Veronique Dieras (Rennes, France)
Centre Eugene - MarquisAuthor Of 6 Presentations
Will new definitions for HER2 status make a difference for my patients? - An Oncologist’s perspective (ID 286)
Round-table discussion (ID 288)
Expanding perspectives: Progress in treatment choice in HER2- aBC (ID 375)
168P - Sacituzumab govitecan (SG) efficacy in patients with metastatic triple-negative breast cancer (mTNBC) by HER2 immunohistochemistry (IHC) status: Findings from the Phase 3 ASCENT study (ID 176)
- Sara A. Hurvitz (Los Angeles, United States of America)
- Aditya Bardia (Boston, United States of America)
- Kevin Punie (Leuven, Belgium)
- Kevin Kalinsky (Atlanta, United States of America)
- Javier Cortes (Madrid and Barcelona, Spain)
- Joyce O'Shaughnessy (Dallas, United States of America)
- Lisa A. Carey (Chapel Hill, United States of America)
- Hope S. Rugo (San Francisco, United States of America)
- Oh Kyu Yoon (Foster City, United States of America)
- Yang Pan (Foster City, United States of America)
- Rosemary J. Delaney (Foster City, United States of America)
- Scott Hofsess (Foster City, United States of America)
- Paul Hodgkins (Foster City, United States of America)
- See-Chun Phan (Foster City, United States of America)
- Veronique Dieras (Rennes, France)
Abstract
Background
HER2 IHC1+ or IHC2+ and in situ hybridization (ISH)-negative results are sometimes referred to as HER2-Low. SG is a novel antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved in mTNBC for the second line (2L) onwards. In the ASCENT study, SG had significant progression-free survival (PFS) and overall survival (OS) benefit vs chemotherapy of physician’s choice (TPC). This ASCENT post hoc subgroup analysis evaluates SG efficacy in HER2 IHC0 and HER2-Low mTNBC.
Methods
Patients (pts) with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity/progression. Primary endpoint was PFS per RECIST 1.1 by central review. Pts with known HER2-positive disease were ineligible, but HER2 status was not assessed centrally in ASCENT. Local HER2 IHC results were analyzed retrospectively.
Results
In the intent-to-treat (ITT) population (SG vs TPC), 149 vs 144, 63 vs 60, and 55 vs 58 pts had HER2 IHC0, HER2-Low, and missing HER2 IHC results, respectively; 79% of the ITT population was HER2-evaluable. Baseline characteristics between HER2 IHC0 vs HER2-Low were comparable and similar to the ITT population. Median PFS and OS were significantly improved, and objective response rate was numerically higher with SG vs TPC in the HER2 IHC0 and HER2-Low groups (Table). HER2-Low had numerically better outcomes vs HER2 ICH0 in both the SG and TPC arms.
Conclusions
Clinical benefit with SG in HER2 IHC0 and HER2-Low mTNBC was consistent with that of the ASCENT ITT population, regardless of HER2 status. SG should be considered an effective treatment option for pts with mTNBC eligible for 2L or later therapy. ISH, in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; mPFS, median progression-free survival; mOS, median overall survival, ORR, objective response rate; SG, sacituzumab govitecan; TPC, treatment of physician’s choice ∗HER2-Low defined as IHC1+ or ICH2+ and ISH-neg
HER2 IHC0 HER2-Low∗ SG (n=149) TPC (n=144) SG (n=63) TPC (n=60) mPFS, mo 4.3 1.6 6.2 2.9 HR (95% CI) 0.38 (0.28-0.50) 0.44 (0.27-0.72) mOS, mo 11.3 5.9 14.0 8.7 HR (95% CI) 0.51 (0.39-0.66) 0.43 (0.28-0.67) ORR, n (%) 46 (31) 5 (3) 20 (32) 5 (8)
Clinical trial identification
NCT02574455.
Editorial acknowledgement
Editorial support was provided by Yao Bian, PhD, of Team 9 Science and funded by Gilead Sciences, Inc.
Legal entity responsible for the study
Gilead Sciences, Inc.
Funding
Gilead Sciences, Inc.
Disclosure
S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options; Financial Interests, Personal, Invited Speaker: aptitude health; Financial Interests, Personal, Invited Speaker: axis medical; Financial Interests, Personal, Invited Speaker: cancer expert now; Financial Interests, Personal, Invited Speaker: ICHE; Financial Interests, Personal, Invited Speaker: MJH Associates; Financial Interests, Personal, Invited Speaker: PER; Financial Interests, Personal, Invited Speaker: Primo; Financial Interests, Personal, Invited Speaker: Projects in Knowledge; Financial Interests, Personal, Invited Speaker: Prova Education; Financial Interests, Personal, Invited Speaker: Research to Practice; Financial Interests, Personal, Invited Speaker: Ultimate Medical Academy; Financial Interests, Personal, Invited Speaker: Vaniam; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Personal, Invited Speaker: Rockpointe; Financial Interests, Personal, Invited Speaker: OBR; Financial Interests, Personal, Invited Speaker: Peer Education; Financial Interests, Personal, Invited Speaker: Spire Learning; Financial Interests, Personal, Invited Speaker: PrecisCA; Financial Interests, Personal, Stocks/Shares, stock options: NK Max; Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal, Ownership Interest, spouse: Ideal Implant; Financial Interests, Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier; Financial Interests, Personal, Royalties: Springer; Financial Interests, Personal, Royalties: Sage; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Royalties: Wiley; Financial Interests, Institutional, Invited Speaker: Ambrx; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Arvinas; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Genentech/Roche; Financial Interests, Institutional, Invited Speaker: Gilead; Financial Interests, Institutional, Invited Speaker: GSK; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Pieris; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: Radius; Financial Interests, Institutional, Invited Speaker: sanofi; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Dignitana; Financial Interests, Institutional, Invited Speaker: Zymeworks; Financial Interests, Institutional, Invited Speaker: Phoenix Molecular Designs, Ltd.; Financial Interests, Institutional, Research Grant: Samumed; Financial Interests, Institutional, Research Grant: Ambrx; Non-Financial Interests, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Advisory Role: Novartis; Non-Financial Interests, Principal Investigator: Genentech; Non-Financial Interests, Principal Investigator: Seattle Genetics; Non-Financial Interests, Advisory Role: Ambrx; Non-Financial Interests, Advisory Role: 4DPharma; Non-Financial Interests, Advisory Role: Dantari; Non-Financial Interests, Advisory Role: Macrogenics; Non-Financial Interests, Advisory Role: Lilly; Non-Financial Interests, Advisory Role: Artios; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Advisory Role: Pyxis; Non-Financial Interests, Advisory Role: Amgen; Non-Financial Interests, Advisory Role: Pieris; Non-Financial Interests, Advisory Role: Arvinas; Non-Financial Interests, Advisory Role: Immunomedics/Gilead; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: AACR; Non-Financial Interests, Other, speaker: National Breast Cancer Coalition; Non-Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network. A. Bardia: Financial Interests, Institutional, Financial Interests, grants: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly; Financial Interests, Personal, Financial Interests, consulting fees: Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Foundation Medicine. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Advisory Board: Vifor Pharma; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Mundi Pharma; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: McCann Health; Financial Interests, Institutional, Advisory Board: Roularta; Financial Interests, Institutional, Advisory Board: Teva; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium. K. Kalinsky: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Cyclacel; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: 4D Pharma; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Stocks/Shares, Employment + Stock = spouse: Grail; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Calithera; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Acetylon; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Zentalis; Financial Interests, Institutional, Invited Speaker: CytomX Therapeutics; Other, Support for attending meetings and/or travel: Eli Lilly; Other, Support for attending meetings and/or travel: AstraZeneca; Other, Support for attending meetings and/or travel: Pfizer; Other, Steering Committee: Immunomedics; Other, Steering Committee: AstraZeneca; Other, Steering Committee: Ambryx; Other, Steering Committee: Genentech. J. Cortés: Financial Interests, Personal, Financial Interests, stock: Leuko, MedSIR, Nektar; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Lilly, Merck Sharp & Dohme, Daachi Sankyo; Financial Interests, Personal, Financial Interests, consulting or advisory role: Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daachi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer, Ingelheim, Ellipses Pharma, HiberCell; Financial Interests, Institutional, Financial Interests, research funding: Ariad, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai Farmaceutica, Guardaanth Health, Merck Sharp & Dohme, Pfizer, Puma Co, Queen Mary University of London, Roche, Piqur; Financial Interests, Personal, Financial Interests, travel, accomodations, expenses: Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax. H.S. Rugo: Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Advisory Board: samsung; Financial Interests, Personal, Invited Speaker: mylan; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Odonate; Financial Interests, Institutional, Invited Speaker: sermonix; Financial Interests, Institutional, Invited Speaker: seattle genetics; Financial Interests, Institutional, Invited Speaker: polyphor; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. O.K. Yoon: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead. Y. Pan: Financial Interests, Personal, Financial Interests, employee: Gilead. R.J. Delaney: Financial Interests, Personal, Financial Interests, employee, stock or stock options: Gilead. S. Hofsess: Financial Interests, Personal, Financial Interests, employee, meeting attendance, stock options: Gilead; Non-Financial Interests, Personal, Non-Financial Interests, unpaid: Chair of the William Paterson University Professional Science Master’s External Advisory Board. P. Hodgkins: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead Sciences. S. Phan: Financial Interests, Personal, Financial Interests, employee, grants or contracts, meeting attendance, stock or stock options, receipt of materials: Gilead. V. Dieras: Financial Interests, Personal, Financial Interests, consulting fees: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Pfizer, Lilly, AstraZeneca, Seagen, Daiichi Sankyo, Gilead, MSD; Financial Interests, Personal, Financial Interests, meeting attendance and/or travel: Roche, Novartis, Pfizer, Seagen, Lilly, AstraZeneca, Daiichi Sankyo, Gilead; Financial Interests, Personal, Financial Interests, data safety monitoring board or advisory board: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie. All other authors have declared no conflicts of interest.
207TiP - Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) (ID 215)
- Veronique Dieras (Rennes, France)
- Miguel Martin Jimenez (Madrid, Spain)
- Ciara C. O'Sullivan (Rochester, United States of America)
- Joohyuk Sohn (Seoul, Korea, Republic of)
- KONSTANTINOS TRYFONIDIS (North Wales, United States of America)
- Libero Santarpia (Bothell, United States of America)
- Shan Yang (Bothell, United States of America)
- Erika P. Hamilton (Nashville, United States of America)
Abstract
Background
The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL).
Trial design
HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned.
Clinical trial identification
NCT05132582.
Legal entity responsible for the study
Seagen Inc.
Funding
Seagen Inc.
Disclosure
V.C. Dieras: Financial Interests, Personal, Other, Travel Expenses: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi Sankyo, Seagen, Gilead, Eisai, Pierre Fabre Oncologie; Financial Interests, Personal, Other, Symposia: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Other, Honoraria: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Funding, Research Funding/Grants: Puma, Roche, Novartis. C.C.M. O'Sullivan: Financial Interests, Personal, Full or part-time Employment: Mayo Clinic Rochester; Financial Interests, Personal, Funding, Research Funding/Grants: Lilly, Seattle Genetics, Bavarian Nordic, Minnemarita Therapeutics, Biovica. J. Sohn: Financial Interests, Personal, Funding: Seagen Inc. K. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck. L. Santarpia, S. Yang: Financial Interests, Personal, Full or part-time Employment: Seagen Inc. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals; Financial Interests, Institutional: Pionyr Immunotherapeutics.
LBA1 - Unraveling the mechanism of action and resistance to Trastuzumab deruxtecan (T-DXd): biomarker analyses from patients from DAISY trial (ID 281)
- Maria Fernanda Mosele (Villejuif, France)
- Amélie Lusque (Toulouse, France)
- Veronique Dieras (Rennes, France)
- Elise Deluche (Limoges, France)
- Agnès Ducoulombier (Nice, France)
- Barbara Pistilli (Villejuif, France)
- Thomas Bachelot (Lyon, France)
- Frédéric Viret (Marseille, France)
- Christelle Levy (Caen, France)
- Nicolas Signolle (Villejuif, France)
- Diep TRAN (Villejuif, France)
- Ingrid J. Garberis (Villejuif, France)
- Loic Le-Bescond (Gif sur Yvette, France)
- ALICIA TRAN DIEN (Villejuif, Cedex, France)
- Nathalie Droin (Villejuif, Cedex, France)
- Maki Kobayashi (Tokyo, Japan)
- Tomoya Kakegawa (Tokyo, Japan)
- Marta Jimenez (Paris, France)
- Magali Lacroix-Triki (Villejuif, France)
- Fabrice André (Villejuif, France)
Abstract
Background
T-DXd is an anti-HER2 antibody-drug conjugate that has demonstrated high antitumor activity in HER2-positive and HER2-low metastatic breast cancer (mBC). We aimed to unravel the mechanism of action and resistance to T-DXd in patients from DAISY trial.
Methods
DAISY is a phase II clinical trial (NCT04132960) that assessed T-DXd efficacy in mBC according to HER2-expression (HER2-positive, HER2-low, and HER2-negative). Bystander effect and T-DXd uptake were analyzed by immunohistochemistry (IHC) (HER2, gH2AX, and T-DXd) on tumor biopsies at baseline and on-treatment (n=10 patients). T-DXd immune effects were explored by multiplex immunofluorescence (CD3, CD4, CD8, CD68, FoxP3, PD-1, PD-L1, CK/SOX10 antibodies) on tumor biopsies at baseline and on-treatment (Day 22 or 43, n=31 patients). Mechanisms of resistance were analyzed on tumor samples at baseline (n=118) and at progression by whole exome sequencing (n=24) and IHC (n=25). The predictive value of HER2 spatial distribution was investigated by artificial intelligence (AI) using weakly supervised and clustering algorithms on HER2-positive slides images at baseline (n=61).
Results
Molecular analyses showed that cancer cells expressing low levels of HER2, but not HER2-null cells, uptake T-DXd (p=0.053). In the whole population (n=31), a decrease of PDL1-positive cells was associated with a best objective response (BOR) (p=0.008). No modulation of T cells and macrophages was observed (p=0.6 and p=0.9 respectively). A decrease of PDL1 expression was detected in HER2-positive mBC (n=18; p=0.02). Clustering algorithms identified a cluster associated with a lower BOR (p=0.007), whose features identified by AI included a high percentage of HER2-negative cells currently under investigation. At progression, a decrease of HER2 expression was observed in 13/25 (52%) patients (p=0.07). DNA sequencing and final AI results will be available at the meeting.
Conclusions
A correlation between HER2 expression and T-DXd uptake in cancer cells was observed in on-treatment biopsies. T-DXd did not modulate intratumoral lymphocytes but decreased PDL1 expression. WES analyses at baseline and progression samples will be presented on-site.
Legal entity responsible for the study
The authors
Funding
Unicancer and Daiichi Sankyo
Disclosure
V. Dieras: Financial Interests, Personal, Advisory Board, Travel Expenses: Roche, Novartis, Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Invited Speaker, Travel Expenses: Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Principal Investigator, Travel Expenses: Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Principal Investigator: AbbVie; Non-Financial Interests, Personal, Advisory Board: Eisai, Pierre Fabre Oncologie. E. Deluche: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Fresenius Kabi, Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, scientific events: Lilly, GSK; Financial Interests, Personal, Other, funding for conference travel: AstraZeneca-Daiichi, Roche, Amgen. B. Pistilli: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, Pfizer; Financial Interests, Personal, Other, Consulting Fees: Myriad, Pierre Fabre; Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, Novartis, Puma; Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Novartis, Puma; Financial Interests, Personal, Other, Attending Meetings and/or Travel: AstraZeneca, Pierre Fabre, MSD; Financial Interests, Institutional, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche. D. Tran: Non-Financial Interests, Institutional, Full or part-time Employment, Full-time: DIEP T. N. TRAN. N. Droin: Non-Financial Interests, Institutional, Full or part-time Employment, Part-time: Nathalie Droin. M. Kobayashi, T. Kakegawa: Other, Personal, Full or part-time Employment, Employee of Daiichi Sankyo RD Novare, which belongs to Daiichi Sankyo Group. Daiichi Sankyo Group is developing T-DXd: Daiichi Sankyo RD Novare. M. Lacroix-Triki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Daiichi Sankyo. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.
Presenter Of 4 Presentations
Will new definitions for HER2 status make a difference for my patients? - An Oncologist’s perspective (ID 286)
Expanding perspectives: Progress in treatment choice in HER2- aBC (ID 375)
168P - Sacituzumab govitecan (SG) efficacy in patients with metastatic triple-negative breast cancer (mTNBC) by HER2 immunohistochemistry (IHC) status: Findings from the Phase 3 ASCENT study (ID 176)
- Sara A. Hurvitz (Los Angeles, United States of America)
- Aditya Bardia (Boston, United States of America)
- Kevin Punie (Leuven, Belgium)
- Kevin Kalinsky (Atlanta, United States of America)
- Javier Cortes (Madrid and Barcelona, Spain)
- Joyce O'Shaughnessy (Dallas, United States of America)
- Lisa A. Carey (Chapel Hill, United States of America)
- Hope S. Rugo (San Francisco, United States of America)
- Oh Kyu Yoon (Foster City, United States of America)
- Yang Pan (Foster City, United States of America)
- Rosemary J. Delaney (Foster City, United States of America)
- Scott Hofsess (Foster City, United States of America)
- Paul Hodgkins (Foster City, United States of America)
- See-Chun Phan (Foster City, United States of America)
- Veronique Dieras (Rennes, France)
Abstract
Background
HER2 IHC1+ or IHC2+ and in situ hybridization (ISH)-negative results are sometimes referred to as HER2-Low. SG is a novel antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved in mTNBC for the second line (2L) onwards. In the ASCENT study, SG had significant progression-free survival (PFS) and overall survival (OS) benefit vs chemotherapy of physician’s choice (TPC). This ASCENT post hoc subgroup analysis evaluates SG efficacy in HER2 IHC0 and HER2-Low mTNBC.
Methods
Patients (pts) with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity/progression. Primary endpoint was PFS per RECIST 1.1 by central review. Pts with known HER2-positive disease were ineligible, but HER2 status was not assessed centrally in ASCENT. Local HER2 IHC results were analyzed retrospectively.
Results
In the intent-to-treat (ITT) population (SG vs TPC), 149 vs 144, 63 vs 60, and 55 vs 58 pts had HER2 IHC0, HER2-Low, and missing HER2 IHC results, respectively; 79% of the ITT population was HER2-evaluable. Baseline characteristics between HER2 IHC0 vs HER2-Low were comparable and similar to the ITT population. Median PFS and OS were significantly improved, and objective response rate was numerically higher with SG vs TPC in the HER2 IHC0 and HER2-Low groups (Table). HER2-Low had numerically better outcomes vs HER2 ICH0 in both the SG and TPC arms.
Conclusions
Clinical benefit with SG in HER2 IHC0 and HER2-Low mTNBC was consistent with that of the ASCENT ITT population, regardless of HER2 status. SG should be considered an effective treatment option for pts with mTNBC eligible for 2L or later therapy. ISH, in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; mPFS, median progression-free survival; mOS, median overall survival, ORR, objective response rate; SG, sacituzumab govitecan; TPC, treatment of physician’s choice ∗HER2-Low defined as IHC1+ or ICH2+ and ISH-neg
HER2 IHC0 HER2-Low∗ SG (n=149) TPC (n=144) SG (n=63) TPC (n=60) mPFS, mo 4.3 1.6 6.2 2.9 HR (95% CI) 0.38 (0.28-0.50) 0.44 (0.27-0.72) mOS, mo 11.3 5.9 14.0 8.7 HR (95% CI) 0.51 (0.39-0.66) 0.43 (0.28-0.67) ORR, n (%) 46 (31) 5 (3) 20 (32) 5 (8)
Clinical trial identification
NCT02574455.
Editorial acknowledgement
Editorial support was provided by Yao Bian, PhD, of Team 9 Science and funded by Gilead Sciences, Inc.
Legal entity responsible for the study
Gilead Sciences, Inc.
Funding
Gilead Sciences, Inc.
Disclosure
S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options; Financial Interests, Personal, Invited Speaker: aptitude health; Financial Interests, Personal, Invited Speaker: axis medical; Financial Interests, Personal, Invited Speaker: cancer expert now; Financial Interests, Personal, Invited Speaker: ICHE; Financial Interests, Personal, Invited Speaker: MJH Associates; Financial Interests, Personal, Invited Speaker: PER; Financial Interests, Personal, Invited Speaker: Primo; Financial Interests, Personal, Invited Speaker: Projects in Knowledge; Financial Interests, Personal, Invited Speaker: Prova Education; Financial Interests, Personal, Invited Speaker: Research to Practice; Financial Interests, Personal, Invited Speaker: Ultimate Medical Academy; Financial Interests, Personal, Invited Speaker: Vaniam; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Personal, Invited Speaker: Rockpointe; Financial Interests, Personal, Invited Speaker: OBR; Financial Interests, Personal, Invited Speaker: Peer Education; Financial Interests, Personal, Invited Speaker: Spire Learning; Financial Interests, Personal, Invited Speaker: PrecisCA; Financial Interests, Personal, Stocks/Shares, stock options: NK Max; Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal, Ownership Interest, spouse: Ideal Implant; Financial Interests, Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier; Financial Interests, Personal, Royalties: Springer; Financial Interests, Personal, Royalties: Sage; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Royalties: Wiley; Financial Interests, Institutional, Invited Speaker: Ambrx; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Arvinas; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Genentech/Roche; Financial Interests, Institutional, Invited Speaker: Gilead; Financial Interests, Institutional, Invited Speaker: GSK; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Pieris; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: Radius; Financial Interests, Institutional, Invited Speaker: sanofi; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Dignitana; Financial Interests, Institutional, Invited Speaker: Zymeworks; Financial Interests, Institutional, Invited Speaker: Phoenix Molecular Designs, Ltd.; Financial Interests, Institutional, Research Grant: Samumed; Financial Interests, Institutional, Research Grant: Ambrx; Non-Financial Interests, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Advisory Role: Novartis; Non-Financial Interests, Principal Investigator: Genentech; Non-Financial Interests, Principal Investigator: Seattle Genetics; Non-Financial Interests, Advisory Role: Ambrx; Non-Financial Interests, Advisory Role: 4DPharma; Non-Financial Interests, Advisory Role: Dantari; Non-Financial Interests, Advisory Role: Macrogenics; Non-Financial Interests, Advisory Role: Lilly; Non-Financial Interests, Advisory Role: Artios; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Advisory Role: Pyxis; Non-Financial Interests, Advisory Role: Amgen; Non-Financial Interests, Advisory Role: Pieris; Non-Financial Interests, Advisory Role: Arvinas; Non-Financial Interests, Advisory Role: Immunomedics/Gilead; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: AACR; Non-Financial Interests, Other, speaker: National Breast Cancer Coalition; Non-Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network. A. Bardia: Financial Interests, Institutional, Financial Interests, grants: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly; Financial Interests, Personal, Financial Interests, consulting fees: Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Foundation Medicine. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Advisory Board: Vifor Pharma; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Mundi Pharma; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: McCann Health; Financial Interests, Institutional, Advisory Board: Roularta; Financial Interests, Institutional, Advisory Board: Teva; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium. K. Kalinsky: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Cyclacel; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: 4D Pharma; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Stocks/Shares, Employment + Stock = spouse: Grail; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Calithera; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Acetylon; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Zentalis; Financial Interests, Institutional, Invited Speaker: CytomX Therapeutics; Other, Support for attending meetings and/or travel: Eli Lilly; Other, Support for attending meetings and/or travel: AstraZeneca; Other, Support for attending meetings and/or travel: Pfizer; Other, Steering Committee: Immunomedics; Other, Steering Committee: AstraZeneca; Other, Steering Committee: Ambryx; Other, Steering Committee: Genentech. J. Cortés: Financial Interests, Personal, Financial Interests, stock: Leuko, MedSIR, Nektar; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Lilly, Merck Sharp & Dohme, Daachi Sankyo; Financial Interests, Personal, Financial Interests, consulting or advisory role: Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daachi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer, Ingelheim, Ellipses Pharma, HiberCell; Financial Interests, Institutional, Financial Interests, research funding: Ariad, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai Farmaceutica, Guardaanth Health, Merck Sharp & Dohme, Pfizer, Puma Co, Queen Mary University of London, Roche, Piqur; Financial Interests, Personal, Financial Interests, travel, accomodations, expenses: Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax. H.S. Rugo: Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Advisory Board: samsung; Financial Interests, Personal, Invited Speaker: mylan; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Odonate; Financial Interests, Institutional, Invited Speaker: sermonix; Financial Interests, Institutional, Invited Speaker: seattle genetics; Financial Interests, Institutional, Invited Speaker: polyphor; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. O.K. Yoon: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead. Y. Pan: Financial Interests, Personal, Financial Interests, employee: Gilead. R.J. Delaney: Financial Interests, Personal, Financial Interests, employee, stock or stock options: Gilead. S. Hofsess: Financial Interests, Personal, Financial Interests, employee, meeting attendance, stock options: Gilead; Non-Financial Interests, Personal, Non-Financial Interests, unpaid: Chair of the William Paterson University Professional Science Master’s External Advisory Board. P. Hodgkins: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead Sciences. S. Phan: Financial Interests, Personal, Financial Interests, employee, grants or contracts, meeting attendance, stock or stock options, receipt of materials: Gilead. V. Dieras: Financial Interests, Personal, Financial Interests, consulting fees: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Pfizer, Lilly, AstraZeneca, Seagen, Daiichi Sankyo, Gilead, MSD; Financial Interests, Personal, Financial Interests, meeting attendance and/or travel: Roche, Novartis, Pfizer, Seagen, Lilly, AstraZeneca, Daiichi Sankyo, Gilead; Financial Interests, Personal, Financial Interests, data safety monitoring board or advisory board: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie. All other authors have declared no conflicts of interest.
207TiP - Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) (ID 215)
- Veronique Dieras (Rennes, France)
- Miguel Martin Jimenez (Madrid, Spain)
- Ciara C. O'Sullivan (Rochester, United States of America)
- Joohyuk Sohn (Seoul, Korea, Republic of)
- KONSTANTINOS TRYFONIDIS (North Wales, United States of America)
- Libero Santarpia (Bothell, United States of America)
- Shan Yang (Bothell, United States of America)
- Erika P. Hamilton (Nashville, United States of America)
Abstract
Background
The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL).
Trial design
HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned.
Clinical trial identification
NCT05132582.
Legal entity responsible for the study
Seagen Inc.
Funding
Seagen Inc.
Disclosure
V.C. Dieras: Financial Interests, Personal, Other, Travel Expenses: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi Sankyo, Seagen, Gilead, Eisai, Pierre Fabre Oncologie; Financial Interests, Personal, Other, Symposia: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Other, Honoraria: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Funding, Research Funding/Grants: Puma, Roche, Novartis. C.C.M. O'Sullivan: Financial Interests, Personal, Full or part-time Employment: Mayo Clinic Rochester; Financial Interests, Personal, Funding, Research Funding/Grants: Lilly, Seattle Genetics, Bavarian Nordic, Minnemarita Therapeutics, Biovica. J. Sohn: Financial Interests, Personal, Funding: Seagen Inc. K. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck. L. Santarpia, S. Yang: Financial Interests, Personal, Full or part-time Employment: Seagen Inc. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals; Financial Interests, Institutional: Pionyr Immunotherapeutics.