Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC): Interim analysis of ANTICIPATE phase II trial.

632 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients (pts) with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: This is a prospective multicenter randomized phase II trial for pts with newly diagnosed MIBC for whom radical cystectomy (RC) is planned, and who are cisplatin ineligible or refuse cisplatin based neoadjuvant chemotherapy. Eligible pts are randomly assigned to group 1 (APL-1202 plus tislelizumab) or group 2 (tislelizumab), with randomization stratified by PD-L1 expression. Neoadjuvant treatment is administered every 3 weeks for 3 cycles. The primary endpoint is pathological complete response (pCR, pT0N0) rate. A Simon’s 2-stage design is employed with planned interim analyses after 18 evaluable pts in group 1 and 14 evaluable pts in group 2. Results: 42 pts have enrolled and results for 32 evaluable pts for stage 1 of the 2-stage design are reported. Radical cystectomy was completed in 18/18 pts in group 1 and 13/14 pts in group 2; 1 patient who could not undergo surgery due to disease progression and 10 pts refused RC. The 32 evaluable pts consisted of 11/18 (61%) and 10/14 (72%) cT2, and 6/18 (33%) and 2/14 (14%) cT3, and 1/18 (6%) and 2/14 (14%) cT4a in group 1 and 2, respectively. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay; 8/18 (44%) pts in group 1 and 7/14 (50%) in group 2 was positive. The pathological response was shown in the table. Treatment emergent adverse events (TEAEs) were reported in 17 (94.4%) pts in group 1 and 11 (78.6%) in group 2; most common (≥ 10%) TEAE of CTCAE grade ≥ 3 were anaemia (4, 22.2%), lymphocyte count decreased (3, 16.7%) in group 1 and intestinal obstruction (3, 21.4%) in group 2. AEs led to drug discontinuation in 3 (16.7%) pts in group 1 (acute kidney injury, anaemia, hepatic function abnormal) and 2 (14.3%) in group 2 (immune hyperthyroidism, COVID-19), and no treatment-related AEs led to death. Conclusions: The pCR rates in both group 1 (APL-1202 plus tislelizumab) and group 2 (tislelizumab) exceeded thresholds to trigger expansion to stage 2 of the 2-stage design. The activity and safety of neoadjuvant APL-1202 plus tislelizumab support further evaluation of this novel regimen (NCT04813107). Clinical trial information: NCT04813107 . [Table: see text]