Updated 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 Small Cell Lung Cancer (SCLC) and Other Neuroendocrine Cancers (NEC).

Himisha Beltran,Melissa Lynne Johnson,Prantesh Jain,Erin L. Schenk,Rachel E. Sanborn,Jonathan Robert Thompson,Afshin Dowlati,Hirva Mamdani,Rahul Raj Aggarwal,Banmeet S. Anand, Ann W. Gramza,Noura J. Choudhury

JOURNAL OF CLINICAL ONCOLOGY（2024）

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Abstract

8090 Background: Delta-like canonical Notch ligand 3 (DLL3) is highly expressed on the cell surface of neuroendocrine carcinomas, which have few approved treatment options in the refractory, metastatic setting. HPN328 is DLL3-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Methods: Pts with relapsed/refractory, metastatic SCLC, neuroendocrine prostate cancer (NEPC) and other NEC associated with DLL3 expression are eligible. Primary objectives are safety, maximum tolerated dose (MTD) and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Overall response rate (ORR) is determined using modified RECIST v1.1 to include extracranial response assessment for pts treated with radiotherapy for brain metastases while on treatment. HPN328 is administered IV QW or Q2W with priming dose preceding target dose in higher dose cohorts. Results: As of January 5, 2024, 86 pts received HPN328 doses of 0.015-24 mg across 14 cohorts (SCLC [n = 54;63%]; other NEC [n = 32;37%]). The median (range) number of prior regimens was 3 (1-7); 83% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 24 of 46 (52%) pts in the dose optimization cohorts (1 mg priming dose with 12 or 24 mg target doses QW or Q2W). Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). No G3-4 CRS was seen at target doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9% of pts, all G1-2. The maximum tolerated priming dose was 1 mg; dose escalation of target dose continued up to 24 mg QW without reaching a maximum tolerated target dose. Among efficacy evaluable pts treated in dose optimization cohorts, the confirmed ORR in SCLC was 50% (12/24), with one complete response (CR). In NEC (other than NEPC) the confirmed ORR was 44% (4/9), with one CR. Four of eleven pts with NEPC had unconfirmed PRs in 1 mg priming dose cohorts, with 5 NEPC pts remaining on treatment > 20 weeks. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active in SCLC, NEC, and NEPC. Current dose optimization cohorts have completed enrollment and data continue to mature; selection of a recommended phase 2 dose will be made based upon complete mature data. Updated safety and efficacy results will be presented. Clinical trial information: NCT04471727 .

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【要点】：研究结果显示，针对DLL3表达的神经内分泌癌，包括小细胞肺癌（SCLC）和其他神经内分泌癌（NEC），HPN328这一三特异性、半衰期延长DLL3靶向T细胞激动剂具有良好的耐受性和临床活性。

【方法】：研究采用开放标签、剂量递增的1/2期临床试验设计，以评估HPN328在复发/难治性、转移性SCLC、神经内分泌前列腺癌（NEPC）和其他与DLL3表达相关的NEC患者中的安全性、最大耐受剂量（MTD）和药代动力学（PK）。

【实验】：截至2024年1月5日，共有86名患者接受了0.015-24 mg剂量的HPN328，分布在14个队列中（SCLC 54例，其他NEC 32例）。结果显示，HPN328的确认客观缓解率（ORR）在SCLC为50%（12/24），其中1例完全缓解（CR）；在非NEPC的NEC为44%（4/9），其中1例CR。实验使用的数据集为临床试验NCT04471727中的患者数据。