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Clinical Trial
. 2024 Dec 16;30(24):5548-5558.
doi: 10.1158/1078-0432.CCR-24-1513.

Trastuzumab Deruxtecan with Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study

Erika Hamilton  1 , Matthew D Galsky  2 , Sebastian Ochsenreither  3 , Gianluca Del Conte  4 , Miguel Martín  5 , Maria José De Miguel  6 , Evan Y Yu  7 , Anja Williams  8 , Maria Gion  9   10 , Antoinette R Tan  11 , Laila Agrawal  12 , Annemie Rutten  13 , Jean-Pascal Machiels  14 , Sara Cresta  15 , Philip R Debruyne  16   17   18 , Audrey Hennequin  19 , Victor Moreno  20 , Anna Minchom  21 , Frances Valdes-Albini  22   23 , Daniel Petrylak  24 , Li Li  25 , Zenta Tsuchihashi  26 , Fumitaka Suto  26 , Fu-Chih Cheng  27 , Maha Kandil  28 , Daniel Barrios  29 , Sara Hurvitz  7   30
Affiliations
Clinical Trial

Trastuzumab Deruxtecan with Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study

Erika Hamilton et al. Clin Cancer Res. .

Abstract

Purpose: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).

Patients and methods: Part 1 determined the recommended dose for expansion of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate by independent central review.

Results: In part 1, seven patients with mBC were enrolled and received T-DXd 3.2 mg/kg (four patients) or 5.4 mg/kg (three patients) plus nivolumab. The recommended dose for expansion for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously every 3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of three administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and four with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the confirmed objective response rates (95% confidence interval) for cohorts 1 to 4 were 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. The median treatment duration (range) with T-DXd in cohorts 1 to 4 was 8.9 (1-23) months, 6.9 (1-21) months, 3.9 (1-21) months, and not assessed, respectively; the most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, and 75.0%, respectively). Adjudicated drug-related interstitial lung disease/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0%, respectively (one grade 5 each, cohorts 1 and 3).

Conclusions: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T-DXd. Interstitial lung disease/pneumonitis is an important risk and requires careful monitoring and prompt intervention.

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Conflict of interest statement

E. Hamilton reports grants and other support from Daiichi Sankyo during the conduct of the study, as well as grants and other support from Accutar Biotechnology, Arvinas, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Gilead Sciences, Eli Lilly and Company, Mersana, Novartis, Olema, Pfizer, Roche/Genentech, and Stemline Therapeutics, grants from AbbVie, Acerta Pharma, ADC Therapeutics, Akesobio Australia, Amgen, Aravive, ArQule, Artios, Atlas Medx, BeiGene, Black Diamond, Bliss Biopharmaceutical, Boehringer Ingelheim, Bristol Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Context Therapeutics, Cullinan, Curis, CytomX, Dana-Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, Fujifilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchison MediPharma, ImmunoGen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InventisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Loxo Oncology, Lycera, MabSpace Biosciences, MacroGenics, MedImmune, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, NuCana, OncoMed, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Pharmaceuticals, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, ProfoundBio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicines, RGENIX, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, Stemcentrx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks, and other support from Circle Pharma, Entos, Fosun Pharma, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson and Johnson, Medical Pharma Services, Tempus Labs, Theratechnologies, Tubulis, Verascity Science, and Zentalis Pharmaceuticals outside the submitted work. M.D. Galsky reports personal fees from Astellas, Bristol Myers Squibb, Merck, Genentech, AstraZeneca, EMD Serono, Seagen, Janssen, Numab, Dragonfly, GSK, Basilea, UroGen, Rappta Therapeutics, Fujifilm, Curis, Gilead Sciences, Asieris, AbbVie, Daiichi Sankyo, and Aktis outside the submitted work. S. Ochsenreither reports other support from Daiichi Sankyo during the conduct of the study; personal fees from Bristol Myers Squibb, Genmab, Immunocore, Ipsen, Janssen, Merck, MSD, and Pfizer; grants from Bayer outside the submitted work; and a patent on T-cell Therapy Target licensed to Fred Hutchinson Cancer Research Center, Seattle, WA. G. Del Conte reports other support from MSD Italia Srl, Janssen-Cilag SpA, and Daiichi Sankyo outside the submitted work. M. Martín reports grants and personal fees from Roche and Novartis and personal fees from Pfizer, Puma, Eli Lilly and Company, Daiichi Sankyo, AstraZeneca, GSK, and MSD outside the submitted work. E.Y. Yu reports grants from Daiichi Sankyo during the conduct of the study, as well as personal fees from Bristol Myers Squibb and grants from Seagen outside the submitted work. A. Williams reports personal fees from Ellipses Pharma and Hospital Corporation of America International outside the submitted work. M. Gion reports grants from AstraZeneca, Gilead, Pfizer, and Novartis outside the submitted work. A.R. Tan reports other support from Merck, Genentech, and GlaxoSmithKline and personal fees from AstraZeneca outside the submitted work. L. Agrawal reports personal fees from Eli Lilly and Company, Pfizer, AstraZeneca, and Breast Cancer Index outside the submitted work. J.-P. Machiels reports other support from Pfizer, Roche, Bayer, Merck Serono, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Incyte, Cue Biopharma, ALX Oncology, iTeos, etherna, Nektar, F-Star, Seagen, Genmab, Astellas, CureVac, MSD, GSK, Merus, Ipsen, Amgen, Gilead, and Sanofi outside the submitted work. P.R. Debruyne reports grants from Pfizer and personal fees from Bristol Myers Squibb, Ipsen, Merck, Astellas, and Bayer outside the submitted work, as well as stock ownership in Alkermes, Mural Oncology, and Biocartis NV. V. Moreno reports other support from AbbVie, Roche, Bayer, Bristol Myers Squibb, Janssen, Syneos, Affimed, and AstraZeneca outside the submitted work, as well as being a principal investigator receiving institutional funding from AbbVie, Achilles, Adaptimmune, ADC Therapeutics, Ascendis Pharma, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, BioInvent, Biomea Fusion, BioNTech, Bristol Myers Squibb, Boehringer Ingelheim, C4 Therapeutics, Calico Life Sciences LLC, Celgene, Constellation, Crescendo Biologics, Cullinan, Daiichi Sankyo, Debiopharm, Dragonfly, Enliven Therapeutics, Epizyme, Exelixis, FameWave, F-star Beta Limited, Genentech, Genmab, Gilead, Grey Wolf Therapeutics, GSK, Hexal AG & Sandoz, HiFiBiO, Hookipa Biotech, HUTCHMED, IGM Biosciences, Imcheck Therapeutics, Immunocore, Immutep, Incyte iOmx Therapeutics, Iovance, Italfarmaco, iTeos, Janssen, Light Chain Bioscience, Eli Lilly and Company, Loxo Oncology, Merck, Merus, Miltenyi Biomedicine, Monta Biosciences, MSD, Mythic Therapeutics, Ningbo Newbay, Novartis, Oxford BioTherapeutics, Pfizer, PharmaMar, PMV Pharma, Prelude Therapeutics Inc., Pyxis Oncology, Regeneron, Relay Therapeutics, Repare Therapeutics, Revolution, Roche, Schrödinger, Scorpion Therapeutics, Seagen, Shattuck Labs, Synthorx, Takeda, Tango Therapeutics, Tesaro, Totus Medicines, Turning Point Therapeutics, and Vividion Therapeutics. A. Minchom reports other support from Daiichi Sankyo during the conduct of the study, as well as personal fees from Janssen, Pfizer, AstraZeneca, Immutep, Chugai, Faron, GSK, Seagen, Takeda, Amgen, Merck, MSD, and Genmab and grants from Astex, Merck, and MSD outside the submitted work. F. Valdes-Albini reports grants from Daiichi Sankyo during the conduct of the study, as well as personal fees and other support from AstraZeneca outside the submitted work. D. Petrylak reports grants and personal fees from Seattle Genetics, Merck, Bicycle Therapeutics, Pfizer, Corbus, Astellas, and Gilead, grants from Arvinas, Exelixis, and Daiichi Sankyo, and personal fees from Bristol Myers Squibb, Bayer, Janssen, ProGenics, and Sanofi outside the submitted work. S. Hurvitz reports grants and nonfinancial support from Daiichi Sankyo during the conduct of the study, as well as grants from Ambrx, Amgen, Bayer, CytomX, Celcuity, Dantari, G1 Therapeutics, GSK, MacroGenics, Orinove, Orum, Phoenix Molecular Designs, Pieris, Radius/Stemline/Menarini, and Sanofi, grants and nonfinancial support from Arvinas, AstraZeneca, Genentech/Roche, Gilead/Immunomedics, Greenwich LifeSciences, Novartis, OBI Pharma, Eli Lilly and Company/Loxo, Pfizer, Puma, Seagen, and Zymeworks/Jazz Pharma, and other support from BriaCell outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Best percentage change from baseline in tumor size by ICR for individual patients in mBC (A) cohort 1 (HER2-positive)a, (B) cohort 2 (HER2-low)b, and in mUC (C) cohort 3 (HER2-high)c. The area above 20% indicates PD, and the area below −30% indicates a PR. aIn cohort 1, two of three patients with HER2-positive mBC treated at T-DXd 5.4 mg/kg RDE in combination with nivolumab 360 mg in part 1 are shown (one patient was missing baseline tumor assessment). bIn cohort 2, 15 of 16 patients are shown (one patient was missing postbaseline tumor assessment); one of three patients who were HR− had a confirmed PR. cIn cohort 3, four patients did not have best percentage change available (two patients were missing postbaseline tumor assessments; two patients were missing baseline tumor assessments), of whom two were IHC 3+. For cohort 4, efficacy endpoints are not summarized because of the small sample size (n = 4). dIn cohort 3, one patient had an unconfirmed CR with −100% change from baseline.
See this image and copyright information in PMC

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