Anti-CTLA-4 Antibody Tremelimumab Shows Efficacy in Patients With Metastatic Bladder Cancer
PHILADELPHIA — Treatment with the investigational anti-CTLA-4 agent tremelimumab showed clinical responses in patients with pretreated metastatic bladder cancer, according to results from a phase II clinical trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
The standard-of-care first-line treatment for patients with metastatic bladder cancer is systemic platinum-based chemotherapy. The U.S. Food and Drug Administration (FDA) has approved the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the PD-L1 inhibitors atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) for the treatment of locally advanced or metastatic bladder cancer that has progressed during or after platinum-based chemotherapy.
“There is a significant unmet medical need to improve long-term treatment outcomes for patients with advanced bladder cancer who have progressed following primary treatment,” said Padmanee Sharma, MD, PhD, professor in the Department of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center. “Our results indicate that blocking CTLA-4 with tremelimumab may produce comparable clinical efficacy as seen with PD-1/PD-L1 inhibitors in this patient population.”
Antibodies that inhibit the immune checkpoint proteins CTLA-4 and PD-1/PD-L1 have distinct mechanisms of action and generate unique T-cell responses, Sharma explained. Further, resistance to the inhibition of one of these pathways does not confer resistance to the inhibition of the other checkpoint pathway, she added. “It is important to develop therapies targeting both of these pathways so that we can manipulate different phases of the immune response and allow for improved antitumor efficacy through combination therapy,” she added.
The aim of this open-label, multicenter trial was to evaluate the safety and efficacy of tremelimumab in patients with advanced solid tumors. This study reports on the subgroup of patients with advanced bladder cancer.
At the time of data cut-off, 32 patients had been enrolled in the trial. All had metastatic disease, and 29 patients had received prior cytotoxic chemotherapy. Patients received 750mg of tremelimumab via IV administration every four weeks for seven cycles, followed by administration every 12 weeks for two additional cycles for up to 12 months. The mean treatment duration was 3.5 months.
After a median follow-up of 9.3 months, the overall response rate was 18.8 percent, including two complete responses and four partial responses. The median overall survival was 10.3 months, and the median progression-free survival was 2.6 months.
More than half of the patients experienced adverse events (AEs) of grade 3 or higher, most commonly colitis (three patients) and anemia (three patients). Roughly one-third of patients had an AE that led to discontinuation of treatment.
“While patients tend to experience more side effects with inhibition of CTLA-4 compared with inhibition of PD-1/PD-L1, the nature of these side effects is very similar to those observed with anti-PD-1/PD-L1 therapies and can be managed using similar approaches,” Sharma explained.
“Our results demonstrate that CTLA-4 blockade via tremelimumab can provide clinical benefit for patients with metastatic bladder cancer, highlighting the need for further studies with larger numbers of patients,” Sharma said. Future work will focus on the administration of tremelimumab in patients whose disease has progressed following treatment with anti-PD-1/PD-L1, she added.
Limitations of the study include the small sample size and lack of a randomized control, which limits its broader applicability, noted Sharma.
This study was sponsored by AstraZeneca.
Sharma reports consulting for, and stock or other ownership in Apricity, BioAtla, Codiak Biosciences, Constellation Pharmaceuticals, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird Bioscience, ImaginAb, Jounce Therapeutics, Lytix Biopharma, Marker Therapeutics, Merck & Co., Neon Therapeutics, Oncolytics Biotech, Pieris Pharmaceuticals, and Polaris Group