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]). Table: 42O

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.

Background

Venous thromboembolic events (VTE), elevated aminotransferases (EAT) and interstitial lung disease (ILD) are adverse events (AEs) for abemaciclib (oral CDK4 & 6 inhibitor). In monarchE, patients (pts) receiving abemaciclib+endocrine therapy (ET) as adjuvant treatment (txt) of HR+, HER2- high-risk early breast cancer (EBC) reported these AEs more frequently vs ET alone pts.

Methods

The safety population (pop) comprised 5591 treated (tx) pts (median duration of abemaciclib: 17 months). The protocol included management guidance for AEs. Pts with history of VTE were not eligible. Risk factors for VTE (Khorana risk score) and adjuvant radiotherapy (95.4% pts) were well balanced across arms.

Results

In abemaciclib tx pts: Most VTEs were G≥3 (1.3%), primarily pulmonary embolism (0.9%) (Table). Of pts experiencing VTE, 94% received anti-coagulants and 19.4% discontinued abemaciclib or all txt due to VTE. VTEs were increased with tamoxifen txt; G≥3 VTEs were higher in pts with body mass index (BMI)> 25 (1.8%) vs BMI<25 (0.6%). 85% of G≥3 EAT were single occurrences; incidence was highest early on txt (∼3 months). Of pts experiencing G≥3 EAT, 71% had dose hold/reduction and 16% discontinued due to EAT. All G≥3 alanine aminotransferase (ALT) increases, per central lab, were reversible with dose modification or discontinuation. No pts had drug-induced liver injury (no Hy’s law cases). Most ILD events were G1 (1.4%). Of pts experiencing ILD, 52% were tx with steroids/antibiotics and 23% discontinued abemaciclib or all txt due to ILD. ILD was higher in Asians (6.6%; G1: 4.9%; G≥3: 0.3%; 13% of Asian pts with ILD discontinued (0.9% of pop)). Table: 44O

Characteristics of VTEs, EAT and ILD

Conclusions

VTE, EAT and ILD were manageable with dose adjustments and comedications in pts with EBC; results were consistent with the known safety profile of abemaciclib. Although ILD was higher in Asian pop, G≥3 AEs and discontinuations were similar. Most pts experiencing these AEs could continue abemaciclib.

Clinical trial identification

NCT03155997.

Editorial acknowledgement

Eglantine Julle-Daniere.

Legal entity responsible for the study

Eli Lilly.

Funding

Eli Lilly.

Disclosure

M. Toi: Honoraria (self), Research grant/Funding (self), Research grant, Lecture honoraria: Chugai, Takeda, Pfizer, Taiho, Eisai, AstraZeneca, Shimadzu, Yakult; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant, Lecture honoraria, Advisory role for a drug development: Kyowa-Kirin, Daiichi Sankyo; Research grant/Funding (self): JBCRG association, Astellas; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Honoraria (self), Lecture Honoraria: MSD, Exact Science, Novartis; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting: Konica Minolta, BMS; Honoraria (self), Research grant/Funding (self), Research Fund and Honoraria for lecture: Nippon Kayaku; Research grant/Funding (self): AFI Technologies; Advisory/Consultancy: Athenex Oncology, Bertis, Terumo, Kansai Medical Net; Advisory/Consultancy, Research grant/Funding (self): Luxonus; Research grant/Funding (self): Shionogi, GL Science; Officer/Board of Directors: JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast Cancer Research Network. N. Harbeck: Shareholder/Stockholder/Stock options: West German Study Group; Honoraria (self): Roche, Novartis, Amgen, Pfizer, Genomic Health, AstraZeneca, Zodiac Pharma, Pierre Fabre; Advisory/Consultancy: Roche/Genentech, Novartis, Celgene, Pfizer, Eli Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohme, Odonate Therapeutics, Seattle Genetics, West German Study Group, Pierre Fabre; Research grant/Funding (institution): Roche/Genentech (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Merck Sharp & Dohme (Inst). J.M. Puig: Honoraria (self), Personal fees: Protocol JPCF. J. Cruz: Honoraria (self), Advisory/Consultancy, Lectures, Travel, Advisory: PharmaMar, Roche, Novartis, Pfizer; Honoraria (self), Advisory/Consultancy, Lectures, Advisory: Eli Lilly, AstraZeneca; Advisory/Consultancy: Daiichi, Seagen, Glaxo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Lectures: Bayer. M. Takahashi: Honoraria (self): Eli Lilly; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Eisai; Research grant/Funding (self): Kyowa Kirin; Research grant/Funding (self): Taiho. M. Hulstijn, E.A. Twum, A. Regev, B. San Antonio: Full/Part-time employment: Eli Lilly. D.M. Median: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Institutional research funding, Honoraria, Lecture fee, Consulting/Advisory role: Eli Lilly; Advisory/Consultancy, Non-remunerated activity/ies, Educational, Lecture fee, Consulting/Advisory role: AstraZeneca; Research grant/Funding (self), Lecture fee: A&D Pharma; Honoraria (self): Clovis; Advisory/Consultancy, Travel/Accommodation/Expenses: Genekor; Honoraria (self), Advisory/Consultancy, Lecture fee, Honoraria, Advisory role: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Lecture fee, Advisory, Travel, Educational: Pfizer; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses, Lecture fee, Honoraria, Travel, Educational: Roche; Honoraria (self): Samsung Bioepis. M. Campone: Honoraria (institution), Advisory/Consultancy, Consulting/advisory/fees to the Institution: AstraZeneca, Sanofi, Servier, AbbVie, Accord, Pfizer, Seagen; Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GT1. All other authors have declared no conflicts of interest.

Background

The phase III ML-2, -3, and -7 trials assessed ribociclib (RIB) with different endocrine therapy (ET) partners in pts with hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Quality-of-life (QOL) results were previously reported for each ML trial and as a pooled analysis. Here, we report on individual dimensions of the EORTC QLQ-C30 PROs, including relevant pt subgroup data from a pooled analysis of the ML trials.

Methods

PROs were collected with EORTC QLQ-C30 questionnaires. QOL was assessed for all pts in ML-2, pts without prior ET for ABC in ML-3, and pts receiving RIB or placebo (PBO) + a nonsteroidal aromatase inhibitor in ML-7. A linear effects model was used to calculate the least-squares mean changes from baseline in global health status (GHS), nausea and vomiting, diarrhea, and anxiety/depression, and these were interpreted using minimally important differences. GHS was also assessed for pt subgroups including age, race, and molecular subtype by PAM50.

Results

A total of 1528 pts were included. Time to definitive deterioration (TDD) for diarrhea and anxiety/depression was prolonged for RIB vs PBO (Table). Diarrhea, anxiety/depression, and GHS across subgroups were improved or maintained from cycle 3 to end of treatment. Median TDD of GHS was longer for RIB vs PBO in pts regardless of age. Median TDD of GHS for RIB vs PBO was longer for White pts, similar for Asian pts, and shorter for pts of other races, although the n in the latter group was small. Median TDD of GHS for RIB vs PBO was longer in pts with luminal subtypes and was more than doubled for the HER2-enriched (HER2E; 30.4 vs 14.8 mo) subtype.

Conclusions

In this pooled analysis of the ML trials, RIB + ET showed delayed deterioration in QOL scores. TDD for GHS favored RIB vs PBO across most subgroups. These results support prior QOL analyses showing the value of RIB + ET in maintaining QOL for pts with HR+/HER2− ABC. Table: 91O

Clinical trial identification

NCT01958021, NCT02422615, NCT02278120.

Editorial acknowledgement

This abstract was developed with editorial assistance provided by Casey Nielsen, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

P.A. Fasching: Research grant/Funding (institution): BioNTech; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Speaker Bureau/Expert testimony: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Macrogenics; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Puma; Research grant/Funding (institution): Cepheid; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca. A. Bardia: Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Radius Health; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics/Gilead; Advisory/Consultancy, Research grant/Funding (institution): Biothernostics Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho; Advisory/Consultancy: Daiichi Pharma/AstraZeneca; Advisory/Consultancy: Puma; Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Mersana. A. Nusch: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Amgen. G. Jerusalem: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Daiichi Sankyo; Advisory/Consultancy: MedImmune; Advisory/Consultancy: Merck. N.S. El Saghir: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly. E. Alba Conejo: Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): NanoString; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution): Sysmex. S-A. Im: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Amgen; Advisory/Consultancy: MediPacto; Research grant/Funding (institution): Roche; Honoraria (self): Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: GSK; Research grant/Funding (institution): Daewoong Pharm. W. Janni: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis. D. Chandiwana, B.R. Lanoue, A. Thuerigen, E. Gu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Harbeck: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Several genomic assays are available to profile early breast cancer (BC) that, according to current evidence, can provide reliable information including the risk of recurrence. However, little is known regarding their current use and the perception of utility across Europe. The PROCURE project aims to develop a consensus on the utility of breast cancer multigene signatures (BCMS) in treatment decision making for different eBC patient profiles based on the opinion of a panel of experts.

Methods

A Scientific Committee of 8 experts in BC from 8 European countries developed a Delphi questionnaire to be administered in two-waves to experienced clinicians across Europe, selected based on their experience in BC. The questionnaire includes 5 sections in order to characterize the participants and their expertise in BCMS, to understand the current clinical practice in eBC and the use of BCMS, to recall the participant’s opinion on the utility of the BCMS in eBC according to the patient profiles, to define recommendations on the use of BCMS in clinical practice and finally, to identify unmet needs and future applications of BCMS. 180 participants, including medical oncologists, surgeons, pathologists and gynaecologists, are expected to answer anonymously the online Delphi questionnaire. 70% agreement will be used to determine consensus on a topic.

Results

At the end of January 2021, 146 participants from 11 European countries (Austria, Denmark, France, Germany, Italy, Norway, Portugal, Spain, Sweden, Switzerland and the UK) registered to participate. 61 of them had already fully completed the 1^st wave Delphi questionnaire. Results from the 1^st wave will be presented to engage larger discussion with congress participants.

Conclusions

The PROCURE Project will provide useful information regarding how BCMS are currently used in clinical practice across Europe and will help to measure the utility attributed to the different BCMS by BC experts for their daily clinical practice, to establish recommendations on the use of BCMS to make treatment decision in different eBC patient profiles and to define current unmet needs and future applications of BCMS according to experts point of view.

Editorial acknowledgement

Adelphi Targis SL.

Legal entity responsible for the study

Veracyte Inc.

Funding

Veracyte Inc.

Disclosure

G. Curigliano: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Veracyte; Advisory/Consultancy: Genomic health; Advisory/Consultancy: Ellipsis. F. Cardoso: Honoraria (self): Amgen; Honoraria (self): Astellas/Medivation; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self): Daiichi Sankyo; Honoraria (self): GE Oncology; Honoraria (self): Genentech; Honoraria (self): GlaxoSmithKline; Honoraria (self): Macrogenics; Honoraria (self): Medscape; Honoraria (self): Merck-Sharp; Honoraria (self): Merus BV; Honoraria (self): Mylan; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): priME Oncology; Honoraria (self): Roche; Honoraria (self): Samsung Bioepis; Honoraria (self): Eisai. M.I. Gnant: Honoraria (self): Veracyte; Honoraria (self): Amgen; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Daiichi Sankyo; Honoraria (self): Tolmar; Honoraria (self): LifeBrain. A-V. Lænkholm: Honoraria (self): Veracyte. F. Penault-Llorca: Honoraria (self), Research grant/Funding (self): Veracyte; Honoraria (self), Research grant/Funding (self): Exact science former Genomic Health; Honoraria (self): Agendia; Honoraria (self), Research grant/Funding (self): Myriad. A. Prat: Honoraria (self): Veracyte; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: AbbVie; Honoraria (institution): NanoString technologies; Research grant/Funding (institution): Incyte; Honoraria (self): Oncolytics; Honoraria (self), Research grant/Funding (self): Novartis; Advisory/Consultancy: Peptomyc; Honoraria (self), Advisory/Consultancy: Guardian health; Honoraria (self), Shareholder/Stockholder/Stock options: Reveal genomics; Advisory/Consultancy: AstraZeneca; Research grant/Funding (self): Incyte. All other authors have declared no conflicts of interest.

Background

Breast cancer ranks first in females, concerning cancer incidence and mortality. Breast cancer in premenopausal patients (vs. postmenopausal patients) has unique gene expression patterns, rendering molecular drivers of tumor progression in premenopausal women of particular clinical interest. Our research focused on premenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), early breast cancer (EBC), and the molecular drivers of distant metastases after standard adjuvant treatment.

Methods

We performed a retrospective, single-center, case-control study in premenopausal HR+/HER2- EBC patients treated at the LMU (Ludwig Maximilian University) breast center. We selected 48 patients who developed metastases before 2018 (the median distant metastasis-free survival was 54 months, range: 7-184 months) and 49 patients who did not (the median follow-up was 149 months, range: 121-191 months). All patients received surgery and endocrine therapy, 85.6% received radiotherapy, and 72.2% received chemotherapy. Total RNA of primary tumor FFPE specimens was extracted using the miRNeasy FFPE kit (Qiagen, Germany). Gene expression profiling was done using the NanoString nCounter® system (NanoString technology, USA) with Breast Cancer 360 panel (BC360®) which includes 776 genes across 48 biological signatures, and analyzed following the panel-specific processing protocol (BC360 data analysis).

Results

The bone was the most common site of distant metastases. Tumor size, histological grade, and stage influenced DMFS (distant metastasis-free survival). Claudin-low, mammary stemness, PGR (Progesterone Receptor) signatures were significantly downregulated in patients who developed metastases, and as expected, ROR (Risk of recurrence) was increased. These four signatures were also correlated to patients' DMFS. Besides, ten differentially expressed genes were identified.

Conclusions

Among the tested biological signatures, claudin-low, mammary stemness, PGR, and ROR impact on DMFS in premenopausal patients. Detailed analyses will be presented at the meeting.

Legal entity responsible for the study

The authors.

Funding

The first author receives scholarship from the China Scholarship Council.

Disclosure

H. Ni: Research grant/Funding (self), Scholarship: China Scholarship Council. J. Kumbrink: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: QUIP; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche Pharma. R. Wuerstlein: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Agendia, Onkowissen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen, Paxman; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Aristo, Palleos; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Aristo Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Carl Zeiss, Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Celgene, Puma Biotechnology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Clinsol, Riemser; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Daiichi Sankyo, Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai, Sandoz/Hexal; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Genomic Health; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Glaxo Smith Kline; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Hexal, Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Lilly, Tesaro Bio; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Medstrom Medical, Teva; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Mundipharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: NanoString; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Odonate. N. Harbeck: Honoraria (self), Advisory/Consultancy: Agendia; Honoraria (self), Advisory/Consultancy: Genomic Health. T.K. Eggersmann: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Aristo Pharma. All other authors have declared no conflicts of interest.

Background

Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US, Canada, Switzerland, Australia, and Singapore for combined treatment with trastuzumab (Tras) and capecitabine for patients with HER2+ metastatic breast cancer (MBC), including patients with brain metastases (BM) who received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-Tras emtansine (T-DM1), approved for treatment of HER2+ MBC after Tras and a taxane, has improved progression-free survival (PFS) and overall survival (OS). Further improvements are needed, including in patients with active BM. A phase Ib trial evaluated TUC+T-DM1 in 50 patients with HER2+ MBC who received prior treatment with Tras and a taxane; 60% of patients had BM at baseline (Borges 2018). Common adverse events, mostly Grade 1/2, were nausea (72%), diarrhea (60%), and fatigue (56%). Median PFS was 8.2 months and objective response rate (ORR) in patients with measurable disease (n=34) was 47%. Brain specific response rate (RECIST v1.1) in patients with measurable BM (n=14) was 36%. This encouraging clinical activity, including in patients with BM, provides rationale to evaluate TUC+T-DM1.

Trial design

HER2CLIMB-02 is a randomized, double-blind, placebo-controlled, phase III study enrolling patients with centrally confirmed HER2+ unresectable locally-advanced or MBC previously treated with Tras and taxane. Patients must have ECOG ≤1. Approximately 460 patients will be randomized 1:1 for 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Prior treatment with investigational anti-HER2 agent, anti-EGFR agent, or HER2 TKI is not permitted. Prior pertuzumab treatment is permitted. Baseline brain MRIs are required; patients with stable, progressing, or untreated BM may be eligible. Treatment response assessments per RECISTv1.1 occur every 6 weeks for the first 24 weeks, and then every 9 weeks. Primary endpoint is PFS per investigator assessment, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US, Canada, EU, Japan, South Korea, Australia, and Israel, and is planned for Singapore.

Clinical trial identification

NCT03975647.

Editorial acknowledgement

Editorial assistance was provided by Craig Bolte of MMS Holdings.

Legal entity responsible for the study

Seagen Inc.

Funding

Seagen Inc.

Disclosure

S.A. Hurvitz: Research grant/Funding (institution): Ambrx, Amgen; Research grant/Funding (institution): AstraZeneca, Arvinas; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Genentech/Roche, Bayer; Research grant/Funding (institution): Gilead, Immunomedics; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Research grant/Funding (institution): Macrogenetics, Novartis; Research grant/Funding (institution): Pfizer, Obi Pharma; Research grant/Funding (institution): Pieris, Puma; Research grant/Funding (institution): Radius, Sanofi; Research grant/Funding (institution): Seagen Inc.; Research grant/Funding (institution): Dignitana, Zymeworks; Research grant/Funding (institution): Phoenix Molecular Designs, Ltd.; Shareholder/Stockholder/Stock options: Nk Max. N. Harbeck: Honoraria (self): AstraZeneca; Honoraria (self): Daiichi Sankyo; Honoraria (self): Eli Lilly; Honoraria (self): MSD Pharmaceuticals; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Sandoz/Hexal; Honoraria (self): Seagen Inc. L. Vahdat: Advisory/Consultancy, Research grant/Funding (institution): Arvinas; Advisory/Consultancy: Roche; Advisory/Consultancy: Berg Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai Co., Ltd.; Advisory/Consultancy, Research grant/Funding (institution): Polyphor Pharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Seagen Inc.; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Oncotherapy Biosciences. S.M. Tolaney: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Daiichi Sankyo, OncoPep; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly, Eisai; Advisory/Consultancy: G1 Therapeutics, Outcomes4Me; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Immunomedics; Advisory/Consultancy: Kyowa Kirin, Silverback Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): NanoString; Advisory/Consultancy, Research grant/Funding (institution): Nektar, Seagen; Advisory/Consultancy, Research grant/Funding (institution): Novartis, Pfizer; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Cyclacel, Odonate; Advisory/Consultancy: Puma Therapeutics, Sanofi; Advisory/Consultancy: Celldex, Paxman, AbbVie; Advisory/Consultancy: Samsung Bioepsis Inc. S. Loi: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Seagen Inc; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Puma Biotech. N. Masuda: Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self): Takeda; Research grant/Funding (institution): Kyowa-Kirin; Research grant/Funding (institution): MSD Pharma; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Nippon-Kayaku; Research grant/Funding (institution): Daiichi Sankyo. J. O'Shaughnessy: Advisory/Consultancy: AbbVie, Agendia; Advisory/Consultancy: Amgen Biotech; Advisory/Consultancy: Aptitude Health; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Celgene, Eisai; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: Genentech; Advisory/Consultancy: Immunomedics; Advisory/Consultancy: Ipsen Biopharma; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Eli Lilly, Merck; Advisory/Consultancy: Myriad, Novartis; Advisory/Consultancy: Ondonate Therapeutics; Advisory/Consultancy: Pfizer, Puma Biotech; Advisory/Consultancy: prIME Oncology; Advisory/Consultancy: Roche, Seagen Inc; Advisory/Consultancy: Syndax Pharmaceuticals. D. Xie: Full/Part-time employment: Seagen Inc. L.N. Walker: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Seagen Inc. E. Rustia: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seagen Inc. V. Borges: Advisory/Consultancy, Research grant/Funding (institution): Seagen Inc; Research grant/Funding (institution): Abbot/AbbVie; Research grant/Funding (institution): Millenium. All other authors have declared no conflicts of interest.