Society of Urologic Oncology (SUO) 21st Annual Meeting

SUO 2020: Neoadjuvant Checkpoints: Exploring the Emerging Utility of Immune Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer

(UroToday.com) At the 2020 Society of Urologic Oncology (SUO) virtual annual meeting, Dr. Neal Shore chaired a session examining the use of newer and emerging agents in bladder cancer, which highlighted a presentation by medical oncologist Dr. Arjun Balar discussing the emerging utility of immune checkpoint inhibitors in muscle-invasive bladder cancer (MIBC).


MIBC is inherently a systemic disease, with approximately 50% developing metastases. The purpose of local therapy is local control/tumor eradiation before the dissemination of micrometastases, with perioperative therapy addressing potential micrometastases. The ideal local therapy definitively addresses local disease reliably, but Dr. Balar questions if radiation is truly definitive. Ideally, local therapy preserves quality of life, granted that cystectomy is a morbid operation with a 60% complication rate.

Dating back almost two decades now was the phase III trial of neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) followed by radical cystectomy.1 In this trial, patients were randomized to 3 cycles of MVAC followed by radical cystectomy versus immediate radical cystectomy. Patients that underwent cystectomy alone (n=154) had a median overall survival of 46 months compared to 77 months for the MVAC plus cystectomy (n=153) (HR for OS 1.33, 95% CI 1.00-1.76, p=0.06; HR for DSS 1.66, p=0.002). Furthermore, Dr. Balar notes that in this trial, the pT0 rate was 38% for those receiving MVAC plus cystectomy, compared to 15% for those undergoing immediate cystectomy, with a 5-year survival rate among patients with pT0 disease of 85%.

Dr. Balar then discussed two key phase II neoadjuvant immunotherapy trials. The first was the PURE-01 trial, which is an open-label, single-arm, phase 2 trial2,3 evaluating the activity, medical and surgical safety, and immune-modulatory effects of pembrolizumab administered prior to radical cystectomy. Key inclusion criteria for this trial included patients with:
  • Predominantly urothelial carcinoma histology (>50%)
  • Clinical stage ≤3bN0M0 disease by CT, MRI, or PET/CT within four weeks of randomization.
  • Residual disease after TURBT
  • GFR ≥20 ml/min
  • ECOG performance status 0-1

Key exclusion criteria include patients previously treated with chemotherapy for bladder cancer, or malignancies within five years of bladder cancer diagnosis. Pembrolizumab was administered at the dose of 200mg, as a 30-minute IV infusion, every 3 weeks for a total of three cycles prior to radical cystectomy.

SUO_TURBT.png

The primary outcome was pathologic complete response (pT0) at the time of radical cystectomy in the intention to treat (ITT) population.

Second, Dr. Balar discussed the ABACUS trial,4 a single-arm, phase II study investigated two cycles of atezolizumab (1200mg every three weeks) prior to radical cystectomy among patients with T2-4N0M0 urothelial carcinoma. Other key eligibility criteria included residual disease post-TURBT and not fit for/rejected cisplatin-based chemotherapy. The co-primary endpoints for the study were pathological complete response occurring in ≥20% of patients, and an increase in CD8 count as a biomarker analysis. Taken together, the pT0 rates of these two trials compared to key neoadjuvant chemotherapy trials is as follows:

SUO_post-TURBT.png



As of October 2020, the current landscape of neoadjuvant immunotherapy data for bladder cancer patients is as follows:

SUO_immunotherapy_trials.png



Additionally, there are several ongoing neoadjuvant phase III immunotherapy trials, including NIAGARA and ENERGIZE. NIAGRA is randomizing patients to durvalumab plus chemotherapy versus chemotherapy, whereas ENERGIZE is randomizing patients to chemotherapy plus nivolumab followed by adjuvant nivolumab versus chemotherapy plus nivolumab plus IDO inhibitor BMS-986205 followed by adjuvant nivolumab plus BMS-986205:


SUO_BMS-986205.png



In the adjuvant disease space, first presented at the 2020 American Society of Clinical Oncology (ASCO) annual meeting, the IMvigor010 trial provides a cautionary note. This trial randomized patients to adjuvant atezolizumab (n=406) versus observation (n=403), with a median DFS of 19.4 months (95% CI 15.9-24.8) in the atezolizumab arm compared to 16.6 months (95% CI 11.2-24.8) in the observation arm (HR 0.89, 0.74-1.08). Additionally, there was no benefit in the PD-L1 IC0/1 or PD-L1 IC2/3 subgroups. However, the CheckMate-274 trial testing adjuvant nivolumab reported in a press release on September 24, 2020, that nivolumab significantly improved DFS versus placebo; we will await the presentation of these encouraging results.

Presented by: Arjun V. Balar, MD, Associate Professor, Department of Medicine and Director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center. NYU Langone Health, New York, New York

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 21st Annual Meeting of the Society of Urologic Oncology (SUO), December 3-5, Virtual Conference

References:
  1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
  2. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018 Dec 1;36(34):3353-3360.
  3. 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 Apr;77(4):439-446.
  4. Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). ASCO 2018 abstr 4506.
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