Combination treatment with tremelimumab and durvalumab was found to be well-tolerated and showed early signs of activity in certain patients with localized bladder cancer who are not eligible for cisplatin-based chemotherapy.
Phase 1 clinical trial results published in Nature Medicine demonstrated that neoadjuvant combination treatment with tremelimumab and durvalumab (Imfinzi) was well-tolerated and showed early signs of activity in certain patients with localized bladder cancer who are not eligible for cisplatin-based chemotherapy.1
Patients included in the study had tumors with high-risk features that are associated with unfavorable outcomes, defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis, and/or high-grade upper tract disease.
“Immune checkpoint therapy has clearly revolutionized cancer care with patients with metastatic disease in multiple tumor types, but we continue to work toward moving these therapies into earlier disease settings for patients in need,” said corresponding author Padmanee Sharma, MD, PhD, professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center, said in a press release.2 “By combining these therapies, we felt we could take advantage of the distinct biologic mechanisms and stimulate a more robust anti-tumor immune response for these patients.”
Between April 2017 and December 2018, researchers enrolled 28 patients with high-risk, cisplatin-ineligible, localized muscle-invasive urothelial carcinoma (MIUC) in the first cohort of the study. Participants had baseline transurethral resection of bladder tumor and were then treated with a combination of durvalumab at a dose of 1,500 mg kg−1 and tremelimumab at a dose of 75 mg kg−1 every 4 weeks for a total of 2 combination doses before cystectomy.
No deaths related to therapy occurred. However, the majority of patients experienced an immune-related adverse event (irAE) of any grade. The most common irAE was grade 1 or 2 rash and asymptomatic increase in amylase, which each occurred in 29% of patients. Additionally, the study did not exceed its safety or futility rules, with a total of 6 patients (21%) experiencing grade 3 or higher irAEs.
Of the 28 patients enrolled in the trial, 24 completed cystectomy per protocol, with 9 (37.5%) achieving a pathologic complete response (pCR). Moreover, in 12 patients with particularly large tumors (stage T3-T4), the pCR rate was 42%, and half saw their tumor size reduced to stage T1 or less.
Importantly, median overall survival (OS) has not yet been reached, and 24 patients were still alive at 1 year. Additionally, 82.8% of patients that had surgery were free of disease recurrence at 1 year.
“This study provides early evidence that neoadjuvant treatment with combination checkpoint inhibitors is feasible in a group of patients who are in need of additional treatment options,” lead author Jianjun Gao, MD, PhD, associate professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, said in the release. “In this small group of patients, the combination treatment had an acceptable safety profile with encouraging activity that supports further clinical studies in this setting.”
Further, the researchers also collected pre- and post-treatment blood and tissue samples from patients to study biomarkers associated with response, identifying a higher density tertiary lymphoid structures (TLS) in pre-treatment tumor samples from patients who responded well to combination therapy compared to those who did not respond. Notably, a higher density of TLS correlated with longer OS and relapse-free survival.
Though this research still needs to be confirmed in larger studies, investigators indicated that the findings suggest that TLS may act as an effective predictive biomarker for patients who will respond to checkpoint blockade.
“In summary, our data indicate that two cycles of neoadjuvant combination therapy had a tolerable safety profile and encouraging efficacy results, which warrant future clinical trials to further develop combination treatment with anti-CTLA-4 plus anti-PD-L1 for cisplatin-ineligible patients with MIUC and determine the optimal duration of therapy,” the authors wrote.
1. Gao J, Navai N, Alhalabi O, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nature Medicine. doi: 10.1038/s41591-020-1086-y
2. Dual checkpoint blockade promising as pre-surgical approach for certain patients with localized bladder cancer [news release]. Published October 12, 2020. Accessed October 14, 2020. https://www.mdanderson.org/newsroom/dual-checkpoint-blockade-promising-as-pre-surgical-approach-for-certain-patients-with-localized-bladder-cancer.h00-159385890.html