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AUA 2023

AUA 2023: Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer

(UroToday.com) In this presentation, Dr. Srikala Sridhar gave a talk on the role of neoadjuvant immunotherapy (IO) for muscle-invasive bladder cancer (MIBC). As she notes off the bat, MIBC is a highly aggressive systemic disease with poor long-term outcomes. Neoadjuvant cisplatin-based chemotherapy (NAC) remains the standard of care – with pathologic complete response (pCR) rates of 36-42%, 2.6 median overall survival (mOS) benefit, 13% risk of death and 5% improvement in OS compared to radical cystectomy alone. Despite these important benefits, uptake of NAC remains poor – many patients are cisplatin-ineligible, and some refuse and ultimately receive surgery alone. Newer algorithms may help increase uptake, but a significant unmet need exists for better-tolerated and more effective approaches in this setting.


IO therapies have significantly changed the landscape. They are already approved in the NMIBC, adjuvant, and first/late-stage metastatic urothelial carcinoma settings. The only setting they have not yet been approved for is in the neoadjuvant setting.

Indeed, theoretically, since the antigen load is higher in the pre-cystectomy setting, this may lead to better priming and better response in the neoadjuvant space.

The first study discussed was the PURE-01 study. This was an assessment of a single-agent IO therapy (pembrolizumab) – and importantly, 90% of patients were cisplatin eligible.1 pCR rate was 37% (similar to NAC), 54% had <ypT2 disease (downstaging), and 3-year OS was 84%. Tumors with high TMB or PD-L1+ were likelier to respond and achieve pCR.

The ABACUS trial utilized single-agent atezolizumab in the cisplatin-ineligible setting. The final results were published last year.2 This agent did not achieve similar outcomes, with pCR rate of 29%, but 2-year OS was 77%. There was no correlation between TMB and PD-L1 status and recurrence-free survival. She noted that ctDNA may be an important biomarker for MIBC, but that biomarkers are not consistent across studies. 

Regarding biomarkers, a recent analysis of both studies yielded identified signatures associated with response to IO therapy that could be used to molecularly stratify patients and suggest therapeutic alternatives for subtypes expected to yield poor response to IO therapy.3

She then moved on to some dual-agent trials.

    1. Need to carefully consider dosing
    2. ICI toxicity management is important
    3. ctDNA may be an important biomarker
  2. DUTRENEO study – dual agent durvalumab/tremelimumab in cisplatin eligible tumors. Patients with “hot tumors” or active inflammation score tumors on an 18 gene panel were randomized to NAC or dual agent IO. “Cold” tumors got NAC. pCR rates were comparable between patients receiving NAC or dual agent IO for hot tumors (36.4 vs. 34.8), but much higher for cold tumors receiving NAC (68.8).
    1. Highlights the importance of selection for IO therapy In a brief summary of key IO and chemotherapy combinations 

pCR rates were comparable to either NAC or IO alone. No additional benefit – but just added clinical (and financial) toxicity.

Lastly, she briefly touched upon targeted therapies. As our understanding of biology improved, targeted therapies have been able to be developed.

  • In metastatic UC, FGFR3 inhibitors are now approved and being tested in combination with IO agents
  • In the NORSE study (erdafitinib/cetrelimab), patients with mUC and FGFR3 mutations – objective response rates were 68%, with CR rates of 21%
  • The planned NERA trial brings this to the neoadjuvant space, testing erdafitinib alone vs. erdafitinib/atezolizumab for cisplatin-ineligible patients with MIBC who are planned for radical cystectomy

There are additional trials planned for IO/targeted therapy combinations.

She also briefly discussed antibody-drug conjugates (ADCs) and combination with IO therapy. Enfortumab vedotin (EV) is a novel ADC targeting nectin-4 – in the neoadjuvant setting for MIBC, it had a pCR rate of 36% and 50% downstaging.

Currently, there has been an evaluation of EV and pembrolizumab for cisplatin-ineligible mUC (64% objective response rate vs. 45.2% for EV alone). As such, is being sent for accelerated approval and will be tested in the neoadjuvant setting as well.

There are also a few perioperative (neoadjuvant and adjuvant) trials ongoing for Cisplatin-eligible MIBC. She highlighted a few below:

  • NIAGARA – GC vs. GC/durvalumab (Neoadjuvant) and then durvalumab vs. placebo (adjuvant) setting
  • Energize – GC vs. GC/nivolumab (Neoadjuvant) and then nivolumab vs. placebo (adjuvant) setting
  • Keynote-866 - GC vs. GC/pembrolizumab (Neoadjuvant) and then pembrolizumab vs. placebo (adjuvant) setting
  • Keynote-B15/EV304 – GC vs. EV/pembro (neoadjuvant) and then EV/pembro vs. placebo (adjuvant)

For cisplatin-ineligible patients:

  • VOLGA – Durvalumab vs. durva/treme vs. placebo (neoadjuvant) vs. same (adjuvant)
  • Keynote905/EV303 – pembro vs. EV/pembro vs. placebo (neoadjuvant) vs. same (adjuvant)

Primary endpoints are pCR and Event-free survival for all the trials. 

Her conclusions were as follows:

  • We have seen significant advances across the field of bladder cancer
  • As we wait for Phase 3 trials to report, NAC remains the standard of care
  • Neoadjuvant setting is ideal for the evaluation of novel therapies (immediate pathology and early outcomes)
  • Need to consider how we sequence available agents, across settings to optimize outcomes
  • Ultimately, large scale collaborations will be the key to moving the field forward

Presented by: Srikala Sridhar, MD, MSc, FRCSC, Department of Medicine at the University of Toronto

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023 

References:

  1. Basile G, Bandini M, Gibb EA, Ross JS, Raggi D, Marandino L, Costa de Padua T, Crupi E, Colombo R, Colecchia M, Lucianò R, Nocera L, Moschini M, Briganti A, Montorsi F, Necchi A. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res. 2022 Dec 1;28(23):5107-5114. doi: 10.1158/1078-0432.CCR-22-2158. PMID: 36190522.
  2. Szabados B, Kockx M, Assaf ZJ, van Dam PJ, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, Tyson C, Stanoeva D, Daelemans S, Rombouts M, Mariathasan S, Tea JS, Mousa K, Sharma S, Aleshin A, Banchereau R, Castellano D, Powles T. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. Eur Urol. 2022 Aug;82(2):212-222. doi: 10.1016/j.eururo.2022.04.013. Epub 2022 May 14. PMID: 35577646.
  3. Robertson AG, Meghani K, Cooley LF, McLaughlin KA, Fall LA, Yu Y, Castro MAA, Groeneveld CS, de Reyniès A, Nazarov VI, Tsvetkov VO, Choy B, Raggi D, Marandino L, Montorsi F, Powles T, Necchi A, Meeks JJ. Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer. Nat Commun. 2023 Apr 27;14(1):2126. doi: 10.1038/s41467-023-37568-9. PMID: 37105962; PMCID: PMC10140274.