Treatment Rechallenge with Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma - Beyond the Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of advanced urothelial carcinoma (aUC). ICIs can prolong overall survival (OS) in patients with aUC after platinum-based chemotherapy (either as switch maintenance or salvage therapy).

Currently, pembrolizumab, nivolumab, and avelumab are FDA-approved after progression on first line platinum-based chemotherapy, while avelumab is also approved as switch maintenance therapy in patients with response or stable disease after frontline platinum-based therapy. Pembrolizumab is also FDA-approved in the first line setting for platinum-ineligible patients, as well as for patients with BCG-unresponsive carcinoma in situ for patients who decline or cannot undergo radical cystectomy. Nivolumab was FDA-approved in August 2021 as adjuvant therapy for patients with high-risk features (based on pathologic stage) after definitive surgery for urothelial cancer. Increasingly, there are promising data emerging for the use of ICIs as part of perioperative regimens in clinical trials, as well as for use early in the metastatic setting, such as the enfortumab vedotin and pembrolizumab combination regimen for cisplatin-ineligible patients. These trends are pointing towards a situation where more patients may be treated with ICI-based regimens earlier in their disease course in the near future.

Upon progression on platinum-based chemotherapy and ICI, there are other therapeutic options, such as enfortumab vedotin, sacituzumab govitecan, erdafitinib (for patients with FGFR2 or FGFR3 activating mutation or fusion), and even salvage chemotherapy. However, once these options are exhausted, ICI remains a potential consideration for rechallenge, particularly in clinical trials. There have not been much data suggesting whether ICI rechallenge provides meaningful outcomes for patients previously treated with ICI. This study helps fill this knowledge gap, investigating a multi-institutional retrospective cohort of patients with aUC who received ICI rechallenge following prior ICI treatment.

In this retrospective cohort including patients across multiple sites in the US and Europe, we identified and described the characteristics and treatment response of 25 patients with aUC who received ICI-based therapy with two distinct ICI-based courses during their treatment. About half of the patients who were rechallenged with an ICI-based regimen achieved disease control, and 13% had response to that second ICI treatment. Most patients received rechallenge with a different ICI than the one used during the 1st course, and about half of patients (12/25) were rechallenged with a drug with a similar mechanism of action (anti-PD1 after anti-PD1, or anti-PDL1 after anti-PDL1). Among 12 patients re-treated with the same ICI class, only 3 (25%) had progressive disease as best response at the time of rechallenge. Importantly, of the 4 patients who stopped 1st ICI due to immune-related toxicity, none had the same toxicity with 2nd ICI. Based on our results, rechallenge with ICI-based therapy in aUC seems feasible and may possibly help a subset of patients, but further data are needed to select patients for this approach optimally.

With this intriguing data, many important questions remain. Are there more favorable clinical scenarios in which to consider ICI rechallenge? For instance, what is the efficacy of ICI rechallenge in patients who have progression after avelumab switch maintenance which is now the standard of care? Another important question is regarding the efficacy of ICI in aUC patients who received ICI in localized settings (ie pembrolizumab in non-muscle invasive bladder cancer or adjuvant nivolumab in muscle-invasive bladder cancer setting). Given the increasing use of ICIs in these earlier treatment settings, these clinical scenarios in aUC will only continue to increase in relevance and frequency. Answers to such questions will require large retrospective and, hopefully, prospective studies for data validation. ICI-based combinations, such as ICI/ADC combinations may likely have a future role as part of ICI rechallenge. Finally, robust biomarker development can hopefully help identify patient subsets with aUC who benefit most from ICI treatment and ICI rechallenge.

Written by:

  • Vadim S. Koshkin, MD, Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, CA
  • Rafee Talukder, MD, Hematology/Oncology Fellow, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA
  • Ali R. Khaki, MD, Medical Oncologist, Clinical Assistant Professor, Department of Medicine, Stanford University, Stanford, CA
  • Petros Grivas, MD, PhD, Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Read the Abstract