I. Krop (Boston, MA, United States of America)
Dana-Farber Cancer InstituteAuthor Of 1 Presentation
42O - Biomarker analysis from KAITLIN, a randomised phase 3 study of adjuvant trastuzumab emtansine (TDM-1; K) plus pertuzumab (P) versus trastuzumab (H) plus taxane (T) plus P after anthracyclines (AC) for high-risk HER2-positive early breast cancer (EBC) (ID 234)
Abstract
Background
KAITLIN (NCT01966471) compared adjuvant AC-KP versus AC-THP in patients with HER2-positive, high-risk EBC. A preplanned exploratory analysis assessed the relationship between invasive disease-free survival (IDFS) and biomarkers (BMs) potentially related to response.
Methods
Baseline tumor samples were used for central assessment of HER2 and pre-specified BMs including HER2 mRNA expression and PTEN IHC expression by median (med) cutoff, and activating PIK3CA hotspot mutations. The effect of treatment and BMs on IDFS was assessed via descriptive analyses.
Results
BMs were well balanced between treatment arms. No BM subgroup showed more benefit from AC-KP than AC-THP. A trend for reduced benefit with AC-KP vs AC-THP was seen in the HER2 <30% expression and 4 to <6 gene copy number subgroups (Table). No clear prognostic relationships were identified in pooled arms (PIK3CA mut vs non-mut HR=1.27 [0.92–1.74]; HER2 IHC3+ vs IHC2+ HR=0.82 [0.55–1.23]; HER2 mRNA ≥ vs < med HR=0.76 [0.56–1.03]). *HER2 IHC0/1+ (n=14), HER2 gene copy number <4 (n=20) and gene ratio <2 (n=11) excluded.
AC-THP (n=918) AC-KP (n=928) HR (95% CI) BM* n 3-yr IDFS, % n 3-yr IDFS, % 130 95.2 127 93.5 1.34 (0.65–2.80) 200 95.9 186 92.8 1.29 (0.71–2.35) 78 97.4 86 87.0 2.77 (1.08–7.09) 446 94.5 442 91.7 1.18 (0.79–1.77) 67 97.0 70 91.1 3.41 (1.10–10.60) 276 95.9 249 89.7 1.31 (0.78–2.20) 329 95.7 348 91.4 1.39 (0.87–2.22)
Conclusions
Consistent with the primary study results, AC-KP did not reduce the risk of an IDFS event compared to AC-THP in any BM subgroup. HP + chemotherapy remains the standard of care for those with high-risk HER2-positive EBC. No BMs had prognostic value in the pooled arm analyses.
Clinical trial identification
NCT01966471.
Editorial acknowledgement
Support for third-party writing assistance was provided by Tracy McNally, PhD and Holly Strausbaugh, PhD (Twist Medical, Burlingame, CA, USA), funded by F. Hoffmann-La Roche.
Legal entity responsible for the study
F. Hoffmann-La Roche.
Funding
F. Hoffmann-La Roche.
Disclosure
O. Metzger: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AbbVie; Advisory/Consultancy, Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): Roche; Research grant/Funding (institution), Non-remunerated activity/ies, Co-chair Advisory Board: Pfizer. C. Lambertini: Full/Part-time employment: F. Hoffmann - La Roche Ltd. I.E. Krop: Honoraria (self), Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Daiichi Sankyo; Honoraria (self): Macrogenics; Honoraria (self): Seattle Genetics; Honoraria (self): Celltrion; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Context Therapeutics. G. Lewis Phillips: Full/Part-time employment: Genentech, Inc; Shareholder/Stockholder/Stock options: F. Hoffmann - La Roche Ltd. C.M. Perou: Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Licensing/Royalties: Bioclassifier LLC; Advisory/Consultancy, Shareholder/Stockholder/Stock options, Licensing/Royalties, Officer/Board of Directors: GeneCentric Therapeutics. F. Symmans: Shareholder/Stockholder/Stock options, Licensing/Royalties, Founder shares, licensed intellectual property: Delphi Diagnostics; Shareholder/Stockholder/Stock options: IONIS Pharmaceuticals; Shareholder/Stockholder/Stock options: Eiger Pharmaceuticals. I. Melero: Honoraria (self), Research grant/Funding (institution): Roche/Genentech; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Alligator Bioscience; Honoraria (self): Bayer; Honoraria (self): Tusk Therapeutics; Honoraria (self): Gossamer Bio; Honoraria (self): Amunix; Honoraria (self): Replimune; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Medincell; Honoraria (self): Monopteros Therapeutics; Honoraria (self): Molecular Partners; Honoraria (self): Biontech; Honoraria (self): PharmaMar. N. Harbeck: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche. E.P. Winer: Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy: Carrick Therapeutics; Honoraria (self), Advisory/Consultancy: G1 Therapeutics; Honoraria (self), Research grant/Funding (institution): Genentech/Roche; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: GSK; Honoraria (self), Advisory/Consultancy: Jounce; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Syros; Honoraria (self), Advisory/Consultancy: Zymeworks. S-A. Im: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Hanmi; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Non-remunerated activity/ies, Investigational agent for trial: Dae Woong. C.H. Barrios: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Mylan; Research grant/Funding (institution): Merrimack; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Bayer; Research grant/Funding (institution): Astellas Pharma; Honoraria (self), Advisory/Consultancy: Eisai; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Abraxis Biosciences, BioMarin, LEO Pharma, AbbVie, Merck, and Millennium; Research grant/Funding (institution): AB Science, Asana Biosciences, Medivation, Exelixis, and Imclone Systems. H. Bonnefoi: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Non-remunerated activity/ies: Daiichi. J.R. Gralow: Honoraria (self): Genentech/Roche; Honoraria (self): Pfizer; Honoraria (self): Puma; Honoraria (self): AstraZeneca; Honoraria (self): Immunomedics; Honoraria (self): Genomic Health; Honoraria (self): Novartis; Honoraria (self): Sandoz/Hexal; Honoraria (self): Radius; Honoraria (self): Inbiomotion. L. Gianni: Advisory/Consultancy: Hexal Sandoz; Advisory/Consultancy: Seattle Genomics; Advisory/Consultancy: Synthon; Honoraria (self), Advisory/Consultancy: Zymeworks; Advisory/Consultancy: Sanofi-Aventis; Advisory/Consultancy: Forty Seven (CD47); Advisory/Consultancy: Genenta; Advisory/Consultancy: METIS Precision Medicine; Advisory/Consultancy: Novartis; Advisory/Consultancy: Odonate Therapeutics; Honoraria (self), Advisory/Consultancy: Revolution Medicine; Advisory/Consultancy: Synaffix; Advisory/Consultancy: Menarini Ricerche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Biomedical Insights Inc.; Honoraria (self): Daiichi Sankyo; Licensing/Royalties, Co-inventor of European Patent Application N. 12195182.6 and 12196177.5 titled \"PDL-1 expression in anti-HER2 therapy\": Roche. M. Toi: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai, Takeda, Pfizer, Taiho, Eisai, AstraZeneca, Shimadzo, Yakult, Nippon Kayaku; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Kyowa-Kirin, Daiichi Sankyo; Research grant/Funding (institution): Astellas, AFI Technologies, JBCRG Association, Astehnologies, Luxonos, Shionogi, GL Science; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Honoraria (self), Speaker Bureau/Expert testimony: MSD, Exact Science, Novartis; Honoraria (self), Advisory/Consultancy: Konica Minolta, BMS; Advisory/Consultancy: Athenex Oncology, Bertis, Terumo, Kansai Medical Net. S.M. Swain: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, support for third party medical writing: Roche/Genentech; Honoraria (self), Advisory/Consultancy: Exact Sciences (Genomic Health); Honoraria (self), Advisory/Consultancy: Molecular Templates; Honoraria (self), Advisory/Consultancy: Silverback Therapeutics; Honoraria (self), Advisory/Consultancy: Tocagen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy: Natera; Honoraria (self), Advisory/Consultancy: Athenex; Honoraria (self), Advisory/Consultancy: Bejing Medical Foundation; Research grant/Funding (institution): Kailos Genetics; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: Caris Life Sciences; Advisory/Consultancy, Scientific Advisory Board: Inivata. T. Boulet: Full/Part-time employment, Employee from Parexel International GmbH contracted by Roche for Statistical services: F. Hoffmann-La Roche Ltd. C. Song: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/Genentech. S. de Haas: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.
Author Of 1 Presentation
128TiP - HER2CLIMB-04: Phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with HER2+ unresectable locally-advanced or metastatic breast cancer with and without brain metastases (Trial in Progress)
Abstract
Background
Tucatinib (TUC) is an oral, reversible, small molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). In the HER2CLIMB trial (NCT02614794), the combination of TUC + trastuzumab (T) + capecitabine (C) demonstrated statistically significant and clinically meaningful improvement in progression free survival (PFS), overall survival (OS), and PFS in patients (pts) with brain metastases (BM) compared to T + C alone, supporting regulatory approvals internationally for pts with HER2+ metastatic breast cancer (MBC). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a topoisomerase I inhibitor payload approved in the US for treatment of HER2+ MBC in pts who have received 2 or more prior anti-HER2 regimens in the metastatic setting. Approval was based on data from the Destiny-Breast01 trial (NCT03248492) where treatment with T-DXd resulted in a confirmed objective response rate (cORR) of 61.4% (95% CI: 54.0, 68.5) in pts with HER2+ MBC who had prior ado-trastuzumab emtansine treatment. Despite these advances, HER2+ MBC remains incurable, and pts will eventually progress on currently available therapies. Combining TUC and T-DXd may result in further improvement on the efficacy seen with either agent.
Trial design
HER2CLIMB-04 (NCT04539938) is a single arm, open-label phase II trial evaluating safety and antitumor activity of TUC + T-DXd in pts with HER2+ unresectable locally-advanced or MBC who have received 2 or more prior HER2-based regimens in the metastatic setting. Pts with BM, including active BM, may be enrolled. Ten pts will be enrolled in the safety lead-in portion of the study and followed for at least 1 cycle. If safety of the combination is acceptable, the trial will continue until approximately 60 response-evaluable pts have been enrolled, approximately evenly distributed between pts with and without BM. The primary endpoint is cORR by investigator (INV) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are PFS, duration of response, and disease control rate by INV per RECIST v1.1, OS, and safety. Enrollment began in late 2020.
Clinical trial identification
NCT04539938.
Editorial acknowledgement
Editorial/writing assistance was provided by Wendi Schultz and Aulma Parker of Seagen Inc.
Legal entity responsible for the study
Seagen Inc.
Funding
Seagen Inc.
Disclosure
E. Hamilton: Advisory/Consultancy, Paid to Institution Only: Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond, and NanoString; Research grant/Funding (institution), Paid to Institution Only: Seagen Inc., Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim. J. Ramos: Shareholder/Stockholder/Stock options: Seagen Inc.; Full/Part-time employment: Seagen Inc. W. Feng: Shareholder/Stockholder/Stock options: Seagen Inc.; Full/Part-time employment: Seagen Inc. I. Krop: Honoraria (self): Celltrion; Advisory/Consultancy: Daiichi Sankyo, Genentech/Roche, Ionis Pharma, Macrogenics, Merck, Novartis, Seagen Inc., Celltrion, BMS; Advisory/Consultancy, DSMB membership: Merck, Novartis; Research grant/Funding (institution): Daiichi Sankyo, Genentech, Pfizer, Seagen, Taiho Oncology; Spouse/Financial dependant, Stock/Stockholder, Leadership, and/or Employment: AMAG Pharma, Freeline.