MK-6070

Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3 expressing malignancies.

HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented.

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.

First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

P1/2, N=162, Recruiting, Harpoon Therapeutics | N=57 --> 162 | Trial completion date: Mar 2023 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Jan 2024

Atezolizumab and durvalumab, anti-PD-L1 antibodies, are approved in combination with platinum-doublet chemotherapy as part of front-line therapy for extensive-stage SCLC. These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combinatorial approach in patients. Clinical studies of HPN328 in combination with atezolizumab are planned.

Concomitant with anti-tumor immune response, we detected increases in memory T cells in the spleens of mice previously treated with HPN328. Together these results indicate that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, suggest a novel mechanism for its activity and efficacy in vivo.

HPN328 is a novel half-life extended DLL3-targeting TCE that is well tolerated and clinically active. AEs have been transient, manageable, and consistent with class. No ≥ Grade-3 CRS occurred.

TriTAC molecules are currently being investigated in multiple phase 1/2 clinical trials in solid tumors, including HPN424 targeting prostate-specific membrane antigen (PSMA) in prostate cancer (NCT03577028), HPN536 targeting mesothelin (MSLN) in multiple malignancies (NCT03872206) and HPN328 targeting Delta Like Canonical Notch Ligand 3 (DLL3) in small cell lung cancer (SCLC) (NCT04471727). In addition, in the MSLN-expressing NCI-H292 lung cancer model that co-expresses constitutive, high levels of PD-L1, both anti-PD1 and anti-PDL1 antibodies significantly enhanced the antitumor effects of the MSLN-targeting TriTAC HPN536 in vivo. Together these results demonstrate the potential utility of PD1/PDL1 blockade to enhance the potency of TriTAC-mediated tumor cell killing, supporting further investigation of these combinatorial approaches in patients.

P1/2, N=52, Recruiting, Harpoon Therapeutics | Not yet recruiting --> Recruiting

P1/2, N=52, Not yet recruiting, Harpoon Therapeutics