A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer, (HCRN GU18-343) ABATE study.

800 Background: Atezolizumab (A) has demonstrated single agent activity as neoadjuvant therapy (NAT) for muscle invasive urothelial carcinoma (MIUC) (ABACUS trial). Cabozantinib (C) has a unique immunomodulatory profile that may foster anti-tumor immunity and has demonstrated clinical activity as monotherapy and in combination with A. We hypothesized that the combination of C and A as NAT for MIUC would improve pathologic response rate (pRR) compared to single-agent A. Methods: This open-label, single arm, multi-center study investigated the efficacy and safety of C 40 mg PO daily with A 1200mg every 3 weeks for 9 weeks as NAT for cT2-T4aN0/xM0 MIUC. Eligibility required patients (pts) to be cisplatin-ineligible or decline cisplatin, with UC as the predominant histology (≥ 50%). Primary endpoint was pRR defined as no residual muscle-invasive cancer in the surgical specimen (< ypT2); patients with progression prior to cystectomy were counted as non-responders. pRR was to be compared to the 39% response rate with the single agent A using a Bayesian evaluation with a Beta (0.5, 0.5) prior. Secondary endpoints were safety and toxicity, pathologic complete response rate (pCR, ypT0N0M0) and event-free survival (EFS). Exploratory end points included patient-reported outcomes and outcome associations with biomarkers. Results: From Feb 2021 to July 2024, 46 pts enrolled at 5 sites. 2 pts were deemed ineligible, and 6 pts did not proceed with cystectomy for reasons other than progression (4 pts opted for bladder preservation, 1 pt died from causes unrelated to tx and 1 pt still undergoing tx). Median follow up is 14 mo. At study entry median age was 71 yrs, 21% were female, 98% Caucasian and 71% were cisplatin ineligible, with T2, T3 and T4 disease in 73%, 18% and 9% respectively. Histology included pure urothelial cancer (56%), squamous (18%), glandular (3%), micropapillary (18%) and plasmacytoid (5%) differentiation. Among 35 pts who underwent cystectomy, 32 (91%) / 3 (9%) completed 3 and 2 doses of A and 15 (43%) / 32 (91%) completed 9 and at least 6 weeks of C. Adverse events are being analyzed. The estimated pRR was 29.5% (95% CrI 16.5% - 44.5%) and the pCR was 20.8% (95% CrI 9.4% - 35.3%). The pCR was lower in pts with variant histology compared to pure UC (13 vs 25%; p=0.39). 2-year EFS was 68.4% (95% CI, 47.7-82.3%). Conclusions: C+A has modest activity as NAT in MIUC and did not meet the pre-specified primary endpoint for pRR. Biomarkers studies are planned. Clinical trial information: NCT04289779 .