HPN328 Shows Clinical Activity and Tolerability in Neuroendocrine Prostate Cancer

Himisha Beltran, MD

Treatment with the DLL3-targeting T-cell engager, HPN328, was well tolerated and elicited responses in patients with neuroendocrine prostate cancer and other neuroendocrine neoplasms, according to data from a phase 1/2 study (NCT04471727) presented at the 2024 Genitourinary Cancers Symposium.

When HPN328 was administered at a priming dose of 2 mg, two dose-limiting toxicities (DLTs) were observed. The priming dose was then de-escalated to 1 mg. At the target doses, no DLTs were reported, and the maximum tolerated dose (MTD) was not yet reached. Adverse effects (AEs) were determined to be manageable, with cytokine release syndrome (CRS) occurring with the first dose of the agent. Most of the CRS events were grade 1 or 2 in severity.

In all response-evaluable patients treated with the 1-mg priming dose of the agent (n = 50), the overall response rate (ORR) was 56%. The confirmed response (CR) rate was 31% (n = 15/48), and the disease control rate (DCR) was 68%. In the genitourinary (GU) neuroendocrine cancer subgroup (n = 12), the ORR was 58%, the CR rate was 25%, and the DCR was 83%.

“HPN328 is a novel DLL3-targeted T-cell engager that is well tolerated and demonstrates promising clinical activity across neuroendocrine carcinomas, including GU neuroendocrine cancers,” Himisha Beltran, MD, said in a presentation of the early-phase data. “…Monotherapy dose optimizing [is] ongoing; maturing data in 12- and 24-mg cohorts will inform the selection of the recommended phase 2 dose [RP2D].”

Beltran is an associate professor of medicine in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology, as well as the director of Translational Research within Medical Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

DLL3 is an inhibitory Notch pathway ligand; it is present in many poorly differentiated neuroendocrine carcinomas, such as de novo neuroendocrine prostate cancer or prostate adenocarcinoma, Beltran shared in the presentation. Because DLL3 is absent on normal, healthy tissues, Beltran noted that this represents an appealing target for clinical investigation.

To this end, HPN328, which redirects CD3-positive T cells to DLL3-positive cancer cells to elicit an immune response, is under evaluation. In preclinical models of DLL3-positive neuroendocrine prostate cancer, HPN328 co-injected with human T cells led to tumor reduction and prolonged survival.

The phase 1/2 study, which utilized a 3+3 design, included patients with neuroendocrine prostate cancer that was relapsed or refractory to standard-of-care (SOC) treatment. The trial also enrolled patients with other DLL3-positive high-grade neuroendocrine neoplasms that were relapsed/refractory to SOC or for whom no SOC was available. Those with small cell lung cancer (SCLC) that was relapsed or refractory following platinum-based chemotherapy were also permitted.

In the dose-escalation portion of the trial, HPN328 was administered either weekly or biweekly, and dose optimization cohorts with a 1-mg priming dose included 6 mg once weekly, 12 mg once weekly and every 2 weeks, and 24 mg once a week and every 2 weeks.

The key objectives were to assess the safety and tolerability of HPN328, determine a RP2D or MTD, characterize the pharmacokinetic and pharmacodynamic profile, and evaluate the preliminary antitumor activity.

Of the 85 patients who received treatment, 24.7% had a GU neuroendocrine cancer, which included 17.6% with neuroendocrine prostate cancer; 62.4% had SCLC; and 12.9% had other neuroendocrine cancers.

In the overall population, the median age was 64 years (range, 41-81) and 58.8% of patients were female. Most patients were White (89.4%), and slightly more than half had an ECOG performance status of 1 (56.5%). The median number of prior therapies received was 3 (range, 1-7) and 78.8% of patients had previously received PD-(L)1 inhibitors. Moreover, 41.2% of patients had metastases in the brain and 51.8% had metastases in the liver.

In the subset of patients with GU neuroendocrine cancer, the median age was 70 years (range, 44-81). Most patients were male (85.7%) and White (85.7%). More than half of patients had an ECOG performance status of 0 (57.1%). The median number of prior therapies received was also 3 (range, 1-7) and 66.7% of patients had prior exposure to PD-(L)1 inhibitors. In this group, 9.5% and 61.9% of patients had metastases in the brain and liver, respectively.

Within the GU neuroendocrine carcinoma group, 1 patient was still undergoing treatment at 55 weeks, according to Beltran. Confirmed responses were observed at different dose levels, and some patients continued treatment beyond radiographic progression due to clinical benefit.

In the presentation, Beltran also shared a patient case. “A patient developed neuroendocrine prostate cancer after treatment with androgen deprivation therapy and abiraterone [acetate (Zytiga),] when he developed new liver metastases with a prostate-specific antigen of 0.08 ng/mL,” she said. “After progression on 2 lines of platinum chemotherapy and platinum immuno-oncology, he enrolled on the study. DLL3 was expressed in 50% of his tumor cells. He had a partial response after cycle 3 but a mixed response after cycle 6, with continued shrinkage of his target liver lesions but increased smaller lesions. Overall, based on clinical improvement and good tolerance, he remained on treatment beyond progression for 11 months.” She added that the differences in response across metastatic lesions suggest some degree of tumor heterogeneity.

Regarding safety, all patients experienced treatment-emergent AEs (TEAEs); in 51.8% of patients, these effects were grade 3 or higher. Treatment-related AEs (TRAEs) occurred in 92.9% of patients with 24.7% of patients experiencing effects that were grade 3 or higher.

The most common TRAEs experienced by 10% or more of patients included CRS (all grade, 58.8%; grade ≥3, 3.5%), dysgeusia (35.3%; 0%), fatigue (32.9%; 1.2%), diarrhea (18.8%; 2.4%), nausea (17.6%; 0%), vomiting (14.1%; 0%), decreased appetite (12.9%; 0%), and neutropenia (9.4%; 4.7%).

AEs of special interest included CRS (grade 1, 30.6%; grade 2, 24.7%; grade 3, 3.5%) and immune effector cell–associated neurotoxicity syndrome (7.1%; 2.4%; 0%). Sixty-seven percent of CRS events occurred after the first dose of the agent. Grade 2 and higher CRS was uncommon following the second or subsequent doses of the agent.

Reference

Beltran H, Dowlati A, Jain P, et al. Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager, in patients (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN). J Clin Oncol. 2024;42(4):121. doi:10.1200/JCO.2024.42.4_suppl.121