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Ref Type abstract
PMID
Authors Erika P. Hamilton, Ololade Dosunmu, Mythili Shastry, Lindsey Finney, Dalila B. Sellami, David W. Sternberg, Vance Wright-Browne, Deborah Toppmeyer, William R Gwin, J. Thaddeus Thaddeus, Jennifer L. Cultrera, Nusayba Ali Bagegni, Katia Khoury, Arielle Lutterman Heeke, Yuan Yuan
Title A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC).
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 41 16 Suppl 2023
URL https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.1004
Abstract Text Background: HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), attached to a topoisomerase 1 inhibitor via a tetrapeptide-based cleavable linker that has shown promising efficacy in pts with HER3-expressing MBC (Krop, 2022). This 3-part Phase 2 study examines efficacy of HER3-DXd across MBC subsets and defines the pt population likely to derive greater benefit (NCT04699630). Methods: Part A is reported here (Data cutoff 6Sep2022). Pts had HER2 negative MBC with measurable disease per RECIST v1.1, 0-2 prior chemo and prior endocrine therapy (ET) + CDK4/6 inhibitor for hormone receptor (HR)+ BC, or 1-3 prior chemo for triple negative BC (TNBC). Prior treatment (tx) with anti-HER3 agents and ADCs with exatecan derivatives were prohibited. Pts provided pre-tx tissue to evaluate the association of biomarker expression with progression free survival at 6 months (PFS6months). Primary endpoints for Part A are objective response rate (ORR) and PFS6months. Secondary endpoints are safety/tolerability, duration of response (DOR), and clinical benefit rate (CBR) (CR, PR or SD ≥180 days). Results: 60 pts were treated in Part A: median age 57.5 y, 98.3% female; median 5 prior lines of therapy (range 1-15). 32% had TNBC. 48% were HR+. 48% had liver and 32% had lung metastases. HER3 membrane expression was evaluated by overall % membrane positivity at 10X. 47/60 (78%) pts provided evaluable samples at baseline. Among evaluable pts, 64% (30/47) had HER3 expression ≥75%, 28% (13/47) had 25-74% expression and 8% (4/47) had <25% expression. The median tx duration was 5.2 mos and 21 pts remained on tx at data cut-off. All pts experienced a tx emergent adverse event and 93% of pts experienced a tx related AE (TRAE) with Gr ≥3 TRAE in 19 pts (32%). The most common (≥ 25%) any grade TRAEs were nausea (50%), fatigue (45%), diarrhea (37%), vomiting (32%), alopecia and anemia (30% each). 7 pts (12%) experienced a serious AE (SAE), including 4 pts (7%) with a related SAE (interstitial lung disease, nausea/vomiting, pneumonitis, thrombocytopenia). 15% of pts experienced a dose reduction and 23% experienced a dose interruption due to an AE. 3 pts died while on tx, 2 unrelated to tx 1 cause unknown. ORR was 35% (95% CIs 23.1, 48.1) for all pts, and the CBR was 48% (95% CIs 35.2, 61.6). Pts with ≥75% HER3 expression had an ORR of 33% and CBR of 50%, pts with HER3 25-74% expression had an ORR of 46% and CBR of 54%. There were 4 pts with HER3 < 25% expression, limiting efficacy assessment. The median DOR was 10.0 mos (95% CIs 5.5, NA). The PFS6months was 60% for all pts, 50% for pts with HER3 ≥75%, and 70% for pts with HER3 25-74%. Conclusions: HER3-DXd had an acceptable safety profile, and the data further confirm the clinical activity in MBC in heavy pre-tx MBC across the broad range of HER3 expression levels. Parts B and Z are ongoing and data from this report support the potential entry of HER3-DXd into the therapeutic paradigm in MBC. Clinical trial information: NCT04699630.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 positive Her2-receptor negative breast cancer predicted - sensitive Patritumab deruxtecan Phase II Actionable In a Phase II trial, Patritumab deruxtecan (U3-1402) treatment resulted in an objective response rate (ORR) of 35%, clinical benefit rate (CBR) of 48%, median duration of response of 10 mo, and 6-mo progression-free survival (PFS) rate of 60% in ERBB3 (HER3)-positive, ERBB2 (HER2)-negative metastatic breast cancer patients, with an ORR of 46 vs 33%, CBR of 54 vs 50%, and PFS rate of 70 vs 50% in those with 25-75% vs >/=75% ERBB3 (HER3) expression (J Clin Oncol 41, 2023 (suppl 16; abstr 1004); NCT04699630). detail...