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Clinical Trial
. 2024 Dec;30(12):3717-3727.
doi: 10.1038/s41591-024-03261-7. Epub 2024 Sep 13.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Nadia Harbeck  1 , Eva Ciruelos  2 , Guy Jerusalem  3 , Volkmar Müller  4 , Naoki Niikura  5 , Giuseppe Viale  6 , Rupert Bartsch  7 , Christian Kurzeder  8 , Michaela J Higgins  9 , Roisin M Connolly  10   11 , Sally Baron-Hay  12 , María Gión  13   14 , Valentina Guarneri  15   16 , Giampaolo Bianchini  17   18 , Hans Wildiers  19 , Santiago Escrivá-de-Romaní  20 , Manoj Prahladan  21 , Helen Bridge  22 , Nataliya Kuptsova-Clarkson  23 , Nana Scotto  24 , Sunil Verma  25 , Nancy U Lin  26 ; DESTINY-Breast12 study group
Collaborators, Affiliations
Clinical Trial

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Nadia Harbeck et al. Nat Med. 2024 Dec.

Erratum in

Abstract

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

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Conflict of interest statement

Competing interests: N.H. has received lecture honoraria from Art Tempi, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi, Seagen, Viatris and Zuellig Pharma; has received consulting or advisory honoraria from Aptitude Health, Gileadn Sciences, Pfizer, Sandox-Hexal, Sanofi and Seagen; has received research funding from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, Merck Sharp & Dohme, Roche, Seagen, TRIO and WSG; has participated on independent data monitoring committees/steering committees for Eli Lilly, Pierre Fabre and Roche; and has ownership interest in the West German Study Group. E.C. has received lecture, consulting or advisory honoraria from AstraZeneca, Daiichi Sankyo, Eli lilly, Gilead Sciences, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Reveal Genomics and Roche; has received support for attending meetings and/or travel from AstraZeneca, Pfizer and Roche; has received research funding from Daiichi Sankyo, Pfizer and Roche; and has participated on steering committees for AstraZeneca, Daiichi Sankyo, Gilead Sciences, Novartis, Reveal Genomics and Roche. G.J. has received consulting honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Diaccurate/Evexta Bio, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, Novartis, Pfizer and Roche; and has received medical writing support from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Novartis and Roche. V.M. has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, high5 Oncology, iMED Institut, Eli Lilly, Medac, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche and Seagen; has received consulting or advisory honoraria from ClinSol, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pierre Fabre, PINK, Roche and Menarini Stemline; and has received research funding from AstraZeneca, Genentech, Novartis, Roche and Seagen. N.N. has received consulting or advisory honoraria from AstraZeneca, Chugai Pharmaceutical and Daiichi Sankyo; has received lecture honoraria from AstraZeneca, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan; and has received research funding from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan. G.V. has received research grants from Dako/Agilent Technologies, Roche/Genentech and Ventana Medical Systems and has received honoraria from AstraZeneca, Daiichi Sankyo, Dako/Agilent Technologies, Gilead Sciences, Merck Sharp & Dohme Oncology, Pfizer, Roche and Ventana Medical Systems. R.B. has held advisory roles at AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Seagen and Menarini Stemline; has received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche and Seagen; and has received research support from Daiichi Sankyo, Merck Sharp & Dohme, Novartis and Roche. C.K. has received lecture honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Novartis, PharmaMar, Pfizer and Roche; has received consulting or advisory honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, PharmaMar and Roche; and has participated on steering committees for AstraZeneca. M.J.H. has received lecture honoraria from AstraZeneca. R.M.C. received an unrestricted educational grant from Pfizer; has received research support from AstraZeneca, Daiichi Sankyo, MSD Ireland and Pfizer; has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences and Seagen; and has received support for attending meetings and/or travel from Gilead Sciences, Novartis and Roche. M.G. has received support for attending meetings and/or travel from AstraZeneca, Gilead Sciences, Roche and Pfizer and has received honoraria from AstraZeneca, Gilead Sciences and Pfizer. V.G. has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Olema Oncology, Pierre Fabre and Roche; has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Menarini Stemline, Novartis, Roche and Zentiva; and has received expert testimony honoraria from Eli Lilly. G.B. has received honoraria from Agendia, Amgen, AstraZeneca, Chugai Pharmaceutical/Roche, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Helsinn Lilly, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Seagen and received a research grant from Gilead Sciences. H.W. has received lecture honoraria from Seagen; has received consulting or advisory honoraria from AstraZeneca, Augustine Therapeutics, Daiichi Sankyo, E Squared Communications, Eli Lilly, Gilead Sciences, Immutep, MediMix, Menarini Stemline, Novartis, NV Hict, Pfizer, PSI CRO and Roche; has received support for attending meetings and/or travel from Daiichi Sankyo and Pfizer; has received research funding from Novartis, Roche and Syneos Health; and has received subscription fees from Gilead Sciences. S.E.-d.-R. has received honoraria from AstraZeneca, COR2ED, Daiichi Sankyo, Jazz Pharmaceuticals, Medistream, Pierre Fabre, Roche and Seagen; has received research funding from AstraZeneca, Byondis, Daiichi Sankyo, Jazz Pharmaceuticals, MEDSIR, Roche, SOLTI and Zymeworks; and has received support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Kern Pharma, Pfizer, Seagen and SOLTI. M.P., H.B., N.K.-C., N.S. and S.V. are employees of AstraZeneca. N.K.-C. holds stocks in AstraZeneca and AbbVie. N.U.L. has received honoraria from AstraZeneca and has received research funding from AstraZeneca. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Patient disposition.
COVID-19, coronavirus disease 2019; DCO, data cutoff.
Fig. 2
Fig. 2. Kaplan–Meier analysis of key efficacy endpoints in patients with baseline BMs.
a, Overall PFS. b, OS. c, CNS PFS per RECIST 1.1 as assessed by ICR. Tick marks indicate censored data. Analysis was based on the full analysis set.
Fig. 3
Fig. 3. Best percentage change in target lesions.
a, Best percentage change from baseline in target lesion size in patients with baseline BMs and measurable disease at baseline (full analysis set). b, Best percentage change from baseline in CNS target lesion size in patients with baseline BMs and measurable CNS disease at baseline. c, Best percentage change from baseline in target lesion size, in patients with no baseline BMs and measurable disease at baseline (full analysis set). All patients had at least one post-baseline scan. Responses were assessed per RECIST 1.1 by ICR. A value of +20% was imputed as best percentage change from baseline if best percentage change could not be calculated because of missing data in the following situations: a patient had a new lesion or progression of non-target lesions or target lesions or a patient had withdrawn because of PD and had no evaluable target lesion data before or at PD. The dashed line indicates a 30% decrease in tumor size (partial response). Asterisks indicate imputed values.
Extended Data Fig. 1
Extended Data Fig. 1. Kaplan-Meier analysis of duration of response.
Duration of response per RECIST 1.1 by ICR in all patients with a confirmed complete or partial response. a, Patients with baseline BMs. b, Patients with no baseline BMs. Tick marks indicate censored data. BM, brain metastasis; ICR, independent central review; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
Extended Data Fig. 2
Extended Data Fig. 2. Kaplan-Meier analysis of time to progression in patients with no baseline BMs.
Time to progression per RECIST 1.1 as assessed by ICR in patients from the full analysis set. Tick marks indicate censored data. BM, brain metastasis; ICR, independent central review; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
See this image and copyright information in PMC

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