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Is There Synergism When Combining Antibody Drug Conjugates and Immune-Oncology Agents for Urothelial Carcinoma?

Patients with urothelial bladder cancer now have many efficacious treatment options, spanning many unique mechanisms of action.  The immune-oncology agents in urothelial carcinoma have had significant success with current regulatory approvals in various disease states for pembrolizumab, nivolumab, atezolizumab, and avelumab.  Likewise, antibody drug conjugates are monoclonal antibodies specific for a tumor antigen, connected by a linker molecule to a cytotoxic drug payload, offering selective intensification of therapy.  Direction of increased drug concentration to the target cancer cell with minimal collateral damage to healthy tissue is a purported advantage of these antibody drug conjugates.  Yet, there is now some discussion surrounding whether increased specificity of targeting is ideal or whether it may be advantageous to have a more cleavable linker that could allow for greater bystander effect against cancer cells that may lack target antigen expression.1


For patients with urothelial carcinoma, we now have regulatory approvals for enfortumab vedotin and sacituzumab govitecan.  Yet, there are many other ongoing studies with other antibody conjugates, such as trastuzumab deruxtecan and disitamab vedotin. We have recently seen some very compelling combination data when certain immune-oncology agents have been used together with antibody drug conjugates.  I first discussed this concept in a Clinical Trials Portal article back in March 2020 that was focused on enfortumab vedotin.2  To briefly review, data from the 2019 European Society of Medical Oncology Congress showed outstandingly high response rates when enfortumab vedotin was combined with pembrolizumab in the EV-103 trial.3  First-line metastatic urothelial carcinoma patients, who were ineligible to receive cisplatin chemotherapy, were treated with pembrolizumab and enfortumab vedotin.  Of 45 treated patients, 32 (71%) had a confirmed response.  With this small number of patients, additional data was needed, and some confirmatory data was recently presented at the European Society of Medical Oncology 2022 Congress.  Data from Cohort K of the EV-103 trial was presented on two separate arms, one with enfortumab vedotin plus pembrolizumab and one with enfortumab vedotin alone.  It is important to note that these two arms were part of a 1:1 randomization, but they were not intended to be statistically compared to one another, hence formal statistical comparisons were not performed.  This data confirmed high response rates with the enfortumab vedotin plus pembrolizumab combination.  Objective response rates were noted in 64.5% of patients.4  The other arm in this trial treated patients with enfortumab vedotin alone and response rates were still high, but notably lower at 45.2%. 

With impressive efficacy of the enfortumab vedotin plus pembrolizumab combination from these cohorts, it is natural to ask if this sort of efficacy will be seen with other such combinations.  We have seen data for patients with HER2-expressing metastatic urothelial carcinoma in patients who have not received prior immune-oncology therapy with nivolumab plus trastuzumab deruxtecan combination therapy.  Data presented at the Genitourinary Cancers Symposium in early 2022, revealed an objective response in 11 out of 30 (36.7%) HER2 2+ and 3+ tumor expressing patients.5  Although this is a respectable response rate, it is hard to dissect independent components with a small sample size of biomarker selected patients, especially since we have not seen single agent trastuzumab deruxtecan data yet.

More recently, we have seen impressive activity of disitamab vedotin (RC48), both as a single agent and in combination with an immune-oncology agent.  In patients with HER2 2-3+ tumor expression, we observed a 50.5% response rate with disitamab vedotin.6  For patients with HER2 0-1+ tumor expression, the objective response rate with disitamab vedotin was 26.3%.7  Yet, when disitamab vedotin was combined with a Toripalimab, a PD-1 antibody, the objective response rate for all-comers, regardless of HER2 expression level, was 71.8%.8  These results, albeit from small sample size studies, may offer further support to combining an antibody drug conjugate with an immune oncology agent.

In regards to the tolerability of an immune-oncology agent combined with an antibody drug conjugate, toxicity does not seem exacerbated.  Response rates for such combinations generally seem at least additive, if not synergistic.  Additional information on whether these combinations may offer the higher response rates that we’ve seen with antibody drug conjugates coupled with the durable responses and stable disease seen with immune-oncology agents will be informative, and we eagerly await such long-term outcome data.  Please see below for more information on ongoing clinical trials where immune-oncology agents are being combined with antibody drug conjugates for patients with urothelial carcinoma. 

Ongoing Trials with Immune-Oncology Agent plus Antibody Drug Conjugate Combination

  • VOLGA – Randomized phase 3 trial of Durvalumab, Tremelimumab and Enfortumab vedotin or Durvalumab and Enfortumab vedotin in patients with cisplatin-ineligible muscle invasive bladder cancer (NCT04960709)
  • KEYNOTE-905/EV-303 – Randomized phase 3 trial of pembrolizumab plus Enfortumab vedotin plus cystectomy vs. cystectomy alone in cisplatin-ineligible muscle invasive bladder cancer (NCT03924895)
  • KEYNOTE-B15 – Randomized phase 3 trial of Enfortumab vedotin plus pembrolizumab vs. neoadjuvant chemotherapy for cisplatin eligible muscle invasive bladder cancer (NCT04700124)
  • EV-ECLIPSE - Phase 2 trial of Enfortumab vedotin and pembrolizumab for node positive bladder cancer planning to undergo surgery (NCT05239624)
  • Phase 1/2 trial of ipilumumab, nivolumab, and Sacituzumab govitecan for metastatic cisplatin-ineligible urothelial carcinoma (NCT04863885)
  • EV-103 - Enfortumab vedotin plus multiple combinations (including with pembrolizumab (NCT03288545)
  • EV-302 – Randomized phase 3 Enfortumab vedotin and vs. chemotherapy (EV-302) (NCT04223856)
  • JAVELIN Bladder Medley – Phase 2 maintenance therapy trial of avelumab and Sacituzumab govitecan (NCT05327530)
  • MORPHEUS-mUC - Phase 1/2 trial of multiple combinations, including Enfortumab vedotin plus Atezolizumab and Sacituzumab govitecan plus atezolizumab (NCT03869190)
  • Phase 2 trial of Disitamab vedotin alone and with pembrolizumab in HER2 expressing urothelial carcinoma (NCT04879329)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:

  1. Modi S, et al. "Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer." N Engl J Med 2022; 387:9-20.
  2. Yu EY. Urotoday Clinical Trials Portal. "Enfortumab Vedotin – Changing the Way We Think About Urothelial Cancer." March 3, 2020.
  3. Hoimes CJ, et al. "EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma." Ann Oncol (2019) 30 (suppl_5):v356-v402.
  4. Rosenberg JE, et al. "Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC)." Ann Oncol (2022) 33 (suppl_7):S808-S869.
  5. Galsky MD, et al. "Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC)." J Clin Oncol 40, 2022 (suppl 6; abstr 438).
  6. Sheng X, et al."Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma." J Clin Oncol 40, no. 16_suppl (June 1, 2022) 4518-4518.
  7. Xu H, et al. "A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma." J Clin Oncol 40, no. 16_suppl (June 1, 2022) 4519-4519.
  8. Sheng X, et al. "RC48-ADC for metastatic urothelial carcinoma with HER2-positive: Combined analysis of RC48-C005 and RC48-C009 trials."J Clin Oncol 40, no. 16_suppl (June 1, 2022) 4520-4520.