LBA18 - Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+; advanced/metastatic breast cancer (mBC) with or without brain metastases (BM): DESTINY-Breast12 primary results

Background

T-DXd intracranial activity has been observed in small or retrospective pt cohorts with HER2+ mBC with stable or active (untreated/treated progressing) BM; this Phase 3b/4, multicenter, open-label study is the largest prospective study of T-DXd in this pt population.

Methods

Adults with HER2+ mBC and progression on ≤2 prior lines of therapy (LOT) in the metastatic setting were enrolled in BM cohort (stable or active [untreated/treated progressing] BM not requiring immediate local therapy; dexamethasone ≤3 mg daily use or equivalent allowed for symptom control) or non-BM cohort. Design did not allow cross-cohort comparison. Pts received T-DXd 5.4 mg/kg intravenously every 3 weeks. Primary endpoints: progression-free survival (PFS; BM cohort) or objective response rate (ORR; non-BM cohort) per RECIST 1.1 by independent central review. Additional endpoints included CNS PFS, CNS ORR and ORR (BM cohort) and safety. Interstitial lung disease (ILD) / pneumonitis was investigator reported with no adjudication committee.

Results

504 pts were treated (n=263 BM cohort; n=241 non-BM cohort); median prior LOT: 1 (range 0–4 both cohorts). Median follow up at final data cutoff, Feb 8, 2024: 15.4 months (mo; range 0.1–30.0 BM cohort) and 16.1 mo (range 0.8–28.4 non-BM cohort). BM cohort 12-mo PFS was 61.6% (95% CI 54.9, 67.6); 12-mo CNS PFS was 58.9% (95% CI 51.9, 65.3). This was similar in pts with stable (57.8% 95% CI 48.2, 66.1) and active (60.1% 95% CI 49.2, 69.4) BM. CNS ORR was 79.2% (95% CI 70.2, 88.3 stable BM) and 62.3% (95% CI 50.1, 74.5 active BM). ILD/pneumonitis occurred in 42 (16.0% BM cohort) and 31 (12.9% non-BM cohort) pts. Five ILD/pneumonitis events were reported as co-occurring with opportunistic infection (1.9% BM cohort). Table: LBA18

*Post hoc analysis^†n=198^‡n=215^§Reporting not systematic; Aspergillus n=1, Pneumocystis jirovecii (PJ) pneumonia n=3; one Gr 4 event with PJ infectionAE, adverse event; gr, grade; Tx, treatment

Conclusions

T-DXd exhibited substantial and durable overall and intracranial clinical activity in pts with HER2+ mBC, including a large cohort with stable/active BM, with no new safety signals.

Clinical trial identification

NCT04739761.

Editorial acknowledgement

We thank the patients who participated in this study, as well as their families and caregivers, and the staff and investigators at all the study sites. We would like to acknowledge Gareth James of Medical Statistics Consultancy Ltd for his assistance with statistical analysis. Medical writing support, under the direction of the authors, was provided by Katrina Rimmer, PhD (Oxford, UK), and Francesca Codrington, BSc (Cheshire, UK), both of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca in accordance with Good Publication Practice (GPP) guidelines.

Legal entity responsible for the study

AstraZeneca and Daiichi Sankyo.

Funding

This study is sponsored by AstraZeneca and Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).

Disclosure

N. Lin: Financial Interests, Personal, Advisory Board, Ad board participation: Seattle Genetics, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Ad board/Steering Committee participation; consultant: AstraZeneca; Financial Interests, Personal, Advisory Board, Ad board/Steering committee participation; travel support: Olema Pharmaceuticals; Financial Interests, Personal, Other, Consultant: Blueprint Medicines, Janssen; Financial Interests, Personal, Other, High level Consulting: Artera Inc.; Financial Interests, Personal, Other, Steering committee: Stemline/Menarini; Financial Interests, Personal, Advisory Board: Eisa; Financial Interests, Personal, Royalties, Royalties for book chapter(s): Up to Date; Financial Interests, Institutional, Funding, Trial funding to institute (and steering committee): Olema Pharmaceuticals, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Funding, Trial funding to institute: Zion Pharmaceuticals; Financial Interests, Institutional, Funding, trial funding to institute: Pfizer, Genentech. E.M. Ciruelos: Financial Interests, Personal, Advisory Role: Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Menarini, MSD, Novartis, Gilead, Reveal Genomics; Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, MSD; Non-Financial Interests, Personal, Steering Committee Member: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Gilead, Reveal Genomics; Financial Interests, Personal, Other, Travel Grant: Roche, Pfizer, AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Pfizer, Daiichi Sankyo. G. Jerusalem: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer, BMS, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, BMS, Lilly, AstraZeneca, Seagen; Financial Interests, Personal, Steering Committee Member: Novartis, AZ/Daiichi Sankyo, BMS; Financial Interests, Institutional, Local PI: Novartis, Roche, Syneos Health, Iqvia, TRIO, Bayer, MSD, IBCSG, PRA, Eli Lilly, PPD, Theradex, ABCSG, Modra, AstraZeneca, Odonate Therapeutics, BMS, ICON, Boehringer, Quintiles, Pfizer, Lilly, Daiichi Sankyo, Seagen, Medimmune; Non-Financial Interests, Member: ASCO, BSMO; Other, Medical writer support: Novartis, Lilly, BMS, AstraZeneca; Other, Support for attending meetings and/or travel: Novartis, Lilly, BMS, Roche, AstraZeneca, Pfizer. V. Mueller: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Lilly, Medscape, Gilead, Pierre Fabre, iMED Institut; Financial Interests, Personal, Advisory Board: Roche, Pierre Fabre, PINK, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Seagen, Gilead, Stemline; Financial Interests, Institutional, Local PI: Novartis, Roche, Seagen, Genentech, AstraZeneca; Non-Financial Interests, Leadership Role: AGO German Breast Cancer Guideline Group. N. Niikura: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Daiichi Sankyo, Chugai, Eli Lilly, MSD; Financial Interests, Personal and Institutional, Research Grant: Chugai, Eisai, Nippon Kayaku; Financial Interests, Personal and Institutional, Coordinating PI: Daiichi Sankyo. G. Viale: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, MSD Oncology, Pfizer; Financial Interests, Personal, Other, Consulting fees: Agilent; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Other, Educational webinar: Medscape; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen, Roche, Novartis, Eli-Lilly, Pierre-Fabre, Daiichi, Gilead, MSD, Pfizer, Eisai, Gruenenthal; Financial Interests, Personal, Advisory Board: Daiichi, AstraZeneca, Roche, Novartis, Eli-Lilly, Pierre-Fabre, MSD, Gilead, Seagen, Eisai, Gruenenthal, Menarini; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Coordinating PI, Drug support for investigator initiated trial: MSD. C. Kurzeder: Financial Interests, Institutional, Invited Speaker: AstraZeneca, GSK, Roche, Eli Lilly, Novartis, PharmaMar, Genomic Health, Pfizer, Gilead; Financial Interests, Institutional, Advisory Board: AstraZeneca, AstraZeneca, GSK, GSK, Roche, Roche, Eli Lilly, Novartis, PharmaMar, Genomic Health, Merck MSD, Gilead; Financial Interests, Institutional, Steering Committee Member: AstraZeneca. R. Connolly: Financial Interests, Personal, Advisory Board, Advisory Board participant-AstraZeneca/Daichii (HER2 low MBC): AstraZeneca/Daichii; Financial Interests, Personal, Advisory Board, AstraZeneca (Olaparib)-Advisory Board participant: AstraZeneca; Financial Interests, Personal, Advisory Board, Gilead (Sacituzumab)-Advisory Board participant: Gilead; Financial Interests, Personal, Advisory Board, Advisory Board participant: Lilly; Financial Interests, Institutional, Funding, Unrestricted Education Grant: Pfizer Global; Financial Interests, Institutional, Research Grant, Research funding to institution for clinical trials: MSD Ireland, Daichii Sankyo, AstraZeneca; Non-Financial Interests, Advisory Role, Advisory Board Chair: Seagen; Non-Financial Interests, Other, Steering Committee Member-AstraZeneca/Daichii (HER2 low obs study): AstraZeneca/Daichii; Non-Financial Interests, Other, Steering Committee member: AICRI, Develop Med -UCD; Non-Financial Interests, Other, Steering Committee Member: Decrescendo; Other, Support for attending St Gallens conference: Novartis; Other, Support for ASCO Conference (virtual): Roche; Other, Support for attending ESMO conference: Novartis; Other, Support for SABCS conference (virtual): Gilead. S.E. Baron-Hay: Financial Interests, Personal, Advisory Board, Participation in an advisory board: Pfizer, Eisai, Novartis, GSK; Financial Interests, Personal, Advisory Board, Participation in an Advisory Board Invited speaker at education meeting: AstraZeneca; Financial Interests, Personal, Invited Speaker, Talks at Gilead education meeting Development of education slide deck: Gilead. M. Gion Cortes: Financial Interests, Personal, Other, Travel grant: Roche, Pfizer, AstraZeneca, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, Gilead, Pfizer. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, GSK, AstraZeneca, Gilead, Exact Sciences; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, merck serono, Exact Sciences, Eisai, Olema Oncology, AstraZeneca, Daiichi Sankyo, Pfizer; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano, Pfizer; Non-Financial Interests, Member: ASCO. G. Bianchini: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche, Amgen, MSD, Chugai, EISAI, Gilead, Seagen, Exact Science, Roche, MSD, Gilead, Lilly, Menarini Stemline; Financial Interests, Personal, Other, Consultancy: AstraZeneca, Daiichi Sankyo, Roche, MSD, Gilead, Sanofi, Seagen; Financial Interests, Personal, Invited Speaker: Lilly, Roche, AstraZeneca, Daiichi Sankyo, MSD, Chugai, EISAI, Gilead, Seagen, Neopharm Israel, Daiichi Sankyo, Gilead; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Roche, Pfizer, MSD, Chugai, Novartis, Gilead, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: Gilead; Financial Interests, Personal and Institutional, Steering Committee Member: Roche, Novartis, Lilly, AstraZeneca; Financial Interests, Institutional, Local PI: Gilead, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis; Non-Financial Interests, Leadership Role, Head of Traslational Research: Fondazione Michelangelo; Non-Financial Interests, Other, Scientific Board Member: Fondation ARC, Fondazione Umberto Veronesi; Non-Financial Interests, Member: AIOM. H. Wildiers: Financial Interests, Institutional, Other, Consultancy: Roche, Gilead, Pfizer, Immutep Limited, Novartis, Augustine Therapeutics, Stemline Therapeutics Switzerland, MediMix BV, NV Hict; Financial Interests, Institutional, Advisory Board, + Consultancy: Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: AstraZeneca, E Squared Communications LLC, PSI CRO AG; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Financial Interests, Institutional, Local PI: Syneos Health; Other, Travel & accomodations: Pfizer; Other, Subscription fee: Gilead; Other, Travel support: Daiichi Sankyo. S. Escrivá-de-Romaní: Financial Interests, Personal, Advisory Role: Daiichi Sankyo/AstraZeneca, Seagen, Pierre-Fabre, Jazz Pharmaceuticals, Cor2Ed, Roche; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo/AstraZeneca, Pfizer, Novartis, Seagen, Cor2Ed; Financial Interests, Institutional, Research Funding: Roche, Byondis, Medsir, SOLTI, Zymeworks, Daiichi Sankyo/AstraZeneca, Jazz Pharmaceuticals; Financial Interests, Personal, Expert Testimony: Cor2Ed, Medistream; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Kern Pharma, Daiichi Sankyo/AstraZeneca, Seagen, SOLTI, AstraZeneca. M. Prahladan: Financial Interests, Personal, Advisory Role, Contract consulting - Active: AstraZeneca; Financial Interests, Personal, Full or part-time Employment, Past employer - Inactive: Amgen; Financial Interests, Personal, Advisory Board, Pharma and health technology & service contracting - Active: Dokcharts. H. Bridge: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Verma: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Funding: BMS, Daiichi Sankyo, MSD, Roche, Seagen, TRIO, WSG, Gilead; Financial Interests, Institutional, Steering Committee Member: Lilly, Pierre Fabre; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal.