DLL3-Targeting T-Cell Engager HPN328 Shows Clinical Activity in SCLC and NEN

Interim results from a phase 1/2 study that evaluated the clinical safety and efficacy of HPN328, a trispecific, delta-like canonical Notch ligand 3 (DLL3)–targeting T-cell engager, in patients with small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NENs) was presented at the 2023 ESMO annual meeting.

The study included patients with relapsed/refractory, metastatic SCLC and other NENs associated with DLL3 expression. HPN328 was administered IV once weekly with a priming dose preceding the target dose in higher dose cohorts. HPN328 was administered intravenously once weekly at doses up to 24 mg; higher-dose cohorts received a priming dose. The primary objectives are safety, determination of the maximum tolerated dose/recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Date of data cutoff was September 12, 2023.

A total of 71 patients received HPN328. Of these, 64.8% had SCLC, 15.5% had neuroendocrine prostate cancer, and 19.7% had NEN. The median number of prior regimens was 2.5; 78.9% previously received a PD-1/PD-L1 inhibitor.

The most common any-grade treatment-related adverse events that occurred in >10% of patients included cytokine release syndrome (CRS; 59.2%), fatigue (33.8%), dysgeusia (33.8%), nausea (16.9%), pyrexia (9.9%), and vomiting (15.5%). Of the 42 CRS events reported, the majority were grade 1/2 (grade 1: 21; grade 2: 19); there were 2 grade 3 CRS events that were deemed a dose-limiting toxicity in 2 patients at a priming dose of 2 mg. Dose escalation continues with a reduced priming dose to 1 mg.

At the data cutoff date, there were 49 patients treated at the minimal effective dose or higher (≥1.215 mg) with ≥1 postbaseline assessment. The overall response rate (ORR) was 45%, confirmed response rate (CRR) was 31%, and the disease control rate (DCR) was 63%. There were 35 patients who had a response in the 1-mg priming dose optimization cohort with ≥1 postbaseline assessment. The ORR in these patients was 54%, CRR was 35%, and DCR was 69%. In patients with SCLC, the ORR was 48%, CRR 32%, and DCR 61%.

HPN328 exhibited linear PK with dose-proportional increases in exposure and a median half-life of 71 hours. Cytokine spikes induced by priming doses were higher than target doses, and T-cell activation was observed after both priming and target doses.

Based on these data, the authors concluded that HPN328 was well tolerated and clinically active in patients with relapsed/refractory, metastatic SCLC and other NENs. Combination dose-escalation cohorts with atezolizumab were recently initiated for patients with SCLC, and monotherapy dose optimization is ongoing with maturing data for 12-mg and 24-mg cohorts that will inform the RP2D.

Source:

Choudhury N. Interim results from a phase I/II study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T cell engager in patients (patients) with small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NEN). Abstract presented at: ESMO Annual Meeting, October 20-24, 2023; Madrid, Spain. Abstract 698P.