Neoadjuvant Dual Checkpoint Blockade in Certain Patients With Localized Bladder Cancer

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Neoadjuvant combination therapy with the anti–CTLA-4 therapy tremelimumab and the anti–PD-1 therapy durvalumab was well tolerated and showed early signs of activity in patients ineligible to receive cisplatin-based chemotherapy, all of whom had tumors with high-risk features that are associated with unfavorable outcomes. These results from a phase I clinical trial were published by Gao et al in Nature Medicine. The study results also offered important insights about biomarkers associated with treatment responses.

“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 study author Jianjun Gao, MD, PhD, Associate Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. “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.”

Study Background

For patients with localized bladder cancer, standard therapy includes cisplatin-based chemotherapy followed by surgery. However, up to half of patients are ineligible for treatment with cisplatin because of conditions such as poor kidney function, heart failure, or neuropathies, explained Dr. 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 study author Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology at MD Anderson. “By combining these therapies, we felt we could take advantage of the distinct biologic mechanisms and stimulate a more robust antitumor immune response for these patients.”

Padmanee Sharma, MD, PhD

Padmanee Sharma, MD, PhD

Study Methods and Findings

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. Eighty-two percent of patiens in the trial were White, and 18% were Black or another race. Median age was 71 years, with men accounting for 71% and women 29% of participants.

Of the 24 patients who completed bladder removal surgery on the study, 9 (37.5%) achieved a pathologic complete response. Additionally, in 12 patients with particularly large tumors (stage T3–T4), the pathologic complete response rate was 42%, and half saw their tumor size reduced to stage T1 or less.

Most patients experienced immune-related side effects, the most common of which were grade 1 or 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 1 year. In addition, 82.8% of patients that had surgery were free of disease recurrence at 1 year.

The researchers also collected pre- and posttreatment 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 Dr. Sharma.

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

While these findings need to be confirmed in larger studies, the data suggest that tertiary lymphoid structures may serve as a useful predictive biomarker for those who will respond to checkpoint blockade, explained Dr. Sharma.

Disclosure: 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. For full disclosures of the study authors, visit

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