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

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.