654O - Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with solid tumors harboring specific HER2-activating mutations (HER2m): Primary results from the international phase II DESTINY-PanTumor01 (DPT-01) study

Background

T-DXd is an antibody–drug conjugate targeting HER2 approved in HER2-expressing breast cancer (BC), HER2-positive gastric cancer (GC), and HER2-mutant non-small cell lung cancer (NSCLC) in the US. Treatment (Tx) options are limited for pts with other solid tumors harboring HER2m.

Methods

In an open-label, multicenter, phase 2 study (NCT04639219) in pts with advanced solid tumors harboring prespecified HER2m (excluding HER2-overexpressing BC and GC, and HER2-mutant NSCLC), and who failed previous systemic Tx received T-DXd 5.4 mg/kg q3w. The primary endpoint was confirmed objective response rate (ORR) by RECIST 1.1 according to independent central review (ICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and safety.

Results

102 pts were assigned to T-DXd (data cutoff Jan 25 2023; median follow-up, 8.61 [range 1.5–22.1] months [mo]) with median 3 [range 1–13] prior lines of systemic therapy. The ORR was 29.4% (95% CI 20.8, 39.3); median DoR was not reached (54.2% of responders remained in response by ICR at 18 mo); median PFS was 5.4 mo (95% CI 2.7, 7.1). Responses were observed across HER2 expression levels, including HER2 IHC 0 tumors. The table shows ORR by tumor type and HER2m domain. Grade (G) ≥3 adverse events (AEs) occurred in 51.0% of pts; 9.8% discontinued Tx due to AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11 pts (10.8% [G3, n=1; G5, n=2]). Table: 654O

AC, adenocarcinoma ^aBy local testing;^bL755S, D769H, Y772_A775dup/A775_G776insYVMA, V777L, G778_P780dup/P780_Y781insGSP, V842I, T862A; ^cS310F, S310Y; ^dR678Q

Conclusions

DPT-01 is the first tumor-agnostic global study of T-DXd in a range of solid tumors with prespecified HER2m. In heavily pretreated pts with limited Tx options, T-DXd demonstrated encouraging anticancer activity and long DoR across multiple tumor types with HER2m and a range of HER2 expression levels, with a known safety profile. Translational research will help characterize pts who may derive greatest benefit from T-DXd.

Clinical trial identification

NCT04639219.

Editorial acknowledgement

Under the guidance of authors, medical writing and editorial support was provided by Jennifer L Mitchell, PhD, of Helios Medical Communications, and was funded by AstraZeneca.

Legal entity responsible for the study

Daiichi Sankyo and AstraZeneca.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

B.T. Li: Financial Interests, Personal, Royalties, Intellectual property rights as a book author: Karger Publishers, Shanghai Jiao Tong University Press; Financial Interests, Institutional, Other, Inventor on institutional patents at MSK (US62/685,057, US62/514,661): Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Institutional clinical trials funding to Memorial Sloan Kettering Cancer Center: Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui, Lilly; Non-Financial Interests, Advisory Role, Uncompensated advisor and consultant: Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Lilly; Non-Financial Interests, Other, Academic travel support, but without compensation: MORE Health, Jiangsu Hengrui Pharmaceuticals; Non-Financial Interests, Member: American Society of Clinical Oncology, International Association for the Study of Lung Cancer. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffmann-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, Loxo Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/ Daiichi Sankyo, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/ Daiichi Sankyo, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR pharma, Novartis, Gardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, Bristol, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Local PI: AbbVie, Boehringer Ingelheim, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, JCOG: Natera. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. M.J. De Miguel Luken: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, BioNTech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto, BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests, Personal, Other, Travel support for a poster presentation at ASCO GI 2023 : Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier, BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. S. Postel-Vinay: Financial Interests, Institutional, Advisory Board, Steering Committee: Daiichi Sankyo; Financial Interests, Institutional, Local PI, As part of the Drug Development Department (DITEP) SPV is Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, F. Hoffmann-La Roche AG, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus: Various drug companies; Financial Interests, Institutional, Research Grant, Translational research funding: IMCore F. Hoffmann-LaRoche; Financial Interests, Institutional, Research Grant, preclinical research funding: AstraZeneca; Non-Financial Interests, Principal Investigator, Principal investigator of phase I/II clinical trials: AstraZeneca, GSK, PEP therapy, BMS, Novartis; Amgen, Oxford Biotherapeutics, Clovis, Roche. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clincial trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. T. Satoh: Financial Interests, Personal, Invited Speaker, invited speaker and advisory: Ono Pharmaceutical, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Invited speaker and adovisory: Bristol-Myers; Financial Interests, Personal, Invited Speaker, Invited speaker and advisory: Elli-Lilly, Yakult-HOnsha; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Merck-Biopharm, Takeda, Taiho; Financial Interests, Personal, Advisory Board: Takara-Bio; Financial Interests, Institutional, Local PI: Merck-Biopharm; Financial Interests, Institutional, Local PI, Research Grant and Endosed Department: Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Local PI, Research Grant: Bristol-Myers, Elli-Lilly, Daiichi Sankyo, Parexell, Giliad, Taiho, Hutch-Med. I. Spanggaard: Financial Interests, Institutional, Local PI: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer; Non-Financial Interests, Principal Investigator: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer. F. Michelini, A. Smith, K. Kalil Machado: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., GSK, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Official College of Physicians of Barcelona (COMB); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer). All other authors have declared no conflicts of interest.