Preoperative APL-1202 Plus Tislelizumab Meets pCR Criteria, Moves to Next Stage of Trial in MIBC

The Safety Monitoring Committee determined that prespecified criteria for pathologic complete response (pCR) were met with the use of the PD-1 inhibitor tislelizumab (BGB-A317) alone or in combination with APL-1202 as neoadjuvant therapy in patients with muscle invasive bladder cancer (MIBC), according to positive topline findings from the interim analysis of the phase 1/2 ANTICIPATE trial (NCT04813107).¹

Since both groups met the criteria for the first-stage efficacy set by the study’s Simon’s two-stage optimal design, both arms will progress to the second stage of the trial. Detailed results from the trial will be presented at an upcoming medical meeting.

“This [is a] promising outcome demonstrating the potential of APL-1202 in combination with tislelizumab as neoadjuvant therapy for MIBC,” Linda Wu, PhD, chief development officer of Asieris, stated in a news release. “We look forward to the potential of this combination therapy for [patients with] MIBC.”

APL-1202 is a reversible, oral METAP2 inhibitor with antiangiogenic and antitumor activity that may augment the rate of pCR achieved with single-agent PD-1 antibodies in patients with MIBC.²

The phase 2 trial is evaluating the safety and efficacy of the combination compared with tislelizumab alone in the neoadjuvant MIBC setting. Eligible patients include those with newly diagnosed MIBC for whom radical cystectomy is planned, and who are cisplatin ineligible or refuse to receive cisplatin-based neoadjuvant therapy.¹

The primary end point of the trial is pCR, defined as the absence of residual tumor lesions in the bladder and lymph node specimens (pT0N0) by histopathological assessment after surgery. Key secondary end points include radiological response, pharmacokinetic parameters, and tumor mutational burden and PD-L1 assessment pre– and post–treatment blood and tumor samples.³

Both arms were evaluated with Simon’s two-stage optimal design, enabling advancement to stage II if at least 5 of the first 18 evaluable patients in the combination arm and at least 3 of the first 14 evaluable patients in the monotherapy arm achieved pCR. Per the trial protocol, interim efficacy analyses would be conducted when both groups completed the first stage.

In December 2021, the first patient was enrolled in the phase 1 portion of the study following approval from the FDA and China National Medical Products Administration Center for Drug Evaluation for its Investigational New Drug application in June and September 2021, respectively.¹

A standard 3+3 dose-escalation design was used, in which patients received 200 mg of intravenous tislelizumab on day 1 of each cycle, plus oral APL-1202 3 times daily, with the dose up titrated from 375 mg to 750 mg and 1125 mg. Intra-patient dose escalation was not permitted.²

Results were presented on the first 9 patients enrolled (APL-1202 dose: 375 mg, n = 3; 750 mg, n = 3; 1125 mg, n = 3) in phase 1 at the 2023 ASCO Annual Meeting. All patients had predominant urothelial cancer with cT2 (n = 6/9) and cT3 (n = 3/9). Only 1 patient tested positive for PD-L1 expression with the VENTANA PD-L1 (SP263) Assay.

No dose-limiting toxicities (DLTs) occurred at any of the 3 dose levels. Treatment-related adverse effects (TRAEs) occurred in 6 patients, most of which were grade 1; 1 case of grade 2 T-wave abnormality on ECG and 1 case of grade 3 liver dysfunction was reported. No grade 4 or 5 TRAEs occurred, and the patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and proceeded to radical cystectomy.

Preliminary efficacy data indicated that 62.5% (n = 5/8) and 12.5% (n = 1/8) of patients experienced pathologic downstaging (< pT2 and pT0, respectively), though 1 patient declined subsequent radical cystectomy. 

In November 2022, the trial proceeded to the second phase after showing no DLTs in dose escalation and reaching a recommended phase 2 dose of 1125 mg once daily.¹

APL-1202 is also being studied in two pivotal, phase 2/3 trials––in combination with intravesical chemotherapy for intermediate- and high-risk patients with non–muscle invasive bladder cancer (NMIBC) following relapse on chemotherapy, and as monotherapy in treatment-naïve patients with intermediate-risk NMIBC.

References

1. Asieris announces positive interim analysis results in phase II clinical trial of oral APL-1202 in combination with tislelizumab, a PD-1 inhibitor, as neoadjuvant therapy for muscle invasive bladder cancer. News release. Asieris Pharmaceuticals. September 13, 2023. Accessed September 13, 2023. https://asieris.com/asieris-announces-positive-interim-analysis-results-in-phase-ii-clinical-trial-of-oral-apl-1202-in-combination-with-tislelizumab-a-pd-1-inhibitor-as-neoadjuvant-therapy-for-muscl/
2. Galsky MD, Sfakianos JP, Ye DW, et al. ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC). J Clin Oncol. 2023;41(suppl 16):e16607. doi:10.1200/JCO.2023.41.16_suppl.e16607
3. A study to evaluate the safety and efficacy of oral APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy in patients with muscle invasive bladder cancer (ANTICIPATE). ClinicalTrials.gov. Updated February 22, 2022. Accessed September 13, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04813107