolutionized this treatment landscape, and fortunately, there are more advances to come. Hence, urologists now have both the opportunity and the impetus to develop advanced bladder cancer clinics to serve bladder cancer patients across the disease spectrum, inclusive of high-risk nonmuscle invasive bladder cancer (NMIBC) and metastatic urothelial bladder cancer (mUC). In this article, I discuss novel therapies, recently approved, cutting edge treatments currently undergoing trial accrual, and practical considerations for implementing an advanced bladder clinic (ABC).
Immune Checkpoint Inhibitors
The discovery that tumor cells inhibit the body’s antitumor immune response by binding programmed cell death 1 (PD-1) receptors on the T-cell surface has facilitated the development of several monoclonal antibodies targeting either the PD receptor (PD-1, PD-2) or its tumor cell ligand, PD-L1. In Phase II/Phase III trials, immune checkpoint inhibitors (CPIs) have demonstrated significantly prolonged survival compared with the standard of care for patients with advanced and metastatic urothelial carcinoma.1-6
To date, five checkpoint inhibitors have received FDA approval for the treatment of advanced and metastatic bladder cancer in the post-platinum setting. Nivolumab (Opdivo®) and pembrolizumab (Keytruda®) target PD-1, while atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®) target PD-L1. In 2017, the FDA also approved atezolizumab and pembrolizumab for the first-line treatment of advanced bladder cancer in cisplatin-ineligible patients.7-9
Because urothelial carcinomas express varying levels of PD-L1, not all patients with advanced bladder cancer are appropriate candidates for PD-1/PD-L1 pathway inhibitor therapy. In the KEYNOTE-361 and IMVIGOR-130 trials, for example, pembrolizumab and atezolizumab were associated with lower survival among patients whose urothelial tumors expressed low levels of PD-L1.10
In response to these findings, the FDA now requires the use of companion diagnostic tests to confirm sufficient PD-L1 levels with immunohistochemistry (IHC) testing before patients can receive first-line therapy with pembrolizumab or atezolizumab.10 The Dako PD-L1 IHC 22C3 PharmDx (or 22C3) assay is approved as a companion diagnostic for use with pembrolizumab, while the Ventana PD-L1 (SP142) Assay® is approved for use with atezolizumab. Both IHC assays are relatively inexpensive and can be readily performed in commercial pathology laboratories and academic centers, and urologists can also outsource the IHC assay testing to commercial laboratories.
Earlier-stage use of immune checkpoint inhibitors
First-line PD-1 pathway inhibitor monotherapy induces responses in approximately 25% to 30% of patients with mUC. A subset of these patients show very impressive and durable complete responses with subsequent prolonged survival times,11 which is especially striking when we consider the typical elderly age and comorbidity burden of this patient population. Consequently, there has been keen interest in moving checkpoint inhibitors more proximally within the bladder cancer disease journey, analogous to the experience of approved therapeutics for castration-resistant metastatic prostate cancer, which has led to the rapid evolution of urologic advanced prostate cancer clinic(APC).
Non-muscle invasive bladder cancer
Over the last 40 years, the FDA has approved very few treatments for non-muscle invasive bladder cancer. Thiotepa was approved in 1959, Bacillus Calmette-Guérin (BCG) Tice and BCG Connaught were approved in 1989 and 1990, and valrubicin was approved in 1998.12 Thiotepa is not widely used in contemporary intravesical treatment regimens, and valrubicin has been considered sparingly for radical cystectomy ineligible patients because, mainly due to its efficacy benefit in fewer than 10% of patients treated.13 Hence, intravesical BCG remains the only FDA recommended first-line therapy for NMIBC, although intravesical mitomycin C (MMC) is an intravesical chemotherapeutic used often, albeit off-label bit incorporated within NCCN, AUA, and EAU guidelines, and alongside other generic intravesical chemotherapies, gemcitabine and docetaxel, are receiving enhanced utilization due to the global BCG shortage.
Given this limited therapeutic landscape, the single-arm, open-label, Phase II KEYNOTE-057 trial has received global attention for its attempt to achieve clinically meaningful benefit for BCG unresponsive patients with high-risk NMIBC. This study evaluated pembrolizumab (200 mg every 3 weeks) for 24 months or until disease recurrence in 103 cystectomy-ineligible or cystectomy-refusing patients with high-risk, BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors.14 At the 2019 meeting of the European Society for Molecular Oncology (ESMO), investigators provided an update based on a median follow-up period of 21.1 months.15 The complete response rate was 41%, the median duration of response was 13.5 months, and 57% of complete responses lasted at least 12 months. Most patients with complete responses also reported stable health-related quality of life over time. Based on these findings, in January 2020 the FDA approved pembrolizumab for use in this patient population.16
Several ongoing Phase III trials are further assessing PD-1/PD-L1 pathway inhibitors for the treatment of non-muscle invasive bladder cancer. The global KEYNOTE-676 study (NCT03711032) evaluates pembrolizumab following cystoscopy or transurethral resection in high-risk BCG-unresponsive patients, which have received BCG but with a lesser requirement compared to KEYNOTE-057.17 The primary endpoint is complete response in patients with CIS, and the targeted enrollment is 550 patients. In addition, the POTOMAC trial (NCT03528694) assesses durvalumab in combination with BCG in completely resected, high-risk non-muscle invasive bladder cancer patients that are BCG naïve. Patients are randomly assigned on a 1:1:1 basis to receive induction-only durvalumab plus BCG, induction and maintenance durvalumab plus BCG, or BCG only.18 The primary endpoint is disease-free survival, and the trial aims to enroll 975 patients. Finally, the ALBAN study (NCT03799835) compares one year of BCG plus atezolizumab therapy versus BCG alone in high-risk, completely resected, BCG-naïve non-muscle invasive bladder cancer.19 The primary endpoint is recurrence-free survival, and the estimated enrollment is 614 patients. Additionally, BCG naïve trials are planned in 2020 with other CPIs, also exploring subcutaneous deliveries.
Muscle-invasive bladder cancer
Cisplatin-based chemotherapy significantly prolongs survival when used in the neoadjuvant setting for patients with muscle-invasive bladder cancer prior to radical cystectomy.20 However, approximately 50% of patients are cisplatin-ineligible, and unfortunately, many patients who are eligible for neoadjuvant platinum-based therapy do not receive the treatment.21 There is considerable interest in identifying alternatives which could demonstrate clinical benefit with enhanced tolerability.
The single-arm, open-label, Phase II PURE-01 study evaluated three courses of pembrolizumab preceding radical cystectomy in 114 patients with T2-T4a muscle-invasive bladder cancer (5% N1, 0% T4b).22 A total of 37% of patients had a pathologic complete response (pT0) and 55% were downstaged to pT≤1. Interestingly, 19% of patients presented with predominantly variant tumor histology, for which chemotherapy is of limited efficacy. Among these patients, 86% of those with squamous cell carcinoma were downstaged to pT<1. High PD-L1 expression was predictive of response regardless of tumor histology. Additionally, the single-arm, open-label, multicenter Phase II ABACUS study, which evaluated two cycles of neoadjuvant atezolizumab prior to radical cystectomy in 74 patients with T2-T4bN0 urothelial carcinoma who not fit for or refused cisplatin-based treatment.23 The pathologic complete response rate was 29%, and 39% of patients were downstaged to non-muscle invasive disease.
These study findings have spurred larger trials of PD-1/PD-L1 checkpoint inhibitors for patients with muscle-invasive bladder cancer undergoing radical cystectomy. The randomized, open-label, global Phase III NIAGARA trial (NCT03732677) compares neoadjuvant durvalumab in combination with gemcitabine and cisplatin, followed by adjuvant durvalumab, versus neoadjuvant gemcitabine-cisplatin without adjuvant therapy.24 The targeted enrollment is 1,050 patients, and the co-primary endpoints are event-free survival and pathologic complete response at cystectomy. Another Phase III trial (NCT03661320) with the same co-primary endpoints randomizes patients to one of three treatment regimens: 1) neoadjuvant chemotherapy alone, 2) neoadjuvant chemotherapy plus nivolumab, followed by adjuvant nivolumab, and 3) neoadjuvant chemotherapy plus nivolumab plus the indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor BMS-986205. This study aims to enroll 1,200 patients.
The vast majority of our patients with muscle-invasive bladder cancer would prefer not to undergo cystectomy. Hence, there is considerable interest in developing multi-modal bladder-sparing strategies. In a single-arm, open-label Phase II trial (NCT02621151), patients with >T2 disease receive pembrolizumab prior to maximal transurethral resection of bladder tumor (TURBT), followed by gemcitabine plus three courses of pembrolizumab plus radiation therapy (52 Gy over 4 weeks), followed by transurethral resection of the tumor bed.25 The primary endpoint is bladder-intact disease-free survival. The randomized Phase III S1806 study (NCT03775265) is also accruing patients with T3-3a bladder cancer who receive radiation and chemotherapy with or without atezolizumab.25 The primary endpoint is bladder-intact event-free survival.
Patients who receive immune checkpoint inhibitors should be actively monitored for toxicities throughout the treatment course. The primary risk of this treatment class is the development of immune-mediated adverse events (IMAEs). Any organ system can be affected, and neuropathies and arthralgias can also occur. The most commonly experienced IMAEs may include pneumonitis, VOLUME 5, ISSUE 1 17 colitis, dermatitis, hepatic transaminitis and thyroiditis. In the KEYNOTE-045 study, each of these four toxicities affected approximately 1% to 6% of patients receiving second-line pembrolizumab for advanced bladder cancer, and 0.4% to 2.3% of events were of grade 3 classification.2
It is essential to educate patients and their caregiver team about the signs and symptoms of immune-mediated adverse events, the fact that they can occur any time during treatment, and the need for prompt reporting to ensure rapid intervention. I recommend developing literature to educate patients on signs and symptoms to watch for and how to report possible toxicities. The American Society of Clinical Oncology (ASCO) recommends taking a graded approach to management of immune-mediated adverse events.26 Treatment can be continued with close monitoring for most grade 1 events, with the exception of certain cardiac, neurologic, and hematologic toxicities. For grade 2 events, it is appropriate to suspend treatment, initiate corticosteroid therapy, and resume checkpoint inhibitor therapy only if the adverse event resolves to grade 1 or less. Grade 3 events often require management with high-dose corticosteroids (prednisone 1 to 2 mg/kg/ day or methylprednisolone 1 to 2 mg/kg/day), which should be tapered over at least 4 to 6 weeks. Grade 4 events should trigger prompt and permanent treatment cessation, unless the patient has an endocrinopathy that is controlled by hormone replacement therapy. Refractory immune-mediated adverse events may require intravenous immunosuppressive therapy with infliximab or mycophenolate, inpatient hospitalization, and multidisciplinary specialty support.
When managing more severe or less common immune-mediated adverse events, it can be advantageous to consult with specialists, such as gastroenterologists, endocrinologists, medical oncologists and other medical specialists. I recommend establishing and maintaining collaborative medical specialty relationships to optimize both the ABC and APC success.
Beyond Checkpoint Inhibition
Other Therapies Several other bladder cancer therapeutic with novel mechanism of action have received FDA approval or are under current FDA review, pending recent completion of a registrational trial. These include immunotoxins, antibody-drug conjugates, inhibitors of fibroblast growth factor receptor (FGFR), and gene therapies.
Immunotoxins and antibody-drug conjugates are proteins consisting of a cytotoxic domain chemically linked to a target-specific binding domain.27 The immunotoxin oportuzumab monatox (Vicinium®) consists of a truncated form of Pseudomonas exotoxin A linked to a humanized antibody fragment targeting epithelial cell adhesion molecule (EpCAM), which is overexpressed on the surface of urothelial carcinoma cells.28 Oportuzumab monatox has a dual mechanism of action that involves both direct cell killing and immune system activation. In a Phase II trial of intravesical oportuzumab monatox for the treatment of BCG-unresponsive CIS or papillary bladder cancer, 16% of patients remained disease-free at 1 year and all patients with a complete response at 1 year remained disease-free for at least 18 months.29 Most adverse events were bladder-specific rather than systemic, and no serious treatment-related adverse events were identified. In a subsequent Phase III trial, patients received a more intensive treatment schedule consisting of intravesical oportuzumab induction therapy twice weekly for 6 weeks and then once weekly for 6 weeks, followed by a maintenance schedule of every other week for up to 2 years.30 In the interim analysis, 68% of patients were recurrence-free at 3 months. Serious adverse events were infrequent.
Antibody-drug conjugates consist of a cytotoxic payload (a cytotoxic antitumor molecule) chemically linked to a monoclonal antibody that targets a tumor cell surface antigen.31 After binding the target antigen, the antibody-drug conjugate undergoes receptor-mediated internalization into the tumor cell, where the chemical linker is degraded by lysosomes, proteases, or reductive agents. The cytotoxic payload is then released and causes microtubule disruption, cell cycle arrest, and apoptosis. These drugs are administered intravenously. The antibody-drug conjugate enfortumab vedotin (PadcevTM) targets Nectin-4, a type 1 transmembrane cell adhesion molecule that is overexpressed in epithelial cancers.
The antibody is bound to the microtubule-disrupting cytotoxic payload monomethyl auristatin E (MMAE) by means of a protease-cleavable chemical linker. In the single-arm Phase II EV-201 study, 44% of patients with metastatic urothelial carcinoma who had previously received anti-PD-1/L1 therapy and platinum-based therapy had a confirmed objective response to enfortumab vedotin (EV), 12% of patients had complete responses, and the median duration of response was 7.6 months.32 Based on these findings, the FDA in December 2019 approved EV for the third-line treatment of locally advanced or metastatic urothelial carcinoma in patients who have previously received both anti-PD-1/L1 and platinum-based therapy.33
EV is now being studied as an earlier-line therapy. The Phase 1b EV-103 study (NCT03288545) evaluates its first-line and second-line use alone or in combination with pembrolizumab and/or chemotherapy for patients with locally advanced or metastatic urothelial carcinoma. In February 2020, preliminary durability results were reported at the American Society of Clinical Oncology 2020 Genitourinary Cancers Symposium (ASCO GU 2020).34 After a median follow-up period of 11.5 months, the confirmed investigator-assessed objective response rate was 73.3%, the complete response rate was 15.6%, and median progression-free survival was 12.3 months. Data on overall survival are pending.
Another antibody-drug conjugate in development is sacituzumab govitecan, which targets Trop-2, an epithelial cell-surface glycoprotein that is highly expressed in muscle-invasive bladder cancer.35 A hydrolysable linker binds the antibody to SN-38, the active metabolite of irinotecan. In a Phase I/II basket trial that included 45 patients with metastatic urothelial carcinoma, sacituzumab govitecan induced responses in 31% of patients overall and 23% of prior recipients of checkpoint inhibitor therapy.36 Median progression-free survival was 7.3 months, and median overall survival was 18.9 months. The FDA is currently reviewing a biologics license application for sacituzumab govitecan for the treatment of triple-negative breast cancer. We may soon see a similar application for its therapeutic use in advanced bladder cancer. The near future will bring more trials of antibody-drug conjugates as later-line therapies for advanced and metastatic bladder cancer. As with other novel treatments, there also is the possibility of combining these agents with other novel agents and potentially moving them for earlier application and benefit within the bladder cancer disease spectrum.
Fibroblast growth factor receptor (FGFR) inhibitors
Fibroblast growth factor receptors (FGFR) are a subfamily of receptor tyrosine kinases that include FGFR1, FGFR2, FGFR3, FGFR4.37 Signaling by these receptors helps regulate cell growth, proliferation, differentiation, and survival. Increased expression of FGFR1 and FGFR3 is observed in urothelial carcinoma, and FGFR3 point mutations have been found in approximately 40% to 70% of non-muscle invasive bladder tumors and 15% to 20% of metastatic tumors.38
Erdafitinib (BalversaTM), a tyrosine kinase inhibitor of FGFR1-4, is orally administered and was evaluated in an open-label Phase II trial of 99 patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations.39 After a median of five treatment cycles, the confirmed response rate was 40% in the overall cohort and 59% among patients who had previously received immuno-oncologic therapy. Median progression-free survival was 5.5 months, and median overall survival was 13.8 months. In all, 46% of patients had grade 3 or higher adverse events that were considered related to treatment. Based on these data, the FDA in April 2019 granted erdafitinib accelerated approval for the treatment of locally advanced or metastatic bladder cancer with relevant FGFR3 or FGFR2 alterations that has progressed on platinum-based neoadjuvant or adjuvant chemotherapy.40 This is the first and only oral drug approved for the treatment of bladder cancer. Note that the FDA has approved the therascreen FGFR RGQ RT-PCR kit as a companion diagnostic to select candidates for treatment with erdafitinib.41
Combination first-line therapy with erdafitinib plus anti-PD-1 therapy is now being evaluated in a randomized Phase I/II trial (NORSE; NCT03473743) of patients with metastatic or surgically unresectable urothelial carcinoma with selected FGFR alterations. In a similar patient population, a Phase III trial (THOR; NCT03390504) compares second-line or third-line treatment with erdafitinib, pembrolizumab, vinflunine, or docetaxel.
In addition to erdafitinib, the oral selected FGFR[1-3] inhibitor pemigatinib is in Phase II studies for the treatment of recurrent, low or intermediate-risk non-muscle invasive bladder cancer, and for the adjuvant treatment of high-risk, FGFR-altered pT3-T4 and/or pN1-3 bladder cancer in patients who have previously received neoadjuvant cisplatin-based chemotherapy.
Nadofaragene firadenovec (rad-FNα/syn3; Adstiladrin®) is an investigational gene therapy for the treatment of high-grade, BCG-unresponsive, non-muscle invasive bladder cancer.42 It consists of a replication-deficient recombinant adenovirus gene transfer vector that delivers the human IFNα2b gene directly into urothelial cell nuclei, thereby increasing endogenous production of alfa-2b within the bladder wall.
Nadofaragene firadenovec has demonstrated substantial efficacy for the treatment of BCG unresponsive high-risk NMIBC. In a single-arm, Phase II trial of patients meeting this description who were cystectomy-ineligible, 35% of all patients and 50% of patients with papillary-only (Ta/T1) disease were alive and free from high-grade recurrence 12 months after receiving nadofaragene firadenovec.43 Furthermore, 79% of patients who responded to treatment remained recurrence-free at approximately two years.
In a subsequent single-arm Phase III trial of 157 patients with BCG-unresponsive non-muscle invasive bladder cancer, nadofaragene firadenovec (administered intravesically once every 3 months, with up to four doses in 12 months) achieved complete responses in 53% of patients with CIS, of whom 46% remained free from high-grade recurrence at 12 months.44 Among patients with high-grade Ta/T1 disease alone, 44% were free from high-grade recurrence at 12 months. Toxicities were considered acceptable, and the treatment schedule was regarded as very patient and clinic friendly.
After several decades of limited therapeutic progress for bladder cancer management, therapies for advanced urothelial carcinoma have expanded remarkably over the last several years. Five anti-PD-1/L1 checkpoint inhibitors are now FDA-approved for use in the second line, and two are approved as first-line treatments for cisplatin-ineligible patients. Ongoing studies of combination regimens, as well as of PD-L1 expression and other potential biomarkers of treatment response, are expected to further enhance outcomes and achieve broader indications. However, the greatest impact is likely to come from the use of checkpoint inhibitors for the management of earlier-stage disease, including the treatment of high-risk NMIBC-BCG naïve patients, the neoadjuvant treatment of muscle-invasive bladder cancer prior to radical cystectomy, and as a component of multimodal bladder-sparing strategies.
In addition to PD-1/PD-L1 pathway inhibitors, the antibody-drug conjugate enfortumab vedotin and the FGFR inhibitor erdafitinib have received accelerated FDA approval for advanced urothelial carcinoma. Other ongoing registrational trials are expected to further broaden our treatment options, as novel treatments and combinations continue to shift into earlier-stage and earlier-line use. Remarkably, we may soon have an approved immuno-oncologic agent and two new intravesical therapies for the management high-risk BCG-unresponsive NMIBC.
These novel bladder cancer therapeutics exhibit unique risk profiles that markedly differ from chemotherapy and require appropriate training for detection and management. Education of patients, families, and the clinical care team is vital to ensure that adverse effects are promptly detected, reported, and managed. Furthermore, the diversity of the treatment landscape and the advent of potential combined and multi-modal therapies mandates collaboration and coordination amongst urologists, medical and radiation oncologists, pathologists, medical specialists and nursing expertise in order to effectively deliver care across the bladder cancer disease spectrum. For dedicated urologists and their physician colleagues, these advances provide an exciting and long-awaited opportunity to initiate and expand the Advanced Bladder Cancer Clinic.
Written by: Neal Shore, MD, Editor-in-Chief, Everyday Urology - Oncology Insights, UroToday.com, Medical Director, The Carolina Urologic Research Center, Myrtle Beach, South Carolina
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