New Drug Development in Urothelial Cancer: An Explosion of Riches?

New Drug Development in Urothelial Cancer: An Explosion of Riches?

Dr. Matthew T. Campbell

Dr. Ashish M. Kamat

By Matthew T. Campbell, MD, MS, and Ashish M. Kamat, MD, MBBS, FACS

Article Highlights

  • In the past year, new, active agents have arrived that have the potential to affect urothelial cancer in all of its states: metastatic, locally advanced, muscle-invasive, and even noninvasive tumors.
  • We are reaching a new depth in molecular understanding of the underpinnings
    of urothelial cancer, and research by separate groups has used molecular profiling to define distinct genetic signatures with differential cancer-related outcomes.
  • Although atezolizumab is currently the only FDA-approved agent to treat metastatic urothelial carcinoma, immunotherapy research for urothelial cancer is ongoing and robust.
  • Despite these advances, we must remember to demonstrate good stewardship with these studies. We must not become complacent, but rather we should be spurred into more active research and furtherance of the current promise that these therapies offer.

The 2017 Genitourinary Cancers Symposium lecture covering the state of urothelial carcinoma will thankfully not include a slide that states, “Little to no progress has been made in drug development since combination chemotherapy circa 1985.”

In the past year, new, active agents have arrived, heralding a change in the treatment landscape of metastatic bladder cancer. Importantly, these agents and others have the potential to affect urothelial cancer in all of its states: metastatic, locally advanced, muscle-invasive, and even noninvasive tumors. These new agents may also help patients who are not eligible for cisplatin-based therapy, who have impaired performance status, and who otherwise have been excluded from many clinical trials. Suddenly, instead of having a patient population of 15,000 patients with unresectable or metastatic urothelial cancer, the entire urothelial cancer population—approximately 75,000 Americans per year—may become eligible for the emerging treatments currently being studied. As expected, our partners in the pharmaceutical industry have taken note, and where once urothelial cancer was often felt to be a very challenging space for investigation, the floodgates for studies have opened. 

In this review of drug development in urothelial carcinoma, we will highlight the state of immunotherapeutics and targeted therapy and discuss the potential impact of biomarkers and molecular subtyping in personalizing therapy.

Molecular Understanding Spurs Drug Discovery

Anatomic location and histologic grading have historically been the key determinants guiding treatment plans for patients with urothelial cancer. Low-grade urothelial cancer of the bladder has a vastly different outcome than high-grade muscle-invasive disease. Although transurethral removal of tumors and adjuvant immunotherapy with bacillus Calmette-Guérin (BCG) are standard for early-stage disease, patients with muscle-invasive, locally advanced, or metastatic disease are recommended to receive chemotherapy with surgery or chemotherapy plus radiation as options for local control. Cisplatin-based combination therapy either in the form of dose-dense MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or gemcitabine plus cisplatin are preferred regimens. Although arguments were presented at previous symposia on which alternative in each setting is most appropriate, these general rules held in the treatment of urothelial cancer. However, the treatment landscape is becoming increasingly complex.

We are reaching a new depth in molecular understanding of the underpinnings of urothelial cancer. Research published since 2010 by separate groups at Lund University, the University of North Carolina at Chapel Hill, The University of Texas MD Anderson Cancer Center, and The Cancer Genome Atlas (TCGA) used molecular profiling to define distinct genetic signatures with differential cancer-related outcomes.1-4 Although each group used differing genetic signatures, key features—namely, the distinction between luminal and basal classes—tied each work together, as summarized in a recent review in The Lancet.5 Further work by our group found that those in the basal signature class had the worst survival when not exposed to cisplatin-based chemotherapy and the best when exposed to cisplatin-based chemotherapy in a small phase II study.6 As exciting as it may be to draw initial conclusions about how to use molecular clustering as a predictive biomarker for therapies, we await and must support studies such as the SWOG COXEN study (NCT02177695), which is testing correlation of response to neoadjuvant chemotherapy in muscle-invasive urothelial disease, and the National Cancer Institute COXEN study (NCT02788201) in the metastatic setting.  

Developments in Systemic Therapies

Immunotherapy has long been the standard of care for patients with non–muscle invasive disease but was restricted to intravesical BCG. Systemic therapy—once a niche field for a few steadfast believers—has emerged as the great new hope to patients and physicians across solid and liquid malignancy. As of this writing, atezolizumab, a PD-L1 monoclonal antibody, is the only U.S. Food and Drug Administration (FDA)–approved agent to treat metastatic urothelial carcinoma. The initial study with atezolizumab, reported by Powles et al., demonstrated a response rate of 26.1% for all patients treated; 43% classified as immunohistochemistry (IHC) 2/3 and 11% classified as IHC 0/1 for PD-L1 expression.7 The study leading to FDA approval was IMVigor 210, reported by Rosenberg et al.8 This phase II, single-arm study of 315 patients found an overall response rate (ORR) of 15% for the entire study population and a slightly higher ORR (27%) for those with an immune infiltrate scored as 2/3 for PD-L1 expression. Ever important in this patient population of often older patients with comorbidities was the excellent side-effect profile, which has been consistent in single-agent PD-1 or PD-L1 antibody studies across malignancies.

The correlative studies from IMVigor 210 examined important hypothesis-generating questions in an attempt to explore if correlations exist between the molecular subtypes of urothelial cancer and immune infiltration, mutation load, and response to therapy. In TCGA’s work with urothelial cancer, four subtypes were identified: luminal I and II and basal I and II. In the IMVigor 210 study, 195 patients underwent gene expression analysis, and in all the TCGA clusters, tumors with higher mutation loads had a higher likelihood of responding to therapy, with the majority of outliers in nonresponders apparently resting within luminal cluster I. Whereas clusters luminal I and II had fewer patients with PD-L1 staining within both tumor cells and the immune infiltrate as compared with the basal III and IV clusters, the highest response rate was found within the luminal II cluster. Thus, the response appeared to be independent of immune infiltrate, challenging the notion that host biology trumps tumor biology entirely when considering immunotherapy responses.

Both single-agent pembrolizumab (anti–PD-1) and nivolumab (anti–PD-1) have been tested in the post-chemotherapy setting in metastatic or unresectable urothelial cancer.9,10 The results of the phase Ib KEYNOTE-012 study of pembrolizumab in urothelial carcinoma was presented during the 2015 ASCO Annual Meeting by Plimack et al. and found a confirmed ORR of 25%, with 19% of patients having no evidence of disease progression at 1 year.9 More recently, the phase I/II results of the CheckMate 032 study of nivolumab were presented during the 2016 ASCO Annual Meeting by Sharma et al.10 The findings were similar to the previous experience with both atezolizumab and pembrolizumab, with 24% of the 78 patients treated having a confirmed response to nivolumab and a subgroup of patients having a prolonged response.

Most recently, preliminary results of KEYNOTE-052 evaluating pembrolizumab in the frontline setting in metastatic and unresectable urothelial cancer were reported by Balar et al.,11 showing a response rate of 24%, with a higher response rate in patients with higher PD-L1 expression in either tumor cells or the immune infiltrate. Merck also reported12 that the phase III KEYNOTE-045 trial investigating the use of pembrolizumab in patients with advanced urothelial cancer previously treated with chemotherapy met the primary endpoint of overall survival and was superior to investigator-choice second-line chemotherapy. Based on a prespecified interim analysis, an independent Data Monitoring Committee has recommended that the trial be stopped early, and we are currently awaiting full results. Similar findings were reported with single-agent atezolizumab in the same patient population.13 With all of these agents, the toxicity profile has been favorable, compared with historical controls treated with later lines of chemotherapy.    

Interestingly, despite its successes in renal cell carcinoma, targeted therapy has had little success in urothelial cancer. After decades of study, FGFR has remained the only promising target in urothelial cancer. FGFR mutations, overexpression, and gene signatures are found more commonly in early-stage urothelial cancer of the bladder, luminal I urothelial cancer, and upper tract disease compared with what is most commonly seen in metastatic urothelial cancer of the bladder.15,16 Current studies are exploring the efficacy of single-agent therapy, with multiple studies in the metastatic or recurrent space (NCT02872714 and NCT02365597), in the non–muscle invasive space (NCT02657486), and in combination with immunotherapy (NCT02925533).  

Ongoing Drug Development in Localized Urothelial Cancer

The localized urothelial cancer space has also seen a spike in mechanism-based drug development. In BCG-unresponsive disease,14 a phase III study of rAd-IFN/Syn3 (NCT02773849)—an adenoviral vector delivering interferon alpha-2b gene with the excipient Syn3—is ongoing after phase II data demonstrated a greater than 30% response. Although not truly drug development, enhanced delivery of intravesical chemotherapy using heating devices, indwelling drug delivery devices, and electromotive enhancements are all being studied (NCT01094964, NCT02695771, NCT02660645, and NCT02471495). Pembrolizumab is being evaluated in patients with non–muscle invasive bladder cancer that has recurred despite BCG therapy (NCT02625961). Similar studies have been proposed with nivolumab, atezolizumab, and durvalumab (anti–PD-1) and are either open or pending activation. The muscle-invasive setting is also being actively explored by the majority of companies with an anti–PD-1 or anti–PD-L1 agent alone (NCT02845323 and NCT02736266), in combination with chemotherapy (NCT02365766), in combination with radiotherapy (NCT02621151), in combination with anti–CTLA-4 therapy (NCT02812420), or with anti–4-1BB (NCT02845323).

Concluding Remarks

In 2017, patients with urothelial cancer in all stages have more clinical trial options than in any previous era. Patients, caregivers, and physicians no longer have to imagine the possibility of offering clinical trials with the potential of durable benefit and perhaps cure, as trials now can allow for high quality of life and potentially even the opportunity to live with a functional bladder.

However, with all new territory comes a word of caution: We must demonstrate good stewardship with these studies. As enthusiastic as we are, we should remember that the majority of patients have disease that does not respond to checkpoint inhibitors. Furthermore, molecular subtyping remains a complex and time-consuming assay, as does PD-L1 staining. The cost of bladder cancer remains among the highest of all malignancies, so introducing therapy into earlier stages of disease must be tied with a high likelihood of success to justify the potential added cost.

We must, therefore, not become complacent but rather should be spurred into more active research and furtherance of the current promise that the plethora of therapies offer. Combinations must be considered because of strong scientific rationale and not just because two agents exist at the same company. As a medical community, we should try to limit duplicative efforts, share information about false starts and failures, and always honor the patients and caregivers who put their trust in us to find a way forward.

About the Authors: Dr. Campbell is an assistant professor in the Department of Genitourinary Medical Oncology with The University of Texas MD Anderson Cancer Center. Dr. Kamat is a professor of urology and the Wayne B. Duddlesten Professor of Cancer Research in the Department of Urology with The University of Texas MD Anderson Cancer Center. He is also associate cancer center director of Sir HN Reliance Foundation Hospital, Mumbai.