698P - 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 (pts) with small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NEN)

Background

HPN328 is a delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE). 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 and other NEN associated with DLL3 expression are eligible. Primary objectives are safety, determination of the maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. HPN328 is administered IV once weekly with a priming dose preceding the target dose in higher dose cohorts. Adverse events (AEs) are graded (G) by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS).

Results

As of 18Apr23, 44 pts received HPN328 doses of 0.015-24 mg across 11 cohorts (SCLC [n=29;66%]; NE prostate cancer [NEPC, n=6;14%]; other NEN [n=9;20%]). Median number of prior regimens was 2 (1-5); 59% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 20 pts. Treatment-related AEs in >10% of pts included CRS (46%), fatigue (23%), dysgeusia (21%), nausea (18%), pyrexia and vomiting (16% each), and anemia (11%). The 27 CRS events were G1 (n=14); G2 (n=11); G3 (n=2). G3 CRS was a dose-limiting toxicity (DLT) in 2 pts at a priming dose of 2 mg; dose escalation continues with a reduced priming dose to 1 mg. Three pts (2 SCLC, 1 NEN) have had confirmed partial response and an additional pt with SCLC had an initial report of complete response following the data cut-off date. Three pts remained on therapy for >1 year. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T_1/2 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. MTD determination and dose escalation are ongoing. Future planned cohorts include every other week dosing and HPN328 + atezolizumab. Updated safety and efficacy results including pts recently enrolled in backfill cohorts will be presented.

Clinical trial identification

NCT04471727.

Editorial acknowledgement

Medical writing support was provided by John Frye, PharmD (Frye Consulting, LLC, San Francisco, CA, USA).

Legal entity responsible for the study

Harpoon Therapeutics, Inc.

Funding

Harpoon Therapeutics, Inc.

Disclosure

N. Choudhury: Financial Interests, Personal, Advisory Board, consulting: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Invited Speaker: OncLive; Financial Interests, Personal, Royalties, Pocket Oncology 3rd Edition: Wolters Kluwer; Financial Interests, Institutional, Local PI: Amgen, Merck, Monte Rosa Therapeutics, AbbVie, Harpoon Therapeutics. P. Jain: Financial Interests, Institutional, Other, Institutional Principal investigator: Harpoon Therapeutics; Financial Interests, Institutional, Other, Principal Investigator: Debiopharm; Financial Interests, Institutional, Other, Site Principal Investigator: Iovance Biotherapeutics, AADi Bioscience, SOPHiA Genetics, Sanofi; Financial Interests, Institutional, Invited Speaker: Harpoon Therapeutics, Debiopharm, Iovance Biotherapeutics, AADi Bioscience, SOPHiA Genetics, Sanofi; Non-Financial Interests, Advisory Role: G1 Therapeutics; Non-Financial Interests, Other, Invited speaker: American Lung Association. A. Dowlati: Financial Interests, Personal, Advisory Board: Ipsen, BMS, AstraZeneca, Seattle Genetics, Puma, Prelude Therapeutics. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics; Financial Interests, Institutional, Advisory Role: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, Seagen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics. H. Mamdani: Financial Interests, Personal, Advisory Board, June 2020 : Zentalis; Financial Interests, Personal, Advisory Board, Immediate family member: MorphoSys, Seagen. R.E. Sanborn: Financial Interests, Personal, Advisory Board: AstraZeneca, EMD Serono, Daiichi Sankyo, Lilly Oncology, Janssen Oncology, Macrogenics, Sanofi Aventis, Regeneron, Mirati Therapeutics, GSK, G1 Therapeutics; Financial Interests, Personal, Invited Speaker: Illumina, GSK, Janssen Oncology; Financial Interests, Institutional, Funding, Funding for investigator-sponsored trial: Merck, AstraZeneca; Financial Interests, Institutional, Other, Institutional research support: BMS; Financial Interests, Institutional, Funding, Clinical trial funding: Jounce. E.L. Schenk: Financial Interests, Personal, Invited Speaker: OncLive, Ideology Health, MJH Life Sciences, Sanofi, MedPro, Janssen; Financial Interests, Personal, Advisory Board: Prescient Advisory, G1 Therapeutics, Regeneron, BioAtla; Non-Financial Interests, Other, Expert member, NSCLC guidelines panel: ASCO. R. Aggarwal: Financial Interests, Personal, Advisory Board: Bayer, Amgen, Merck, AstraZeneca, Bioexcel Therapeutics; Financial Interests, Personal, Other, Consultant: Boxer Capital, Tersara, Cepton, Lumanity, EcoR1; Financial Interests, Personal, Invited Speaker: OncLive, Targeted Oncology, Grand Rounds in Urology; Financial Interests, Personal, Other, Data and Safety Monitoring Board: Prostate Cancer Clinical Trials Consortium; Financial Interests, Institutional, Invited Speaker: Janssen, Fortis Therapeutics; Financial Interests, Institutional, Funding: Merck, Zenith Epigenetics, Amgen. L.N. Walker, B. Anand: Financial Interests, Personal, Full or part-time Employment: Harpoon Therapeutics. H. Beltran: Financial Interests, Personal, Advisory Board: Pfizer, Janssen, Foundation Medicine, Blue Earth Diagnostics, AstraZeneca, Amgen, Daiichi Sankyo, Merck, Loxo; Financial Interests, Institutional, Funding: Janssen, AbbVie/Stemcentrx, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Circle Pharma; Financial Interests, Personal, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.