Studies show that although radical cystectomy has long been recognized as the standard-of-care for localized muscle-invasive bladder cancer (MIBC), the surgery carries significant morbidity and the risk of subsequent loss of quality of life for patients. Preclinical studies have suggested that a combination of immune checkpoint inhibitors that target different immune checkpoints, including CTLA-4 and PD-L1, plus radiation therapy may improve antitumor activity in this patient population.
The results from the phase II IMMUNOPRESERVE clinical trial—which investigated a multimodal approach, including durvalumab and tremelimumab plus concurrent radiotherapy for patients with MIBC—show that the combined therapy demonstrated a high rate of complete responses in patients, which in turn allowed for bladder preservation. The study by Garcia-del-Muro et al was published in Clinical Cancer Research.
Study Methodology
The researchers enrolled 32 patients with localized MIBC in clinical stages T2 to T4a with no metastases or lymph node involvement who had not previously received immunotherapy other than bacillus Calmette-Guérin or radiotherapy to the bladder. The patients underwent transurethral resection, followed by durvalumab at 1,500 mg plus tremelimumab at 75 mg every 4 weeks for three doses and concurrent radiotherapy (64–66 Gy to the bladder). Patients with residual or relapsed MIBC underwent salvage cystectomy.
The primary endpoint of the study was complete response, defined as the absence of MIBC at post-treatment biopsy. Secondary endpoints were bladder-intact disease-free survival, distant metastasis–free survival, and overall survival.
KEY POINTS
- Combination immunotherapy plus radiation therapy achieved a high rate of complete response (81%) in patients with muscle-invasive bladder cancer, which allowed for bladder preservation.
- The estimated 2-year overall survival and distant metastasis–free survival rates were 84% and 83%, respectively.
- Further research on this approach as an alternative to cystectomy is warranted.
Results
Complete response was documented in 26 (81%) of patients. Two patients had residual MIBC, and four patients were not evaluated. After a median follow-up of 27 months, two patients underwent salvage cystectomy. The 2-year rates for bladder-intact disease-free survival, distant metastasis–free survival, and overall survival were 65%, 83%, and 84%, respectively. The 2-year estimates of non-MIBC relapse, MIBC, and distant metastasis were 3%, 19%, and 16%, respectively. Grade 3 to 4 toxicities were reported in 31% of the patients, with diarrhea (6%) and acute kidney failure (6%) being the most frequently occurring adverse events.
“This multimodal approach, including durvalumab plus tremelimumab with concurrent radiotherapy, is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of patients. Further research on this approach as an alternative to cystectomy is warranted,” concluded the study authors.
Translational Relevance
The researchers plan to confirm these findings in larger studies with more patients, a longer follow-up, and direct comparisons to other treatment regimens, including radiation plus chemotherapy.
“While this is an early exploratory study, the results are encouraging and highlight the potential of radiotherapy plus combination immunotherapy to improve quality of life without compromising survival,” said first study author Xavier Garcia-del-Muro, MD, PhD, Professor of Medical Oncology at the University of Barcelona and the Institut Catalá d’Oncologia in Barcelona, Spain, in a statement.
Disclosure: Funding for this study was provided by the Spanish Oncology Genitourinary Group and AstraZeneca. For full disclosures of the study authors, visit aacrjournals.org/clincancerres.
