Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma

In light of the historic advances in the treatment of patients with advanced urothelial cancer with the advent of immune checkpoint blockade, we recently published a review highlighting the clinical efficacy of approved PD-1 and PD-L1 antibodies as well as some of the ongoing immune-oncology trials in this disease.¹ In the metastatic setting, immune checkpoint blockade has now been widely adopted both in second-line platinum-refractory setting, as well as in the first-line cisplatin-ineligible setting.

While five agents targeting the PD-1 pathway are FDA-approved for second-line platinum-refractory disease, the PD-L1 antibody atezolizumab, and the PD-1 antibody pembrolizumab are additionally approved in the first-line cisplatin-ineligible setting.^2-3 Atezolizumab and pembrolizumab initially received broad approval in the first-line cisplatin-ineligible setting, however, a recent FDA safety alert prompted a label restriction to PD-L1 positive patients due to a report of decreased survival in patients with low PD-L1 expression treated with PD-1/L1 monotherapy relative to platinum-based chemotherapy in IMvigor130 and KEYNOTE-361. Notably, these data remain unpublished, and subsequent analyses will be necessary to fully understand the role of PD-L1 testing in the first-line cisplatin-ineligible setting, especially given the improved safety and the potential for durable responses and complete responses with PD-1 pathway inhibitors.

Beyond the approved indications in metastatic urothelial cancer, several exciting trials are investigating the efficacy of incorporating PD-1/L1 blockade into the treatment of muscle-invasive and non-muscle invasive bladder cancer. In the adjuvant space, we highlight CheckMate274, IMvigor010, and AMBASSADOR, all of which are randomized phase 3 trials of PD-1/L1 blockade versus observation in patients with the high-risk muscle-invasive disease after surgery.^4-6 In the neoadjuvant setting, PURE-01 and ABACUS were single-arm phase 2 trials demonstrating impressive pathologic complete response rates of 42% and 29% for pembrolizumab and atezolizumab, respectively.^7-8 While cisplatin-based chemotherapy remains the standard of care in the neoadjuvant setting, these data support continued investigation of immune checkpoint blockade, either alone or in combination in muscle-invasive bladder cancer. Furthermore, biomarkers such as PD-L1 expression or tumor mutational burden will likely play an important role in patient selection.

In non-muscle invasive bladder cancer (NMIBC), a number of immune-oncology trials are ongoing. Of particular interest is Keynote 057, an interim analysis of which was recently presented at the 2019 ASCO GU Symposium.⁹ Keynote 057 is an ongoing single-arm phase 2 study of pembrolizumab in the treatment of high-risk BCG-unresponsive NMIBC. Specifically, data were presented on the 102 patients enrolled in Cohort A, which is comprised of patients with CIS with or without the papillary disease (high-grade Ta or T1). Among these patients, the three-month complete response (CR) rate was 40.2%, with a median CR duration of 12.7 months. Based on these promising data, a randomized phase 3 trial – Keynote 676 – has been initiated.

Aside from approved immune-oncology agents, a number of trials are examining novel immunotherapy agents and combinations in the metastatic setting. Two distinct CTLA-4+PD-1/L1 combinations are currently being investigated in metastatic urothelial cancer. Checkmate 032 is a multi-cohort phase 1/2 study of nivolumab with or without ipilimumab which reported an impressive 38% response rate in the platinum-refractory second-line setting with ipilimumab (3mg/kg) and nivolumab (1mg/kg).¹⁰ Additionally, in a multicohort phase 1 trial, the combination of durvalumab with the CTLA-4 antibody tremelimumab achieved a 20.8% response rate among the platinum-refractory metastatic urothelial cancer expansion cohort.¹¹ Both combinations are being further studied in the ongoing randomized phase 3 studies, Checkmate 901 and DANUBE, in first-line metastatic bladder cancer.

Finally, a wide spectrum of trials are exploring the use of various novel immune-oncology agents. In particular, PIVOT-02, a multi-cohort phase 1/2 study, is generating exciting data regarding a pegylated interleukin-2 agent NKTR-214 (bempegaldesleukin).¹² An interim analysis recently presented at the 2019 ASCO GU Symposium demonstrated a response rate of 48% among a small cohort of 23 patients with metastatic urothelial cancer, including 4 (17%) complete responses. While these data are limited by a small sample size and the inclusion of platinum-eligible patients who declined chemotherapy, the 48% response rate with combination bempegaldesleukin and nivolumab compares very favorably to key first-line studies of PD-1/L1 monotherapy, hinting at a possible added benefit with the addition of bempegaldesleukin. This question will be further tested in larger, randomized studies of NKTR-214 which are eagerly anticipated.

Written by: Michael Lattanzi, MD, PGY-III Resident in Internal Medicine, NYU School of Medicine, and Arjun V. Balar, MD, Associate Professor of Medicine and Director of Genitourinary Medical Oncology, NYU School of Medicine and Perlmutter Cancer Center, NYU Langone Health, New York, NY

References:
1. Lattanzi M, Balar AV. Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma. Current oncology reports. 2019 Mar 1;21(3):24.
2. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. The Lancet. 2017 Jan 7;389(10064):67-76.
3. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. The Lancet Oncology. 2017 Nov 1;18(11):1483-92.
4. Bajorin D, Galsky MD, Gschwend JE, Tomita Y, Azrilevich A, Witjes F. 921TiPA Phase III, randomized, double-blind, multicenter study of adjuvant nivolumab vs placebo in patients (pts) with high-risk invasive urothelial carcinoma (UC; CheckMate 274). Annals of Oncology. 2017 Sep 1;28(suppl_5).
5. Castellano D, Albers P, Gschwend JE, Culine S, Bullmunt J, Hussain M, Shen X, Nelson B, Powles T. 1143 A phase III study of the efficacy and safety of adjuvant atezolizumab (anti-PDL1) vs observation in patients with muscle-invasive urothelial carcinoma of the bladder (IMvigor 010). European Urology Supplements. 2016 Mar 1;15(3):e1143.
6. Apolo AB, Rosenberg JE, Kim WY, Chen RC, Sonpavde G, Srinivas S, Mortazavi A, Watt C, Mallek M, Graap K, Diaz C. Alliance A031501: Phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC)(AMBASSADOR) versus observation.
7. Necchi A, Bandini M, Gallina A, Bianchi M, Raggi D, Farè E, Messina A, Chung J, Ali SM, Madison R, Anichini A. First survival outcomes and additional secondary analyses from PURE-01: Pembrolizumab (pembro) before radical cystectomy (RC) in muscle-invasive urothelial bladder carcinoma (MIBC).
8. Powles T, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Font Pous A, Gravis G, Anido Herranz U, Protheroe A, Ravaud A, Maillet D. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS).
9. Balar AV, Kulkarni GS, Uchio EM, Boormans J, Mourey L, Krieger LE, Singer EA, Bajorin DF, Kamat AM, Grivas P, Seo HK. 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).
10. Rosenberg JE, Sharma P, de Braud FG, Basso U, Calvo E, Bono P, Morse M, Ascierto PA, Lopez-Martin JA, Brossart P, Rohrberg KS. LBA32 Nivolumab (N) alone or in combination with ipilimumab (I) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (mUC), including the nivolumab 1 mg/kg+ ipilimumab 3 mg/kg expansion from CheckMate 032. Annals of Oncology. 2018 Oct 1;29(suppl_8):mdy424-038.
11. Balar AV, Mahipal A, Grande E, Villalobos VM, Salas S, Kang TW, Kim SH, Powles T, Tsai F, Naing A, Razak A. Abstract CT112: Durvalumab+ tremelimumab in patients with metastatic urothelial cancer.
12. Siefker-Radtke AO, Fishman MN, Balar AV, Grignani G, Diab A, Gao J, Tagliaferri MA, Hannah AL, Karski EE, Zalevsky J, Hoch U. NKTR-214+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02.

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