Efficacy outcomes and biomarker analysis from phase II trial of escalating doses of neoadjuvant atezolizumab in patients with muscle-invasive urothelial carcinoma ineligible for cisplatin-based chemotherapy.
Authors: Vadim S Koshkin, Tanya Jindal, Jun Yan He, Li Zhang, Celine N. Galang, Divya Natesan, Vipul Kumar, Xiaolin Zhu, Jonathan Chou, Rahul Raj Aggarwal, Eric J. Small, Maxwell Meng, Sima P. Porten, David Yoonsuk Oh, Lawrence Fong, Terence W. Friedlander
Journal: Journal of Clinical Oncology (2024)

602 Background: There are no current standard of care options for patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy (cisplatin). This trial investigated the safety and efficacy of escalating doses of neoadjuvant atezolizumab (ATZ) prior to radical cystectomy (RC) (NCT02451423). Methods: This single-arm, single institution, phase II trial investigated treatment with 1 (n=6), 2 (n=6) or 3 (n=11) cycles of ATZ (1200 mg IV every 3 weeks) in pts with MIBC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0), cisplatin-ineligibility, and eligibility for RC. High-risk pts (&gt;pT2 or LN+ at RC) could receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0/Ta/TisN0). Secondary endpoints included rate of pathologic downstaging (≤T1N0), 2-year recurrence-free survival (RFS), overall survival (OS), and biomarker assessments of pre and post-treatment biopsies. Pts had RC between 7/2016 and 6/2021. The censor date for survival outcomes was 9/10/2023, representing the final efficacy analysis. Results: A total of 23 pts received ATZ; 1 pt was excluded from efficacy analyses due to lack of confirmed MIBC (≥T2). Among 22 included pts, median age was 70, 74% were men, 83% Caucasian; reasons for cisplatin-ineligibility were renal impairment (37%), hearing loss (27%) or neuropathy (9%); remainder declined cisplatin (27%). At enrollment, cT2/T3/T4 rates were 77%, 14%, and 9%, while 9% were cLN+. All pts completed intended treatment and had RC in the defined timeframe (&gt;3 weeks from last and &lt;12 weeks from first treatment). pCR at RC was 14% (3/22), occurring in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 23% (5/22), occurring at all three dose levels. Adjuvant ATZ was given to 8 pts. Another 4 pts received off-study adjuvant therapy with cisplatin (3) or nivolumab (1). After median follow-up of 51.4 months from RC, mRFS and mOS were Not Reached. Two-year RFS and OS were 77% and 90%. In 13 pts with available paired pre and post treatment samples, there was significant increase in T-cell % following ATZ (Wilcoxon signed rank test, p&lt;0.05), driven by increase in % and density of CD8+ T-cells (p&lt;0.05). All T-cell populations were significantly more abundant in tumor than in adjacent normal tissue post-treatment but not pre-treatment (CD3 + ,CD3 + CD8 + , CD3 + CD4 + , p&lt;0.001 for all; CD4 + FOXP3 + , p=0.01). Conclusions: Neoadjuvant ATZ results in durable long-term survival rates in cisplatin-ineligible pts with MIBC. These data are comparable to previously reported trials with immunotherapy based regimens, despite a lower pCR rate. Changes suggestive of T-cell migration into the tumor microenvironment were observed following ATZ treatment. Clinical trial information: NCT02451423 .