Erika P. Hamilton (Nashville, United States of America)
Sarah Cannon Research Institute-Cancer CentreAuthor Of 3 Presentations
162O - Primary analysis from DS8201-A-U105: A 2-part, open label, phase 1b trial assessing trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer (ID 304)
- Erika P. Hamilton (Nashville, United States of America)
- Charles L. Shapiro (New York, United States of America)
- Valentina Boni (Madrid, Spain)
- Miguel Martin Jimenez (Madrid, Spain)
- Gianluca Del Conte (Milan, Italy)
- Javier Cortes (Madrid and Barcelona, Spain)
- LAILA Agrawal (Louisville, United States of America)
- Hendrik-Tobias Arkenau (London, United Kingdom)
- Antoinette R. Tan (Charlotte, United States of America)
- Philip R. Debruyne (Cambridge, United Kingdom)
- Anna R. Minchom (London, United Kingdom)
- Annemie Rutten (Wilrijk, Belgium)
- Frances Valdes-Albini (Miami, United States of America)
- Evan Yu (Seattle, United States of America)
- Fumitaka Suto (Basking Ridge, United States of America)
- Fu-Chih Cheng (Basking Ridge, United States of America)
- Bincy Augustine (Basking Ridge, United States of America)
- Ben Cheng (Basking Ridge, United States of America)
- Daniel Barrios (Basking Ridge, United States of America)
- Sara A. Hurvitz (Los Angeles, United States of America)
Abstract
Background
In DESTINY-Breast01 (NCT03248492), T-DXd showed efficacy and safety in pts with HER2+ metastatic breast cancer (MBC) with prior T-DM1. Preclinical models showed that T-DXd combined with an anti–PD-1 antibody had greater efficacy vs either agent alone (Iwata Mol Cancer Ther 2018). This was a 2-part, open-label, multicenter, phase 1b study of T-DXd with nivo in pts with HER2-expressing MBC or advanced urothelial cancer (NCT03523572). Primary results from part 2 for MBC pts are reported.
Methods
Pts were immunotherapy naive with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+) MBC after T-DM1 or HER2 low (IHC 1+ or IHC 2+/ISH-) MBC after standard-of-care. Pts received the recommended dose for expansion T-DXd 5.4 mg/kg and nivo 360 mg IV Q3W. The primary endpoint was confirmed ORR (cORR) assessed by independent central review (ICR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), and safety.
Results
At the primary analysis data cutoff (July 22, 2021), 48 pts (HER2+, n = 32; HER2 low, n = 16) received T-DXd and nivo. Median follow-up duration was 18.7 mo for HER2+ pts and 12.7 mo for HER2-low pts. The cORR by ICR was 65.6% (95% CI, 46.8-81.4) and 50% (95% CI, 24.7-75.3); median PFS was 11.6 mo (95% CI, 6.9-NE) and 7.0 mo (95% CI, 2.3-10.8); and median DOR was NE (95% CI, 7.9-NE) and 5.5 mo (95% CI, 2.8-8.0) for HER2+ and HER2 low pts, respectively. Overall, median treatment duration was 7.9 mo for T-DXd and 5.8 mo for nivo. In parts 1 and 2 (T-DXd 5.4 mg/kg, nivo 360 mg; n = 48), TEAEs grade ≥3 occurred in 50.0% of pts; nausea (56.3%) was the most common any-grade TEAE; and 7 (14.6%) HER2+ pts had adjudicated drug-related interstitial lung disease (6 grade 2; 1 grade 5).
Conclusions
Results of T-DXd plus nivo show antitumor activity consistent with previously reported data for T-DXd monotherapy in HER2+ BC, with no discernable benefit with the addition of nivo in this late-line setting. Data from the small HER2-low cohort are insufficient to determine the effects of PD-1/PD-L1 combination therapy. The combination safety profile was similar to that of each study drug as monotherapy.
Clinical trial identification
NCT03523572.
Editorial acknowledgement
Under the guidance of authors, assistance in medical writing and editorial support was provided by Jill Seabrook, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.
Legal entity responsible for the study
Daiichi Sankyo, Inc. and AstraZeneca.
Funding
Daiichi Sankyo, Inc. and AstraZeneca.
Disclosure
E.P. Hamilton: Financial Interests, Institutional, Advisory Board: Arcus, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech; Financial Interests, Institutional, Research Grant: AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, 3 ArQule, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Inst., Deciphera, eFFECTOR The. C.L. Shapiro: Financial Interests, Personal, Other, Honoraria: UF Breast Symposium; Financial Interests, Personal, Advisory Board: 2nd MD, Anthenum, Gilead; Financial Interests, Personal, Other, Royalties: UptoDate. V. Boni: Financial Interests, Personal, Other, Honoraria: Director of Clinical Cancer Research, NEXT Madrid, Universitary Hospital QuirónSalud Pozuelo; Financial Interests, Institutional, Other, Honoraria: AbbVie; ACEO; Adaptaimmune; Amcure; Amgen; AstraZeneca; BMS Cytomx; GSK; Genentech/Roche; H3; Incyte; Janssen; Kura; Lilly; Loxo; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; Puma; Sanofi; Taiho; Tesaro; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly. M. Martin Jimenez: Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Daiichi Sankyo, Seagen, AstraZeneca, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: Roche, Novartis, Daiichi Sankyo, Seagen, AstraZeneca, Pfizer, Lilly; Financial Interests, Institutional, Research Grant: Roche, Puma, Novartis. G. Del Conte: Financial Interests, Personal, Advisory Board: Novartis, BMS; Financial Interests, Personal, Other, Travel Expenses: Janssen, Astellas, Pfizer. J. Cortés: Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymework; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman- La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca. L. Agrawal: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Immunomedics, Breast Cancer Index; Financial Interests, Personal, Speaker’s Bureau: Lilly. H. Arkenau: Financial Interests, Personal, Advisory Board: Roche, LabGenius, Cell Centric, Daiichi Sankyo, Bicycle Therapeutics; Guardant Health, BioNTech, Bayer, Beigene, Servier; Financial Interests, Personal, Other, Honoraria: Bicycle Therapeutics, BioNTech, Bayer, Beigene, Servier, Roche and Guardant Health; Financial Interests, Personal, Other, Travel Expenses: Amgen; Financial Interests, Personal, Full or part-time Employment: Sarah Cannon. A.R. Tan: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi Sankyo. P.R. Debruyne: Financial Interests, Personal, Other, Honoraria: BMS, Merck/Pfizer, MSD, Roche, Bayer; Financial Interests, Personal, Stocks/Shares: Alkermes; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Janssen. A.R. Minchom: Financial Interests, Personal, Other, Honoraria: Chugai Pharmaceuticals, Novartis Oncology, Faron Pharmaceuticals, Bayer Pharmaceuticals; Financial Interests, Personal, Advisory Board: Janssen Pharmaceuticals, Merck Pharmaceuticals, Takeda Pharmaceuticals and Genmab Pharmaceuticals; Financial Interests, Personal, Other, Travel Expenses: Amgen Pharmaceuticals and LOXO Oncology. E. Yu: Financial Interests, Personal, Advisory Board: Advanced Accelerator Applications, Bayer, Janssen, Merck, Exelus, Clovis, AbbVie, Sanofi; Financial Interests, Invited Speaker: Daiichi Sankyo, Dendreon, Taiho, Merck, Seagen, Blue Earth, Bayer, Lantheus. F. Suto, F. Cheng, B. Augustine, B. Cheng, D. Barrios: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo, Inc. S.A. Hurvitz: Financial Interests, Institutional, Research Grant: Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Orinove, Pieris, Puma, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks, Pho; Financial Interests, Personal, Principal Investigator: Novartis, Daiichi Sankyo, Seagen, GNE/Roche; Financial Interests, Personal, Advisory Board: Novartis, Lilly, Daiichi Sankyo/AZ, GNE/Roche, Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Lilly; Non-Financial Interests, Personal, Other, Uncompensated consulting/ad boards: 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Lilly, Novartis, NK Max, Pieris, Pyxis, Seagen, Biotheranostics. All other authors have declared no conflicts of interest.
204TiP - A Phase II Study of HER3-DXD in Patients (pts) with Metastatic Breast Cancer (MBC) (ID 212)
- Erika P. Hamilton (Nashville, United States of America)
- Nusayba A. Bagegni (St. Louis, United States of America)
- J. T. Beck (Springdale, United States of America)
- Jennifer L. Cultrera (The Villages, United States of America)
- Ololade Dosunmu (Nashville, United States of America)
- William R. Gwin (Seattle, United States of America)
- Arielle L. Heeke (Charlotte, United States of America)
- Katia Khoury (Birmingham, United States of America)
- Dalila Sellami (Basking Ridge, United States of America)
- Mythili Shastry (Nashville, United States of America)
- David W. Sternberg (Basking Ridge, United States of America)
- Deborah Toppmeyer (New Brunswick, United States of America)
- Vance M. Wright-Browne (Port Charlotte, United States of America)
- Yuan Yuan (Duarte, United States of America)
Abstract
Background
HER3, a member of the HER receptor tyrosine kinase (RTK) family, is overexpressed in many solid tumors including breast cancer (BC), and this overexpression is associated with decreased survival. HER3 lacks intrinsic kinase activity and forms heterodimers with other RTKs, most notably HER2, and subsequent downstream signaling promotes tumorigenesis and metastasis. HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative (DXd), via a tetrapeptide-based cleavable linker. A phase I/II study with HER3-DXD demonstrated the safety and preliminary clinical activity in heavily pretreated HER2-negative (HER2-) MBC pts regardless of high/low HER3 expression. This phase II study is investigating HER3-DXD in MBC to determine the subset of pts likely to derive the greatest benefit (NCT04699630).
Trial design
The study will enroll ∼120 pts with HER2- locally advanced or MBC in 2 Parts. Males/females ≥18 years with an ECOG PS 0-1 with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 are eligible. Pts with triple-negative BC are allowed 1-3 prior lines of chemotherapy (chemo). Hormone receptor (HR)+ pts require prior endocrine therapy (ET) + CDK 4/6 inhibitor with no limit on prior ET lines; only 0-2 prior chemos for MBC are allowed. Prior treatment (Tx) with anti-HER3 targeting agents is exclusionary. Primary endpoints are overall response rate and 6-month progression-free survival. Patients will undergo CT scans every 6 weeks (wks) for 6 months, then every 9 wks thereafter. Part A will enroll ∼60 pts who will provide pre-Tx tissue to determine whether specific biomarker expression (ER/PR/HER2/HER3) show higher preliminary efficacy after 24-wk analysis. Blood for correlatives and on-Tx biopsy samples are required. Part B will enroll ∼60 pts (20 pts in up to 3 subgroups) as defined from the biomarker expression pattern and preliminary efficacy findings from Part A. Pts from the same biomarker subgroups in Parts A and B will be pooled for the final efficacy analysis. Enrollment to Part A was initiated in November 2020.
Clinical trial identification
NCT04699630.
Legal entity responsible for the study
Sarah Cannon Development Innovations, LLC.
Funding
Daiichi Sankyo, Inc.
Disclosure
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; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs. N.A. Bagegni: Financial Interests, Institutional, Invited Speaker: Sermonix Pharmaceuticals, Inc., Pfizer, AstraZeneca, Daiichi Sankyo, Xcovery Holding Company, LLC, Novartis Pharmaceuticals, Inc. J.T. Beck: Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo. W.R. Gwin: Financial Interests, Personal, Invited Speaker, Honorarium: AstraZeneca, Puma; Financial Interests, Personal and Institutional, Invited Speaker: Veanna Therapeutics. A.L. Heeke: Financial Interests, Personal, Invited Speaker, Speaking fees: Merck; Financial Interests, Institutional, Invited Speaker, Consulting: Amgen, Pfizer, Daiichi Sankyo, Caris Life Sciences. D. Sellami, D.W. Sternberg: Financial Interests, Personal, Invited Speaker, Stock ownership: Daiichi Sankyo. D. Toppmeyer: Financial Interests, Personal, Invited Speaker: Merck. Y. Yuan: Financial Interests, Personal and Institutional, Invited Speaker, Research Support, Consultant, Speaker: Eisai, Novartis, Pfizer; Financial Interests, Personal and Institutional, Invited Speaker, Research Support, Speaker: Genentech; Financial Interests, Institutional, Invited Speaker, Research Support: Merck, Puma; Financial Interests, Personal and Institutional, Invited Speaker, Consultant, Speaker: Immunomedics; Financial Interests, Personal, Invited Speaker, Speaker: AstraZeneca, Daiichi Sankyo. 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.
Presenter Of 2 Presentations
162O - Primary analysis from DS8201-A-U105: A 2-part, open label, phase 1b trial assessing trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer (ID 304)
- Erika P. Hamilton (Nashville, United States of America)
- Charles L. Shapiro (New York, United States of America)
- Valentina Boni (Madrid, Spain)
- Miguel Martin Jimenez (Madrid, Spain)
- Gianluca Del Conte (Milan, Italy)
- Javier Cortes (Madrid and Barcelona, Spain)
- LAILA Agrawal (Louisville, United States of America)
- Hendrik-Tobias Arkenau (London, United Kingdom)
- Antoinette R. Tan (Charlotte, United States of America)
- Philip R. Debruyne (Cambridge, United Kingdom)
- Anna R. Minchom (London, United Kingdom)
- Annemie Rutten (Wilrijk, Belgium)
- Frances Valdes-Albini (Miami, United States of America)
- Evan Yu (Seattle, United States of America)
- Fumitaka Suto (Basking Ridge, United States of America)
- Fu-Chih Cheng (Basking Ridge, United States of America)
- Bincy Augustine (Basking Ridge, United States of America)
- Ben Cheng (Basking Ridge, United States of America)
- Daniel Barrios (Basking Ridge, United States of America)
- Sara A. Hurvitz (Los Angeles, United States of America)
Abstract
Background
In DESTINY-Breast01 (NCT03248492), T-DXd showed efficacy and safety in pts with HER2+ metastatic breast cancer (MBC) with prior T-DM1. Preclinical models showed that T-DXd combined with an anti–PD-1 antibody had greater efficacy vs either agent alone (Iwata Mol Cancer Ther 2018). This was a 2-part, open-label, multicenter, phase 1b study of T-DXd with nivo in pts with HER2-expressing MBC or advanced urothelial cancer (NCT03523572). Primary results from part 2 for MBC pts are reported.
Methods
Pts were immunotherapy naive with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+) MBC after T-DM1 or HER2 low (IHC 1+ or IHC 2+/ISH-) MBC after standard-of-care. Pts received the recommended dose for expansion T-DXd 5.4 mg/kg and nivo 360 mg IV Q3W. The primary endpoint was confirmed ORR (cORR) assessed by independent central review (ICR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), and safety.
Results
At the primary analysis data cutoff (July 22, 2021), 48 pts (HER2+, n = 32; HER2 low, n = 16) received T-DXd and nivo. Median follow-up duration was 18.7 mo for HER2+ pts and 12.7 mo for HER2-low pts. The cORR by ICR was 65.6% (95% CI, 46.8-81.4) and 50% (95% CI, 24.7-75.3); median PFS was 11.6 mo (95% CI, 6.9-NE) and 7.0 mo (95% CI, 2.3-10.8); and median DOR was NE (95% CI, 7.9-NE) and 5.5 mo (95% CI, 2.8-8.0) for HER2+ and HER2 low pts, respectively. Overall, median treatment duration was 7.9 mo for T-DXd and 5.8 mo for nivo. In parts 1 and 2 (T-DXd 5.4 mg/kg, nivo 360 mg; n = 48), TEAEs grade ≥3 occurred in 50.0% of pts; nausea (56.3%) was the most common any-grade TEAE; and 7 (14.6%) HER2+ pts had adjudicated drug-related interstitial lung disease (6 grade 2; 1 grade 5).
Conclusions
Results of T-DXd plus nivo show antitumor activity consistent with previously reported data for T-DXd monotherapy in HER2+ BC, with no discernable benefit with the addition of nivo in this late-line setting. Data from the small HER2-low cohort are insufficient to determine the effects of PD-1/PD-L1 combination therapy. The combination safety profile was similar to that of each study drug as monotherapy.
Clinical trial identification
NCT03523572.
Editorial acknowledgement
Under the guidance of authors, assistance in medical writing and editorial support was provided by Jill Seabrook, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.
Legal entity responsible for the study
Daiichi Sankyo, Inc. and AstraZeneca.
Funding
Daiichi Sankyo, Inc. and AstraZeneca.
Disclosure
E.P. Hamilton: Financial Interests, Institutional, Advisory Board: Arcus, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech; Financial Interests, Institutional, Research Grant: AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, 3 ArQule, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Inst., Deciphera, eFFECTOR The. C.L. Shapiro: Financial Interests, Personal, Other, Honoraria: UF Breast Symposium; Financial Interests, Personal, Advisory Board: 2nd MD, Anthenum, Gilead; Financial Interests, Personal, Other, Royalties: UptoDate. V. Boni: Financial Interests, Personal, Other, Honoraria: Director of Clinical Cancer Research, NEXT Madrid, Universitary Hospital QuirónSalud Pozuelo; Financial Interests, Institutional, Other, Honoraria: AbbVie; ACEO; Adaptaimmune; Amcure; Amgen; AstraZeneca; BMS Cytomx; GSK; Genentech/Roche; H3; Incyte; Janssen; Kura; Lilly; Loxo; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; Puma; Sanofi; Taiho; Tesaro; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly. M. Martin Jimenez: Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Daiichi Sankyo, Seagen, AstraZeneca, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: Roche, Novartis, Daiichi Sankyo, Seagen, AstraZeneca, Pfizer, Lilly; Financial Interests, Institutional, Research Grant: Roche, Puma, Novartis. G. Del Conte: Financial Interests, Personal, Advisory Board: Novartis, BMS; Financial Interests, Personal, Other, Travel Expenses: Janssen, Astellas, Pfizer. J. Cortés: Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymework; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman- La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca. L. Agrawal: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Immunomedics, Breast Cancer Index; Financial Interests, Personal, Speaker’s Bureau: Lilly. H. Arkenau: Financial Interests, Personal, Advisory Board: Roche, LabGenius, Cell Centric, Daiichi Sankyo, Bicycle Therapeutics; Guardant Health, BioNTech, Bayer, Beigene, Servier; Financial Interests, Personal, Other, Honoraria: Bicycle Therapeutics, BioNTech, Bayer, Beigene, Servier, Roche and Guardant Health; Financial Interests, Personal, Other, Travel Expenses: Amgen; Financial Interests, Personal, Full or part-time Employment: Sarah Cannon. A.R. Tan: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi Sankyo. P.R. Debruyne: Financial Interests, Personal, Other, Honoraria: BMS, Merck/Pfizer, MSD, Roche, Bayer; Financial Interests, Personal, Stocks/Shares: Alkermes; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Janssen. A.R. Minchom: Financial Interests, Personal, Other, Honoraria: Chugai Pharmaceuticals, Novartis Oncology, Faron Pharmaceuticals, Bayer Pharmaceuticals; Financial Interests, Personal, Advisory Board: Janssen Pharmaceuticals, Merck Pharmaceuticals, Takeda Pharmaceuticals and Genmab Pharmaceuticals; Financial Interests, Personal, Other, Travel Expenses: Amgen Pharmaceuticals and LOXO Oncology. E. Yu: Financial Interests, Personal, Advisory Board: Advanced Accelerator Applications, Bayer, Janssen, Merck, Exelus, Clovis, AbbVie, Sanofi; Financial Interests, Invited Speaker: Daiichi Sankyo, Dendreon, Taiho, Merck, Seagen, Blue Earth, Bayer, Lantheus. F. Suto, F. Cheng, B. Augustine, B. Cheng, D. Barrios: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo, Inc. S.A. Hurvitz: Financial Interests, Institutional, Research Grant: Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Orinove, Pieris, Puma, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks, Pho; Financial Interests, Personal, Principal Investigator: Novartis, Daiichi Sankyo, Seagen, GNE/Roche; Financial Interests, Personal, Advisory Board: Novartis, Lilly, Daiichi Sankyo/AZ, GNE/Roche, Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Lilly; Non-Financial Interests, Personal, Other, Uncompensated consulting/ad boards: 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Lilly, Novartis, NK Max, Pieris, Pyxis, Seagen, Biotheranostics. All other authors have declared no conflicts of interest.
204TiP - A Phase II Study of HER3-DXD in Patients (pts) with Metastatic Breast Cancer (MBC) (ID 212)
- Erika P. Hamilton (Nashville, United States of America)
- Nusayba A. Bagegni (St. Louis, United States of America)
- J. T. Beck (Springdale, United States of America)
- Jennifer L. Cultrera (The Villages, United States of America)
- Ololade Dosunmu (Nashville, United States of America)
- William R. Gwin (Seattle, United States of America)
- Arielle L. Heeke (Charlotte, United States of America)
- Katia Khoury (Birmingham, United States of America)
- Dalila Sellami (Basking Ridge, United States of America)
- Mythili Shastry (Nashville, United States of America)
- David W. Sternberg (Basking Ridge, United States of America)
- Deborah Toppmeyer (New Brunswick, United States of America)
- Vance M. Wright-Browne (Port Charlotte, United States of America)
- Yuan Yuan (Duarte, United States of America)
Abstract
Background
HER3, a member of the HER receptor tyrosine kinase (RTK) family, is overexpressed in many solid tumors including breast cancer (BC), and this overexpression is associated with decreased survival. HER3 lacks intrinsic kinase activity and forms heterodimers with other RTKs, most notably HER2, and subsequent downstream signaling promotes tumorigenesis and metastasis. HER3-DXd is an antibody drug conjugate (ADC) comprised of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab), covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative (DXd), via a tetrapeptide-based cleavable linker. A phase I/II study with HER3-DXD demonstrated the safety and preliminary clinical activity in heavily pretreated HER2-negative (HER2-) MBC pts regardless of high/low HER3 expression. This phase II study is investigating HER3-DXD in MBC to determine the subset of pts likely to derive the greatest benefit (NCT04699630).
Trial design
The study will enroll ∼120 pts with HER2- locally advanced or MBC in 2 Parts. Males/females ≥18 years with an ECOG PS 0-1 with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 are eligible. Pts with triple-negative BC are allowed 1-3 prior lines of chemotherapy (chemo). Hormone receptor (HR)+ pts require prior endocrine therapy (ET) + CDK 4/6 inhibitor with no limit on prior ET lines; only 0-2 prior chemos for MBC are allowed. Prior treatment (Tx) with anti-HER3 targeting agents is exclusionary. Primary endpoints are overall response rate and 6-month progression-free survival. Patients will undergo CT scans every 6 weeks (wks) for 6 months, then every 9 wks thereafter. Part A will enroll ∼60 pts who will provide pre-Tx tissue to determine whether specific biomarker expression (ER/PR/HER2/HER3) show higher preliminary efficacy after 24-wk analysis. Blood for correlatives and on-Tx biopsy samples are required. Part B will enroll ∼60 pts (20 pts in up to 3 subgroups) as defined from the biomarker expression pattern and preliminary efficacy findings from Part A. Pts from the same biomarker subgroups in Parts A and B will be pooled for the final efficacy analysis. Enrollment to Part A was initiated in November 2020.
Clinical trial identification
NCT04699630.
Legal entity responsible for the study
Sarah Cannon Development Innovations, LLC.
Funding
Daiichi Sankyo, Inc.
Disclosure
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; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs. N.A. Bagegni: Financial Interests, Institutional, Invited Speaker: Sermonix Pharmaceuticals, Inc., Pfizer, AstraZeneca, Daiichi Sankyo, Xcovery Holding Company, LLC, Novartis Pharmaceuticals, Inc. J.T. Beck: Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo. W.R. Gwin: Financial Interests, Personal, Invited Speaker, Honorarium: AstraZeneca, Puma; Financial Interests, Personal and Institutional, Invited Speaker: Veanna Therapeutics. A.L. Heeke: Financial Interests, Personal, Invited Speaker, Speaking fees: Merck; Financial Interests, Institutional, Invited Speaker, Consulting: Amgen, Pfizer, Daiichi Sankyo, Caris Life Sciences. D. Sellami, D.W. Sternberg: Financial Interests, Personal, Invited Speaker, Stock ownership: Daiichi Sankyo. D. Toppmeyer: Financial Interests, Personal, Invited Speaker: Merck. Y. Yuan: Financial Interests, Personal and Institutional, Invited Speaker, Research Support, Consultant, Speaker: Eisai, Novartis, Pfizer; Financial Interests, Personal and Institutional, Invited Speaker, Research Support, Speaker: Genentech; Financial Interests, Institutional, Invited Speaker, Research Support: Merck, Puma; Financial Interests, Personal and Institutional, Invited Speaker, Consultant, Speaker: Immunomedics; Financial Interests, Personal, Invited Speaker, Speaker: AstraZeneca, Daiichi Sankyo. All other authors have declared no conflicts of interest.