(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16th and 18th was host to a Prostate Cancer Rapid Abstract Session. Dr. Rahul Aggarwal presented the results of a phase 2a trial evaluating the oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype.
De novo and treatment emergent SCNC are associated with adverse survival outcomes. BXCL701 (talabostat) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP 8/9 and DPP4, triggering inflammasomes to alert and prime immune cells, leading to induction of IL-18 and IL-1 β, bridging innate and adaptive immune cascades.1
A phase 1b safety lead-in tested two total daily doses of BXCL701 (0.4 mg and 0.6 mg) [SITC 2020]. On-target adverse events (AE) consistent with cytokine activation were seen at the highest daily dose of 0.6 mg. Improved tolerability with daily dose splitting and step-up dosing led to improved tolerability with no reported dose-limiting toxicities and lower rates of AEs of interest with hypotension and peripheral edema.
This single arm, phase 2a trial evaluated the combination of pembrolizumab and BXCL701 in patients with:
- Histologically confirmed de novo SCNC or treatment emergent SCNC
- ≥1 prior line of systemic therapy
- Progression as defined by PCWG-3 criteria
- Serum testosterone <50 ng/dL during screening, except for patients with de novo SCNC
- ECOG performance status of 0-2
Key exclusion criteria included:
- >2 cytotoxic chemotherapy regimens for mCRPC
- Prior treatment with anti-PD-1, anti-PD-L1, anti-programmed death-ligand 2 (PD-L2) agent or with agent directed to another co-inhibitory T-cell receptor
Patients received pembrolizumab 200 mg IV q3 weeks on day 1 + BXCL701 0.3 mg PO BID days 1-4 of a 21-day cycle. The step-up dosing in Cycle 1 for BXCL701 was as follows: 0.2 mg PO BID for days 1-7, then BXCL701 0.3 mg PO BID for days 8-14. The primary objective was composite response rate, either objective response by RECIST 1.1 criteria, and/or circulating tumor cell (CTC) conversion from ≥5/7.5 mL to <5/7.5 mL, and/or ≥50% decline from baseline. Secondary objectives included duration of response, safety, and changes in circulating cytokines.
This study included 34 patients. Median age was 67.5 years, 62% had visceral metastases (including 32% liver), and the median number of lines of prior systemic therapy was 3 (range: 1 – 8). Prior systemic therapies included:
- Androgen signaling inhibitors: 25 (89%)
- Platinum-based chemotherapy: 19 (68%)
- Taxane chemotherapy: 17 (50%)
The median duration of cohort follow-up was 30.8 weeks (range: 1.9 – 86.9 weeks). The median duration of treatment was 9 weeks (range: 0.7 to 73 weeks). As of December 19, 2022, there were 28 evaluable patients:
Of 25 patients with RECIST evaluable disease, 5 (20%) had an objective response rate (4 confirmed partial, 1 unconfirmed partial response). The median duration of response was 6+ months (range: 1.8 – 9.8 months). Stable disease was noted in 7 (28%) with 13 (52%) having progressive disease.
Amongst patients with a confirmed response (5/25), all were microsatellite stable (MSS) and/or had low tumor mutational burdens (TMB). 4/5 responders had received prior platinum chemotherapy.
With regards to the safety profile, grade 3 or worse AEs were observed in 16 patients (47%), with only one grade 4-5 AE. AEs leading to treatment discontinuation were observed in 6 patients (18%). Grade 3 or worse immune-related AEs were observed in 1 patient (grade 3 colitis).
Dr. Aggarwal went on to present a case study of a patient of his with treatment emergent SCNC and liver metastases who had previously received an LHRH agonist, abiraterone + prednisone, and cisplatin + etoposide. The patient’s tumor was microsatellite stable and had low TMB.
As demonstrated in the CT image below, there was a 58% reduction in the size of the tumor lesion following three cycles of treatment. The patient had evidence of significantly increased cytokine expression (IFN-gamma, TNFalpha, IL-18) in the circulation.
Dr. Aggarwal concluded his presentation as follows:
- BXCL701 + pembrolizumab demonstrated encouraging activity with durable responses observed in a subset of patients with platinum pre-treated, small cell neuroendocrine prostate cancer
- All responders were MSS and/or TMB low, with low probability of response to pembrolizumab monotherapy
- BXCL701 + pembrolizumab demonstrated manageable safety profile
- Split and step-up dosing to mitigate cytokine release
- No evidence of potentiation of immune-related AEs
- Evolution of DPP9 overexpression as a predictive biomarker is ongoing
- A phase 2b randomized study in SCNC will commence soon
Presented by: Rahul Raj Aggarwal, MD, Associate Director for Clinical Sciences, UCSF Helen Diller Family Comprehensive Cancer Center; Associate Professor of Hematology/Oncology, University of California in San Francisco, San Francisco, CA
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
References:
- Tagawa ST, et al. BXCL701: First-in-class oral activator of systemic innate immunity combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small-cell neuroendocrine carcinoma (SCNC) phenotype—Phase 2a interim results. J Clin Oncol 2022;40(6): Suppl
BXCL701 Combined with Pembrolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer of Small Cell Neuroendocrine Phenotype - Rahul Aggarwal