1319MO - Intracranial efficacy of HER3-DXd in patients with previously treated advanced EGFR-mutated NSCLC: Results from HERTHENA-Lung01

Background

For patients (pts) with EGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy (PBC), available therapies provide limited benefit. CNS metastases occur in the majority of these pts and portend a poor prognosis. HER3-DXd (patritumab deruxtecan) is an antibody-drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In the phase 2 HERTHENA-Lung01 trial (NCT04619004), HER3-DXd showed promising efficacy and a manageable safety profile in pts with advanced EGFR-mutated NSCLC following an EGFR TKI and PBC. Pts with stable brain metastases (treated or untreated) were included. We report an exploratory analysis of intracranial efficacy.

Methods

In pts (N=225) treated with HER3-DXd 5.6 mg/kg IV Q3W, intracranial responses were assessed by blinded independent central review of cranial CT/MRI (CNS BICR; per CNS RECIST) at baseline, every 6 wk to wk 24, every 12 wk thereafter.

Results

95 pts had brain metastases at baseline; 23 had measurable target lesions and 72 only had nontarget lesions. Pts had a median of 3 (range, 1-11) prior systemic therapies in the advanced setting. As of 21 Nov 2022, median study duration was 13.1 (range, 9.0-20.5) mo, median treatment duration was 4.2 (range, 0.7-14.7) mo. CNS BICR confirmed objective response rate (cORR) was 20% (Table; in pts with no prior radiotherapy to the brain, cORR was 37%). Median duration of response was 8.5 mo. 60% of pts had a CNS best objective response of SD and 14% had PD. In pts with target lesions, 15/23 had a reduction in the sum of diameters (cORR, 22%).

Conclusions

HER3-DXd demonstrated efficacy in EGFR-mutated NSCLC CNS metastases, with durable responses. These data add to the growing body of evidence that systemic treatment is feasible in pts with brain metastases and support further investigation of HER3-DXd in this context. Table: 1319MO

CR, complete response; DOR, duration of response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. ^a CR + PR. ^b 11 pts with CR only had nontarget lesions

Clinical trial identification

NCT04619004.

Editorial acknowledgement

Medical editorial assistance was provided by Amos Race, PhD, CMPP (Articulate Science, LLC), and funded by Daiichi Sankyo, Inc. Editorial support was provided in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo.

Disclosure

M.L. Johnson: Financial Interests, Institutional, Advisory Role: Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GSK, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, Ideaya Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, VBL Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, Sanofi; Financial Interests, Institutional, Research Funding: EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stem CentRx, Novartis, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amgen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Acerta Pharma, Takeda, Shattuck Labs, GSK, Apexigen, Atreca, OncoMed, Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Inc., Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Inc, Harpoon, Helsinn Healthcare, Hutchison MediPharma, Ideaya Biosciences, IGM Biosciences, Memorial Sloan-Kettering Cancer Center, NeoImmuneTech, Numab, RasCal, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics, Inc., Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics. 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I receive post-marketing royalties from this invention: Patent; Financial Interests, Personal, Stocks or ownership: Gatekeeper Pharmaceuticals, Loxo; Financial Interests, Personal, Research Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution Medicines. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fisher; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Guardant Health, Preferred Network; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Preferred Network. K. 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