Dual checkpoint blockade promising as pre-surgical approach for certain patients with localized bladder cancer

October 12, 2020

HOUSTON -- Neoadjuvant, or pre-surgical, combination treatment with the immune checkpoint inhibitors tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-1) was well-tolerated and showed early signs of activity in certain patients with localized bladder cancer who do not have standard treatment options available, according to a Phase I clinical trial conducted by The University of Texas MD Anderson Cancer Center.

This represents the first neoadjuvant trial of combination immunotherapy for bladder cancer patients ineligible to receive cisplatin-based chemotherapy, all of whom had tumors with high-risk features that are associated with unfavorable outcomes. The study results, published today in Nature Medicine, also shed important insight into biomarkers associated with treatment responses.

Of the 28 patients enrolled in the trial, 24 completed bladder removal surgery on the study with nine (37.5%) achieving a pathologic complete response (pCR), meaning there were no signs of cancer evident at the time of surgery. Additionally, 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.

"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," said lead author Jianjun Gao, M.D., Ph.D., associate professor of Genitourinary Medical Oncology. "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."

Advancing new immunotherapy options for patients in need

For patients with localized bladder cancer, standard therapy includes cisplatin-based chemotherapy followed by surgery. However, up to half of patients are ineligible for cisplatin treatment because of conditions such as poor kidney function, heart failure or neuropathies, leaving them without standard therapy options, explained Gao.

Previous clinical trials have evaluated neoadjuvant immune checkpoint blockade in bladder cancer, but these studies included only single agents and did not focus on those with high-risk tumors.

High-risk tumors are marked by certain features, including large size, variant histology, lymphovascular invasion, hydronephrosis, and/or disease located in the upper tract of the urothelium. Patients with these tumors tend to have poor survival compared to the average patient with localized 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, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. "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."

The current trial builds on longstanding efforts by Sharma at MD Anderson to advance checkpoint inhibitors for treating patients with localized disease. In 2008, Sharma and colleagues published results from the first-ever trial of neoadjuvant checkpoint blockade (ipilimumab) in patients with localized bladder cancer in the Proceedings of the National Academy of Sciences.

Evaluating dual checkpoint blockade and biomarkers of response

The trial enrolled 28 cisplatin-ineligible patients with high-risk localized bladder cancer at MD Anderson. Each patient received two doses of durvalumab and tremelimumab in combination and 24 patients completed surgery following treatment. Trial participants were 82% Caucasian and 18% Black or other races. Median age was 71 with men accounting for 71% and women 29% of participants.

Most patients experienced immune-related side effects, the most common of which were grade 1-2 rash (29%) and asymptomatic increases in amylase (29%). Six patients (21%) experienced grade 3 or higher immune-related adverse events, including asymptomatic laboratory values, hepatitis and colitis. No treatment-related deaths occurred.

Median overall survival has not been reached, and 24 patients were still alive at one year. In addition, 82.8% of patients that had surgery were free of disease recurrence at one year.

The researchers also collected pre- and post-treatment blood and tissue samples from patients to study biomarkers associated with response in collaboration with MD Anderson's immunotherapy platform, which is co-led by Sharma. The platform is part of MD Anderson's Moon Shots Program®, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patient's lives.

The researchers identified a higher density of specialized immune-cell clusters called tertiary lymphoid structures (TLS) in pre-treatment tumor samples from patients who responded well to combination therapy relative to those who did not respond. A higher density of TLS correlated with longer overall survival and relapse-free survival.

While these findings need to be confirmed in larger studies, the data suggests that TLS may serve as a useful predictive biomarker for those who will respond to checkpoint blockade, explained Sharma. These findings are in agreement with previously published MD Anderson research reporting that an enrichment of B cells within TLS were predictive of response to checkpoint inhibitors in patients with melanomas, soft-tissue sarcomas and renal cell carcinomas.

This research was supported by a collaboration between MD Anderson's immunotherapy platform and AstraZeneca/MedImmune, the MD Anderson Physician-Scientist Award, the Khalifa Fellows Award, which was established by the Khalifa Bin Zayed Al Nahyan Foundation, the Andrew Sabin Family Foundation Fellows Award, and Wendy and Leslie Irvin Barnhart. Sharma and co-author James P. Allison, Ph.D., are members of the Parker Institute for Cancer Immunotherapy (PICI) and co-directors of PICI at MD Anderson.

In addition to Gao and Sharma, additional collaborators on this study include: Neema Navai, M.D., Ashish Kamat, M.D., Surena Matin, M.D., John Papadopoulos, M.D., and Colin Dinney, M.D., all of Urology; Omar Alhalabi, M.D., Arlene Siefker-Radtke, M.D., Matthew Campbell, M.D., John Araujo, M.D., Ph.D., Amishi Shah, M.D., Pavlos Msaouel, M.D., Ph.D., Paul Corn, M.D., Ph.D., Jianbo Wang, M.D., Ph.D., Jianfeng Chen, Ph.D., and Sangeeta Goswami, M.D., Ph.D., all of Genitourinary Medical Oncology; Rebecca Slack Tidwell and Yu Shen, Ph.D., both of Biostatistics; Charles Guo, M.D., of Pathology; Jorge Blando, D.V.M, Fei Duan, Ph.D., Sreyashi Basu, Ph.D., Shalini Singh Yadav, Ph.D., Wenbin Liu, Yuwei Zhang, Ph.D., Marc Daniel Macaluso, Ph.D., Ying Wang, Ph.D., all of the immunotherapy platform; Jianhua Zhang, Ph.D., and Andrew Futreal, Ph.D., both of Genomic Medicine; and James P. Allison, Ph.D., of Immunology and the immunotherapy platform. A full list of authors' disclosures can be found with the paper here.
About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution's sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Report's "Best Hospitals" survey. It has ranked as one of the nation's top two hospitals for cancer care since the survey began in 1990, and has ranked first 16 times in the last 19 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

University of Texas M. D. Anderson Cancer Center

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