The 2024 American Society for Radiation Oncology (ASTRO) annual meeting highlighted the integration of novel therapeutics and biomarkers into bladder cancer treatment, particularly focusing on bladder preservation strategies and optimizing trimodal therapy (TMT).
Immunomodulatory Effects of Radiation Therapy
Radiation therapy (RT) exerts substantial immunomodulatory effects within the tumor microenvironment. RT-induced cell death releases immunogenic damage-associated molecular patterns (DAMPs), activating inflammatory pathways and immune cell activation. However, RT can also induce lymphopenia, potentially leading to immunosuppression. Optimizing the timing and dose of radiation delivery is crucial to modulate these effects effectively.
Drawing parallels from lung cancer treatment, the PACIFIC study demonstrated the benefits of integrating immunotherapy with RT. This phase III trial showed that durvalumab following concurrent chemoradiotherapy (CRT) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with unresectable, stage III non-small-cell lung cancer (NSCLC).
Ongoing Trials: Keynote 992 and SWOG S1806
The Keynote 992 phase 3 RCT is examining the combination of an immune checkpoint inhibitor (ICI) with TMT, specifically pembrolizumab versus placebo in patients with muscle-invasive bladder cancer (MIBC) opting for bladder preservation with concurrent CRT. The primary endpoint is bladder-intact event-free survival (BIEFS).
Similarly, the Tour de Force study SWOG S1806 randomized patients with clinical T2-T4N0M0 bladder cancer to receive either CRT alone or CRT combined with atezolizumab for 9 cycles. The primary endpoint, similar to Keynote 992, is BIEFS. Results from this trial are eagerly awaited.
Antibody-Drug Conjugates in Urothelial Carcinoma
Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), has become a significant player in locally advanced/metastatic urothelial carcinoma (la/mUC). EV binds to receptors on cancer cells, internalizes, and releases monomethyl auristatin E (MMAE), a cytotoxic compound causing microtubular disruption and apoptosis. The EV-302 trial established EV plus pembrolizumab as a first-line treatment for mUC, demonstrating a progression-free survival (PFS) hazard ratio (HR) of 0.45 and an overall survival (OS) HR of 0.47 compared to gemcitabine and cisplatin (GC).
The EV-103 study explored neoadjuvant EV in cisplatin-ineligible patients with MIBC. The pathological complete response (pCR) rate was 36.4%, and the pathological downstaging (pDS) rate was 50%. These results have led to the launch of two large phase 3 randomized controlled trials (RCTs): EV-303 (EV plus pembrolizumab versus pembrolizumab alone versus upfront RC in cisplatin-ineligible patients) and EV-304 (EV plus pembrolizumab versus gemcitabine and cisplatin followed by RC in cisplatin-eligible patients).
Combining ADCs with Radiation Therapy: Preclinical and Clinical Evidence
Preclinical data in mice suggest that combining ADCs with RT can significantly reduce tumor volume and weight with minimal toxicity. A retrospective safety analysis of 109 patients with metastatic urothelial carcinoma who received RT with EV showed that toxicity was not exacerbated by RT, and no treatment-limiting toxicities were attributed to RT. The STAR-EV trial, a phase 1/2 trial, is evaluating EV with sequential or concurrent stereotactic body radiation (SBRT) in cisplatin-ineligible urothelial cancer patients planned for RC.
Predictive Biomarkers: ERCC2 and ctDNA
ERCC2 (Excision Repair Cross-Complementation Group 2) is a gene involved in DNA damage repair (DDR). Mutations in ERCC2 have been linked to improved outcomes following chemoradiotherapy and higher pathologic complete response (pCR) rates. The RETAIN trial utilized chemotherapy alone in biomarker-selected patients, showing a 2-year metastasis-free survival of 72.8%. Another study, Alliance A031701, is ongoing to examine bladder preservation following chemotherapy in biomarker-selected patients.
Analysis of genomic and transcriptomic features in MIBC patients treated with TMT revealed that somatic mutations in the ERCC2 gene were significantly associated with favorable outcomes, demonstrating improved BIEFS compared to those without ERCC2 mutations.
Circulating tumor DNA (ctDNA) has been identified as a predictive biomarker for long-term survival and recurrence after radical cystectomy (RC). The IMvigor 010 trial showed that patients with positive ctDNA had significantly worse recurrence-free survival. Data presented at ASTRO also demonstrated a strong correlation between persistent ctDNA and increased risk of recurrence after RT.
