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Clinical Trial
. 2024 Aug;30(8):2208-2215.
doi: 10.1038/s41591-024-03021-7. Epub 2024 Jun 2.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial

Javier Cortés  1   2   3 , Sara A Hurvitz  4 , Seock-Ah Im  5 , Hiroji Iwata  6 , Giuseppe Curigliano  7   8 , Sung-Bae Kim  9 , Joanne W Y Chiu  10 , Jose L Pedrini  11 , Wei Li  12 , Kan Yonemori  13 , Giampaolo Bianchini  14 , Sherene Loi  15 , Giuliano S Borges  16 , Xian Wang  17 , Thomas Bachelot  18 , Shunsuke Nakatani  19 , Shahid Ashfaque  20 , Zhengkang Liang  20 , Anton Egorov  21 , Erika Hamilton  22
Affiliations
Clinical Trial

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial

Javier Cortés et al. Nat Med. 2024 Aug.

Abstract

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .

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Conflict of interest statement

The authors declare the following competing interests: J.C. has received research grants from Roche, ARIAD Pharmaceuticals, AstraZeneca, Baxalta/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, IQVIA and the Queen Mary University of London; has received honoraria from Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead and Stemline Therapeutics; has received stock from Leuko (relative) and MAJ3 Capital; has received support for attending meetings, accommodations and/or travel from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead, Merck Sharp & Dohme and Stemline Therapeutics; has held consulting or advisory roles for Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, GEMoaB, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, ExpreS2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, BridgeBio, BioNTech and Biocon; and has the following patents: pharmaceutical combinations of a PI3K inhibitor and a microtubule destabilizing agent (J. Cortés Castán, A. Piris Giménez, V. Serra Elizalde; WO 2014/199294A (issued)) and HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy (A. Prat, A. Llombart, J.C.; US 2019/0338368 A1 (licensed)). S.A.H. has received research grants from Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, BioMarin, Lilly, Merrimack, Cascadian Therapeutics, Seagen, Daiichi Sankyo, MacroGenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs, CytomX Therapeutics, Samumed, Dantari, Orinove, Greenwich LifeSciences, AstraZeneca/Daiichi Sankyo, G1 Therapeutics and Orum Therapeutics; has received stock and other ownership interests from ROM Tech; and has received support for attending meetings and/or travel from Lilly. S.-A.I. has received research grants from AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai and Boryung Pharmaceuticals; and has held consulting or advisory roles at AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, MSD and Daiichi Sankyo. H.I. has received research grants from MSD, AstraZeneca, Kyowa Kirin, Daiichi Sankyo, Chugai Pharma, Nihokayaku, Lilly Japan, Novartis, Bayer, Pfizer, Boehringer Ingelheim, Sanofi and Amgen; has received honoraria from Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Lilly Japan, Kyowa Kirin, Taiho Pharmaceutical and MSD; and has held consulting or advisory roles at Chugai Pharma, Daiichi Sankyo, Pfizer, AstraZeneca, Lilly Japan, Kyowa Kirin, Novartis, MSD and Sanofi. G.C. has received research grants from Merck; has received honoraria from Ellipses Pharma; has received support for attending meetings and/or travel from Roche/Genentech, Pfizer, Daiichi Sankyo and AstraZeneca; has a leadership role for the ESMO, the European Society of Breast Cancer Specialists and ESMO Open; is a speakers’ bureau member for Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung, Daiichi Sankyo, Seagen, Menarini, Gilead Sciences, AstraZeneca and Exact Sciences; and has held consulting or advisory roles for Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, Bristol Myers Squibb, Samsung, AstraZeneca, Daiichi Sankyo, Boehringer Ingelheim, GlaxoSmithKline, Seagen, Guardant Health, Veracyte, Celcuity, Hengrui Therapeutics, Menarini, Merck, Exact Sciences, Blueprint Medicines and Gilead Sciences. S.-B.K. has received research grants from Genzyme; has received honoraria from DAEHWA Pharmaceutical, LegoChem Biosciences and Kalbe Farma; has received stock and other ownership interests from Genopeaks; and has held consulting or advisory roles for Lilly, AstraZeneca, DAEHWA Pharmaceutical, ISU Abxis, BeiGene, Daiichi Sankyo/AstraZeneca, OBI Pharma and Ensol Biosciences. J.W.Y.C. has a leadership role for Precision Oncology; and has held consulting or advisory roles at Lilly. K.Y. has received research grants from Ono Pharmaceutical, MSD, Daiichi Sankyo/AstraZeneca, AstraZeneca/MedImmune, Taiho Pharmaceutical, Pfizer, Novartis, Takeda, Sanofi, Seagen, Eisai, Lilly, Genmab, Boehringer Ingelheim, Kyowa Kirin, Haihe Pharmaceutical and Nihokayaku; has received honoraria from Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical, Lilly Japan, Daiichi Sankyo/AstraZeneca, Takeda, Fujifilm, Ono Pharmaceutical, Chugai Pharma and MSD Oncology; and has held consulting or advisory roles for Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai, OncXerna Therapeutics and Henlius. G.B. has received research grants from Gilead Sciences; has received honoraria from Roche, Eisai, MSD, Lilly, Pfizer, Novartis, Exact Sciences, AstraZeneca/Daiichi Sankyo, Gilead Sciences and Seagen; has received support for attending meetings and/or travel from Novartis, Roche, Pfizer, AstraZeneca/Daiichi Sankyo and Gilead Sciences; and has held consulting or advisory roles for Roche, AstraZeneca/Daiichi Sankyo, Pfizer, Lilly, Novartis, Gilead Sciences, Exact Sciences, Eisai, MSD, Seagen and Agendia. S.L. has received research grants from Roche/Genentech, Novartis, Merck, Puma Technology, Bristol Myers Squibb, Seagen, AstraZeneca, Nektar and Lilly; has received honoraria from Roche/Genentech, Novartis, MSD Oncology and Mersana; has a leadership role for Bristol Myers Squibb; has received support for attending meetings and/or travel from Bristol Myers Squibb; and has held consulting or advisory roles for Roche/Genentech, Novartis, G1 Therapeutics, Puma Biotechnology, GlaxoSmithKline, AstraZeneca, Seagen, Bristol Myers Squibb, Silverback Therapeutics, Pfizer, Gilead Sciences, Daiichi Sankyo/Lilly and Tallac Therapeutics. T.B. has received research grants from Novartis, AstraZeneca, Seagen, Pfizer and Daiichi Sankyo/AstraZeneca; has received support for attending meetings and/or travel from Roche, Pfizer, AstraZeneca and Novartis; and has held consulting or advisory roles for Novartis, Pfizer, Seagen, Daiichi Sankyo/AstraZeneca and Lilly. S.N. is employed by Daiichi Sankyo/Arqule; and has received stock and other ownership interests from Daiichi Sankyo. S.A. is employed by Daiichi Sankyo. Z.L. is employed by Daiichi Sankyo. A.E. is employed by Daiichi Sankyo/AstraZeneca; and has received stock and other ownership interests from Daiichi Sankyo/AstraZeneca. E.H. has received research grants from AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stemcentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Harpoon, Black Diamond Pharmaceuticals, Orinove, Molecular Templates, Seagen, Compugen, G1 Therapeutics, Karyopharm Therapeutics, the Dana Farber Cancer Hospital, Onconova Therapeutics, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, ImmunoGen, Plexxikon, Amgen, Akeso Biopharma, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repertoire Immune Medicines, Treadwell Therapeutics, Jacobio, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, ProfoundBio, Cullinan Oncology, Bristol Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics and Stemline Therapeutics; and has held consulting or advisory roles for Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Greenwich LifeSciences, Orum Therapeutics, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnology, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services and Zentalis. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Patient disposition.
Efficacy analysis was conducted in the full analysis set (all patients who were randomly assigned to a treatment group), and safety analysis was conducted in the safety analysis set (all patients who were randomly assigned and received at least one dose of T-DXd or T-DM1).
Fig. 2
Fig. 2. Kaplan–Meier estimates.
a, PFS. b, PFS2. c, OS. Crosses indicate where data were censored; numbers of patients censored are not stated.
Extended Data Fig. 1
Extended Data Fig. 1. Kaplan-Meier estimates of DoRa.
DoR, duration of response; NE, not estimable; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. aThe DoR rate at 36 months was 48.9% (95% CI, 41.3-56.1%) with T-DXd and 28.7% (95% CI, 18.9-39.2%) with T-DM1.
Extended Data Fig. 2
Extended Data Fig. 2. Sensitivity analysis for OS.
RPSFTM adjusted Kaplan-Meier curve of OS for the T-DM1 group plotted with the unadjusted OS curves for the T-DXd group and T-DM1 group. OS, overall survival; RPSFTM, rank-preserving structural failure time models; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.
See this image and copyright information in PMC

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