AIBCCR 2021: Role of Immunotherapy (IO) in Urothelial Cancer

(UroToday.com) Petros Grivas (Seattle Cancer Care Alliance) chaired the first session of the 7th Annual Leo and Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium on immuno-oncology, setting the scene for the role of immunotherapy (IO) in urothelial cancer (UC) by summarizing recent advances and outlining unanswered questions.


Following the success of immune checkpoint inhibitors (CPI) in the advanced urothelial cancer setting, research efforts have focused on using these agents earlier in the disease spectrum. To this end, Dr. Shilpa Gupta (Cleveland Clinic) provided a comprehensive overview of IO trials in the neoadjuvant and adjuvant settings for muscle-invasive bladder cancer (MIBC).

In the neoadjuvant setting, treatment options for cisplatin-ineligible MIBC patients are lacking and urgently needed. Fortunately, as highlighted by Dr. Gupta, several trials are investigating the utility of CPIs in this domain. One example is the NABUCCO trial, which evaluated the combination of ipilimumab and nivolumab, showing promising efficacy with >50% downstaging to pT1 or below.1 Dr. Gupta pointed out that, with the exception of ABACUS and PURE-01, the majority of these trials have not reported surgical complications.

Dr. Gupta then reviewed the ongoing phase 3 perioperative immunotherapy trials in cisplatin-eligible MIBC including KEYNOTE-866 (NCT03924856), KEYNOTE-B15/EV-304 (NCT04700124), NIAGRA (NCT03732677) and ENERGIZE (NCT03661320). These trials are still accruing with results expected in the next few years.

Dr. Gupta also discussed the phase 3 adjuvant IO trials in MIBC including IMvigor010 (atezolizumab vs. observation), CheckMate 274 (nivolumab vs. observation), and AMBASSADOR (pembrolizumab vs observation). Although IMvigor010 failed to show an improvement in disease-free survival (DFS), CheckMate274 did meet its primary endpoint of DFS improvement leading to subsequent FDA approval of nivolumab in this setting.2 The AMBASSADOR trial has recently completed accrual and is set to shed further light on the role of IO in the adjuvant setting. Dr. Gupta concluded her talk by looking to the future and projecting the potential role of artificial intelligence in studying biomarkers of response and resistance to immunotherapy.

The second speaker of the session was Dr. Andrea Apolo (National Cancer Institute) who discussed the role of CPI and tyrosine kinase inhibitor (TKI) combinations in metastatic UC. Tyrosine kinase inhibitors have immunomodulatory effects that may promote an anti-tumour immune microenvironment and enhance the activity of CPIs. Indeed, many CPI/TKI combinations are currently being evaluated in phase 1, 2, and 3 trials, and Dr. Apolo provided a comprehensive overview of these.

She began by highlighting the results of a phase I study evaluating cabozantinib and nivolumab ± ipilmumab in patients with metastatic UC and other genitourinary tumours.4 The ORR was 31% for all patients and 39% for patients with metastatic UC, who showed durable responses. Following this was a discussion of the ICONIC study (NCT03866382) which will evaluate the same combination in rare GU cancers. Accrual for this trial is going well with several cohorts closed.

Dr. Apolo concluded by discussing the LEAP-011 (pembrolizumab/lenvatinib vs. pembrolizumab/placebo) and MAIN-CAV (maintenance cabozantinib/avelumab vs. maintenance avelumab) trials; these randomized phase 3 studies are currently underway to evaluate these combinations in patients with previously treated advanced urothelial cancer.

The penultimate speaker was Dr. Mathew Milowsky (UNC Lineberger Comprehensive Cancer Center) who presented his work on the use of digital spatial profiling to evaluate the impact of tumour architecture on anti-tumour immunity with chemo-immunotherapy in MIBC.

Concluding the session was Dr. Ali Khaki (Stanford Medicine) whose talk focused on optimizing quality, value, and effectiveness of CPIs in urothelial cancer. Dr. Khaki began by discussing the efficacy-effectiveness gap, which is the concept that the results seen in clinical trials do not always translate to real-world settings. This is, in part, because patients selected for trial are often younger with fewer comorbidities. However, this does not appear to be the case in advanced UC, with Dr. Khaki highlighting real-world evidence confirming a similar response rate and overall survival for most subpopulations of advanced UC treated with CPIs.3 Notable exceptions included those patients with ECOG PS≥ 2 and neuroendocrine mixed histology.

With regards to cost-effectiveness, although CPI may be cost-effective for patients with advanced UC, current evidence suggests that this probably not the case for patients with NMIBC or NAC. As such, Dr. Khaki discussed potential strategies to improve cost-effectiveness including price reduction, reducing the frequency or duration of therapy, and improving efficacy through the use of biomarkers.

Presented by: Petros Grivas, MD, PhD, Seattle Cancer Care Alliance; Shilpa Gupta, MD, Cleveland Clinic Taussig Cancer Institute; Andrea Apolo, MD, National Cancer Institute; Matthew Milowsky, MD, (UNC Lineberger Comprehensive Cancer Center); Ali Khaki, MD, (Stanford Medicine)

Written by: Niyati Lobo, MD, The Urology Foundation Fulbright Scholar, Twitter: @niyatilobo, with Ashish Kamat, MD, MBBS, President, International Bladder Cancer Group (IBCG), Professor of Urology & Cancer Research, MD Anderson Cancer Center, Houston, Texas, Twitter: @UroDocAsh at the 7th Annual Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium, Sept 16, 2021- Sep 18, 2021.


References:

  1. van Dijk N, Gil-Jimenez A, Silina K et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020; 26: 1839-1844.
  2. Bajorin DF, Witjes JA, Gschwend JE et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial cancer. N Engl J Med. 2021; 384:2102-2114
  3. Khaki AR, Li A, Diamantopoulos LN et al. Impact of performance status on treatment outcomes: a real-world study of advanced urothelial cancer treated with immune checkpoint inhibitors. Cancer. 2020; 126: 1208-1216
  4. Apolo AB, Nadal R, Girardi DM. Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. J Clin Oncol. 2020; 38: 3672-3684.
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