BXCL701 Plus Pembrolizumab Elicits Durable Responses in Small Cell Neuroendocrine mCRPC

The combination of BXCL701 and pembrolizumab (Keytruda) produced durable responses in patients with platinum-resistant small cell neuroendocrine carcinoma (SCNC) metastatic castration-resistant prostate cancer (mCRPC), according to data from a phase 2a trial (NCT03910660) presented at the 2023 Genitourinary Cancers Symposium.

Among 28 evaluable patients, the composite response rate, including unconfirmed partial responses (PRs), was 25% (95% CI, 8.3%-41%). The response rate by RECIST v1.1 criteria was 20% (95% CI, 6.8%-40.7%) among 25 evaluable patients; this included 4 confirmed PRs and 1 unconfirmed PR. Twenty-eight percent of patients had stable disease, and 52% had progressive disease. The disease control rate was 48%.

The composite median duration of response (DOR) with the regimen was 6+ months (range, 1.3-17.4); the median DOR by RECIST v1.1 criteria was also 6+ months (range, 1.8-9.8).

Moreover, among the 4 patients evaluable for circulating tumor cells (CTCs), the CTC response rate was 25% (95% CI, 0.6%-80.6%). In the 27 patients evaluable for prostate-specific antigen (PSA), 11% (95% CI, 2.4%-29%) had a PSA reduction of at least 50% from baseline.

“Of [the] 5 responders, 4 had [received] prior platinum-based chemotherapy. The striking [aspect] was the median DOR, which was more than 6 months,” lead study author Rahul Aggarwal, MD, said in an interview with OncLive®. “The overall composite response rate was 25%, which in this patient population, given how heavily pretreated they are and the aggressiveness of the type of cancer, was encouraging and has spurred us to the next phase of the study.”

Aggarwal is an associate director for Clinical Sciences at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, and an associate professor of hematology/oncology at UCSF in San Francisco, California.

BXCL701 is designed to modulate the tumor microenvironment by activating innate immunity, followed by adaptive immunity, ultimately resulting in cancer cell death. Previously, BXCL701 was evaluated at 0.4 mg and 0.6 mg in the safety lead-in portion of the phase 1b trial. Data presented at the 2020 SITC Annual Meeting showed that splitting the daily dose and step-up dosing improved the tolerability of the agent. No dose-limiting toxicities were reported. Moreover, there were lower rates of hypotension and peripheral edema, which were two adverse effects (AEs) of interest.

The trial enrolled those with histologically confirmed de novo or treatment-emergent SCNC. To be eligible for enrollment, patients needed to have received 1 or more prior lines of systemic therapy, experienced disease progression per Prostate Cancer Clinical Trials Working Group 3 criteria, and an ECOG performance status of 0 to 2. For those with treatment-emergent SCNC, a serum testosterone level of less than 50 ng/dL during screening was required.

Patients were excluded if they had received more than 2 cytotoxic chemotherapy regimens for mCRPC or had prior treatment with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent. Prior treatment with another agent directed to another co-inhibitory T-cell receptor was also prohibited.

“This study was focused on the highest-risk patients with [SCNC mCRPC, as] we know that these patients have limited survival outcomes and a short DOR [with] chemotherapy,” Aggarwal explained. “We designed the study to a test a novel immunotherapy combination, largely in patients who have received prior chemotherapy, to get a sense of the response rate, the durability of response, and safety profile in this patient population.”

Upon enrollment, participants were given 200 mg of intravenous pembrolizumab once every 3 weeks plus 0.3 mg of oral BXCL701 twice daily on days 1 to 14 of each 21-day cycle. Step-up dosing in cycle 1 consisted of BXCL701 given at 0.2 mg twice daily on days 1 to 7, followed by 0.3 mg twice daily on days 8 to 14.

The primary objective of the trial was to evaluate composite response rate, either in the form of objective responses per RECIST v1.1 criteria and/or CTC conversion from at least 5/7.5 mL to less than 5/7.5 mL, and/or at least a 50% decline in PSA from baseline.

Secondary objectives included DOR, progression-free survival, changes in circulating cytokines, and correlation of outcome with baseline tumor characteristics.

In the phase 2a cohort (n = 34), the median age was 67.5 years (range, 54-80). Additionally, 47% of patients had an ECOG performance status of 0, 47% had a status of 1, and 6% had a status of 2. Sixty-two percent of patients had a visceral metastasis at any site, and 32% had visceral metastases of the liver. The median number of prior lines of systemic therapy received was 3 (range, 1-8). Eighty-nine percent of patients previously received androgen-signaling inhibitor(s), 68% had platinum-based chemotherapy, and 50% had prior taxane chemotherapy.

The median duration of follow-up was 30.8 weeks (range, 1.9-86.9), and the median duration of treatment was 9 weeks (range, 0.7-63). The data cutoff date for the analysis was December 19, 2022.

Regarding safety, 97% of patients experienced any-grade treatment-emergent AEs (TEAEs). Eighty-five percent of the TEAEs were attributed to BXCL701, and 68% of the events were attributed to pembrolizumab. Forty-seven percent of patients experienced grade 3 TEAEs, but no grade 4 events were reported. One patient experienced a grade 5 TEAE in the form of tumor lysis syndrome.

The most common any-grade treatment-related AEs consisted of fatigue (32%), hypotension (21%), pruritus (21%), dizziness (18%), and nausea (12%). Any-grade immune-related AEs occurred in 41% of patients, including 7% who experienced grade 3 or higher events.

Eighteen percent of patients discontinued treatment due to AEs; 18% of cases were attributed to BXCL701 and 15% were attributed to pembrolizumab.

“This is a high unmet medical need in SCNC [mCRPC]. We don’t have a standard of care beyond platinum-based chemotherapy. In the next phase, phase 2B, if we see an impressive response rate, [the intent is] to go down a regulatory path, hopefully for approval. It depends on the response rate and the durability of those responses,” Aggarwal concluded.

Reference

Aggarwal RR, Zhang J, Monk P, et al. First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype: Phase 2a final results. J Clin Oncol. 2023;41(suppl 6):176. doi:10.1200/JCO.2023.41.6_suppl.176.