GU Oncology Now spoke with Guru P. Sonpavde, MD, medical director of genitourinary oncology and assistant director of the Clinical Research Unit, AdventHealth Cancer Institute, regarding the current state and momentum of different research efforts to advance treatment strategies in muscle-invasive bladder cancer (MIBC).
Research has shown that neoadjuvant immunotherapy is safe and leads to favorable pathologic complete response rates in MIBC. Can you provide a summary of ongoing trials and data related to neoadjuvant combinations of immunotherapy plus chemotherapy and how this approach compares with individual immunotherapy or chemotherapy?
Dr. Sonpavde: In patients eligible for cisplatin treatment, neoadjuvant cisplatin-based combination chemotherapy is the standard of care. Different combinations like cisplatin plus gemcitabine; methotrexate, vinblastine sulfate, adriamycin, and cisplatin (MVAC); or dose-dense MVAC are all reasonable options. Combining cisplatin-based regimens with programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) inhibitors has been explored in nonrandomized studies. These studies demonstrate feasibility and potential effectiveness, although definitive conclusions on superiority over cisplatin-based chemotherapy alone are challenging due to the lack of randomized trials. Pathologic complete remission rates range from 40% to 60% across various trials. Phase 3 trials comparing cisplatin-based chemotherapy alone versus the combination with PD-1/PD-L1 inhibitors will provide definitive insights.
Can you elaborate on ongoing research regarding immunotherapy combined with antibody-drug conjugates (ADCs) and radiation therapy?
Dr. Sonpavde: Another approach involves replacing cisplatin with immune checkpoint inhibition while pairing it with different drugs. For instance, enfortumab vedotin (EV), an ADC-targeting nectin-4, has shown promise in metastatic disease. In first-line metastatic cisplatin-ineligible cases, EV plus pembrolizumab yielded response rates of 65% to 70%. This combination received accelerated approval in the United States based on phase 1b/2 trials. This success prompted investigations of EV plus pembrolizumab in the neoadjuvant setting for both cisplatin-eligible and cisplatin-ineligible patients.
In cisplatin-eligible patients, the comparison of EV/pembrolizumab with cisplatin/gemcitabine is ongoing. In cisplatin-ineligible patients, EV/pembrolizumab and pembrolizumab alone are being evaluated, given the lack of standard neoadjuvant therapy. These trials might introduce a new treatment approach for cisplatin-ineligible patients. Additionally, neoadjuvant trials are exploring chemoradiation combined with PD-1/PD-L1 inhibitors like pembrolizumab and atezolizumab. Although superiority over chemoradiation alone is not confirmed, phase 3 trials could provide clarity.
What is the rationale behind omitting cisplatin-based chemotherapy? Is it due to toxicity concerns, or is there a growing body of evidence that suggests the efficacy of these immunotherapy options?
Dr. Sonpavde: The distinction between cisplatin-eligible and cisplatin-ineligible patients is essential. Cisplatin may not be suitable for those with poor performance status, kidney issues, or certain comorbidities. Renal dysfunction is common due to both the impact of bladder cancer and underlying conditions. As cisplatin alternatives like carboplatin are less effective, efforts focus on improving cisplatin-ineligible patients’ systemic therapy. EV, unlike cisplatin, is kidney-friendly and suits those with renal dysfunction, which leads to EV plus pembrolizumab being investigated in both the cisplatin-eligible and cisplatin-ineligible neoadjuvant settings.
Could you outline the current landscape of biomarkers for patients with MIBC? Is the pace of biomarker discovery keeping up with treatment advancements?
Dr. Sonpavde: Biomarkers are indeed lagging behind treatment progress. Ideally, drug development should involve biomarkers to select patients effectively. Currently, some biomarkers exist for muscle-invasive urothelial carcinoma. Notably, circulating tumor DNA (ctDNA) assessment postradical cystectomy is promising for detecting molecular residual disease (MRD). Patients with MRD might benefit from adjuvant atezolizumab, as indicated by retrospective analysis of the phase 3 IMvigor010 trial. Prospective validation of this ctDNA assay in the IMvigor011 trial is ongoing. Additionally, adjuvant nivolumab approval in Europe is tied to PD-L1 expression, while it is approved in the United States regardless, pending survival data from the CheckMate 274 trial.
Which predictive molecular biomarkers are most needed in this context?
Dr. Sonpavde: The ctDNA assay indicates disease presence but needs further validation for treatment benefits. Combining ctDNA positivity with high TMB or PD-L1 expression could refine patient selection for adjuvant nivolumab. Non-tumor-informed assays are emerging for MRD detection, including urine tumor DNA and ctDNA sequencing with methylation profiling. These approaches require more development but hold potential.
Could advancing biomarkers and targeted treatments in the neoadjuvant setting enhance bladder-preservation efforts?
Dr. Sonpavde: Certainly. While the quick nature of neoadjuvant therapy challenges biomarker utilization, having predictive assays would guide tailored treatment choices. Developing assays that rapidly predict optimal therapies, such as chemotherapy, immunotherapy, or targeted agents, could promote bladder preservation. Although studies exploring bladder preservation postneoadjuvant treatment have shown promise, they are not yet mature for clinical use. Molecular assays like ctDNA and urine tumor DNA may aid in selecting patients for bladder preservation, but further research is needed.