Background

Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 inhibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola ± cer or ada as 2nd–3rd line in pts with mTNBC.

Methods

Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1–7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1–3, 8–10 + ola 200 mg BID (ada+ola), 21-d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade ≥3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data.

Results

Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n=83; HR 1.02 [90% CI 0.63–1.66, P=0.94], HRRm: n=40; 0.54 [0.28–1.03, 0.13], non-HRRm: n=103; 0.76 [0.50–1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n=8) vs ola (4%, n=2) (odds ratio 4.45; 90% CI 1.30–21.20, P=0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade ≥3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented.

Conclusions

Cer+ola did not improve PFS vs ola as 2nd–3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.

Clinical trial identification

NCT03330847.

Editorial acknowledgement

Medical writing assistance, funded by AstraZeneca, was provided by Anna Frangou, PhD, and Stephan Lindsey, PhD, of Peloton Advantage, LLC, an OPEN Health company, under the direction of the authors.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

A. Tutt: Financial Interests, Personal, Advisory Board, Personal fees /Advisory Board related to targeted therapies in DNA repair deficient: Pfizer; Financial Interests, Personal, Advisory Board, Personal fees from /Advisory Board related to targeted therapies in DNA repair deficient: Vertex; Financial Interests, Personal, Advisory Board, Personal fees/Advisory Board related to targeted therapies in DNA repair deficient: Artios; Financial Interests, Personal, Advisory Board, Personal fees/Advisory Board related to targeted therapies in DNA repair deficient: prIME Oncology; Financial Interests, Personal, Advisory Board, Personal Fees/Moon Shot Breast Cancer Scientific Advisory Board Honoraria: MD Anderson; Financial Interests, Personal, Advisory Board, Personal fees/Scientific Ad Board function and stock options: Inbiomotion; Financial Interests, Personal, Invited Speaker, Speaking role at mini symposium: SABCS 2020; Financial Interests, Personal, Advisory Board, Personal fees relating to advisory board: Gilead 21.05.21; Financial Interests, Institutional, Expert Testimony, CRUK expert panel monies going to my research account at the Institute of Cancer Research/Honoraria associated with Deputy Chair also going into research account: CRUK; Financial Interests, Institutional, Invited Speaker, Paid into research account at the Institute of Cancer Research: AZ Symposium ESMO 2021; Financial Interests, Personal, Advisory Board, Personal fees from Advisory Boards: MERCK Serano; Financial Interests, Institutional, Expert Testimony, Paid into research institute account: GE Healthcare 17.06.21; Financial Interests, Personal, Expert Testimony, Personal fees paid for expert testimony: EM Partners 16.06.21; Financial Interests, Institutional, Invited Speaker, Speaker at round table and monies went into research account: VJ Oncology 11.06.21; Financial Interests, Personal, Expert Testimony, Personal fees for an educational video: Medscape Education; Financial Interests, Personal, Advisory Board, Personal and institution fees for Ad Board: Gilead; Financial Interests, Personal, Full or part-time Employment, Head of Division for Breast Research, Director Breast Cancer Now Research Centre, Honorary Consultant Clinical Oncologist, Royal Marsden Hospital, joint leadership appointment with KCL that is processed through ICR payroll: Institute of Cancer Research; Financial Interests, Personal, Full or part-time Employment, Director of Breast Cancer Now Research Unit, King's College London, Honorary Consultant Clinical Oncologist, Breast Unit, Guy’s and St Thomas’ NHS Foundation Trust, joint leadership appointment with ICR that is processed through ICR payroll: King's College London; Financial Interests, Personal, Stocks/Shares: Inbiomotion; Financial Interests, Personal, Royalties, AstraZeneca with royalties paid to The Institute of Cancer Research (ICr) for the use of PARP inhibitors in DNA deficient cancers, licensee - AstraZeneca. ICR rewards to inventor's payments paid to Andrew Tutt's research accounts at The Institute of Cancer Research and to personal accounts: AstraZeneca; Financial Interests, Institutional, Research Grant, Received research support for TNT trial: Myriad genetics; Financial Interests, Personal and Institutional, Invited Speaker, Financial support to my academic and hospital institutions for costs associated with global academic study chair and local site costs for OlympiA trial/Travel expenses related to any trial related travel. Payments through Breast International Group for trial conduct in Olympic trial and through CRO's for commercial PARP inhibitor trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Local site trial associated with clinical trial DNA: MERCK KGAA; Financial Interests, Institutional, Research Grant, Financial support for research at ICR: Medivation; Non-Financial Interests, Other, Member of Strategy Group: NCRI Strategy Group; Non-Financial Interests, Other, Member of the Committee: ESMO Guidelines Committee; Non-Financial Interests, Officer, Committee Member: ESMO 2023 Scientific Committee; Non-Financial Interests, Institutional, Product Samples, Responsible for care of patients receiving Olaparib on named patient programme in Breast Cancer @ Guy's London: Guy's Hospital; Other, Grant funded to study homologous recombination deficient breast and other cancers, BCN receive payments through AstraZeneca related to PARP inhibitor patents: Breast Cancer Now; Other, Grant funded to study homologous recombination deficient breast and other cancers, CRUK receive payments through AstraZeneca related to PARP inhibitor patents: CRUK. Z. Nowecki: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Sanofi Aventis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, Traveler Grant: Roche. R. Szoszkiewicz: Financial Interests, Personal, Principal Investigator: Centrum Medyczne Pratia Poznan. S. Im: Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Personal, Advisory Role: Eisai; Non-Financial Interests, Personal, Advisory Role: GSK; Non-Financial Interests, Personal, Advisory Role: Hanmi; Non-Financial Interests, Personal, Advisory Role: Idience; Non-Financial Interests, Personal, Advisory Role: Lilly; Non-Financial Interests, Personal, Advisory Role: MSD; Non-Financial Interests, Personal, Advisory Role: Pfizer; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Daewoong Pharm; Financial Interests, Institutional, Research Grant: Boryung Pharm; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Roche. H. Arkenau: Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Invited Speaker: Guardant; Financial Interests, Personal, Advisory Board: iOnctura; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Institutional, Invited Speaker: multiple small and large Pharma/Biotechs. A. Armstrong: Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Conference Fees: Gilead; Financial Interests, Personal, Other, Conference Fees: MSD; Financial Interests, Institutional, Other, Research Funding: AstraZeneca; Financial Interests, Personal, Other, Spousal Shares: AstraZeneca. W. Jacot: Financial Interests, Institutional, Other, Research Funding: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Other, Personal, Other, Congress Travel Support: AstraZeneca; Other, Personal, Other, Congress Travel Support: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly France; Other, Personal, Other, Congress Travel Support: Lilly France; Financial Interests, Personal, Advisory Board: Eisai; Other, Personal, Invited Speaker, Congress Travel Support: Eisai; Financial Interests, Personal, Advisory Board: BMS; Other, Personal, Other, Congress Travel Support: Chugai Pharma; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Other, Personal, Other, Congress Travel Support: Glaxo Smith Kline; Financial Interests, Personal, Advisory Board: Novartis; Other, Personal, Other, Congress Travel Support: Novartis; Financial Interests, Personal, Advisory Board: MSD; Other, Personal, Other, Congress Travel Support: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Other, Personal, Other, Congress Travel Support: Roche; Financial Interests, Personal, Advisory Board: Rain Pharmaceuticals; Other, Personal, Other, Congress Travel Support: Sanofi Aventis; Financial Interests, Personal, Advisory Board: Seagen. J.H. Kim: Financial Interests, Institutional, Other, Research Funding: Ono Pharma Korea Co., Ltd. M. Webster: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Knight; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: Genomic Health. J. Balmana: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Pfizer. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pierre fabre; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Advisory Board: Isis/servier; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker: Roche Genentech; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Orion; Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM. N. Lukashchuk: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Odegbami, A.B. Loembe, M.W. Drachsler: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E. Casson: Financial Interests, Personal, Full or part-time Employment, Independent contractor: AstraZeneca. E.J. Dean: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. K. Punie: Financial Interests, Personal, Other, Travel Support: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Invited Speaker: Medscape; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Institutional, Invited Speaker: MundiPharma; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Personal, Other, Travel Support: Pfizer; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Advisory Role: Pierre Fabre; Financial Interests, Personal, Other, Travel Support: Roche; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Advisory Role: Teva; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Advisory Role: Vifor Pharma; Financial Interests, Personal, Other, Travel Support: PharmaMar.

Background

SASCIA (NCT04595565) is an ongoing phase III study randomising patients (pts) with HER2- BC and residual disease after neoadjuvant chemotherapy (NACT) or hormone receptor (HR)+ with a CPS+EG score ≥3 or 2 and ypN+ after NACT to SG or treatment of physicianś choice (TPC, capecitabine, platinum, observation). We present the results of the pre-planned SIA.

Methods

The analysis was performed after the first 50 randomized pts had completed 4 therapy cycles. Pts were included if they received ≥2 cycles, were observed ≥6 wks or discontinued earlier. Objectives were to assess adverse events (AEs) grade (G) 1-4, G3-4 and compliance (dose reductions, delays, discontinuation) between arms.

Results

At the time of the analysis, 142 pts were randomized, 88 were included in the SIA. 45 pts received SG, 32 capecitabine, 11 were observed. Median age was 46 (24-71) in SG vs 51 (32-74) yrs in TPC arm, median BMI (25.8 (20.0-42.6) vs 23.8 (18.2-35.4) kg/m²), more pts in SG arm had a Ki67>20% (N=29, 64.4% vs N=21, 48.8%); 30 (66.7%) vs 29 (67.4%) were HR-, 15 (33.3%) vs 14 (32.6%) HR+. All pts had AEs G1-4 in SG arm vs 37 (86.0%) in TPC arm, and 30 (66.7%) vs 9 (20.9%) G3-4 (Table), no death occurred. 6 (13.6%) pts under SG vs 3 (9.4%) under capecitabine discontinued therapy prematurely; 30 (66.7%) vs 13 (43.2%) had ≥1 dose delay, due to hematological (N=21, 46.7% vs N=3, 10.0%) and non-hematological AEs (N=3, 6.7% vs N=7, 23.3%); 12 (26.7%) vs 9 (28.1%) had ≥1 dose reduction (hematological N=6, 13.3% vs N=1, 3.1%; non-hematological N=5, 11.1% vs N=6, 18.8%). Table: 58O

Statistically significant different AEs between arms

Conclusions

SG showed a higher rate of AEs compared to TPC, which includes observation only. AEs, especially G3-4 AEs rate were in line with the known safety profile of SG and led to more dose delays. AEs due to SG therapy was well manageable using the recommended supportive measures. The study continues as planned.

Clinical trial identification

NCT04595565.

Legal entity responsible for the study

German Breast Group.

Funding

The trial is financially supported by Gilead Sciences, Inc.

Disclosure

F. Marmé: Financial Interests, Personal and Institutional, Research Grant, Grant, Personal fees: Gilead/Immunomedics; Financial Interests, Personal, Other, Personal fees: Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, Genomic Health, CureVac, Eisai, BMS, Clovis, Janssen-Cilag, GSK, MSD, Seagen, Myriad, Pierre Fabre. C. Hanusch: Financial Interests, Personal, Other, Personal Fees: Roche, Novartis, Lilly, AstraZeneca. T. Link: Financial Interests, Personal, Other: Pfizer, Roche, Tesaro, Amgen, Novartis, Lilly, Myriad, Eisai, Gilead; Non-Financial Interests, Personal, Other: MSD, Clovis, GSK; Non-Financial Interests, Institutional, Other: BMS, Daiichi Sankyo. C. Denkert: Financial Interests, Personal, Ownership Interest, Stock and Other Ownership Interests: Sividon Diagnostics; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca Merck, Lilly; Financial Interests, Personal and Institutional, Advisory Role, Consulting or Advisory Role, Research Funding: Roche; Financial Interests, Institutional, Research Grant, Research Funding: Myriad Genetics; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: VMScope Digital Pathology Software, WO2015114146A1, WO2010076322A1, WO2020109570A1. P.A. Fasching: Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Novartis, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Seagen, Roche, Gilead; Financial Interests, Institutional, Research Grant, Grant: BioNTech, Cepheid; Financial Interests, Personal and Institutional, Advisory Board, Advisory Board, Invited Speaker, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory Board: Pierre Fabre, Hexal, Agendia, Sanofi Aventis. C. Jackisch: Financial Interests, Personal, Other: Roche, AstraZeneca, Pfizer, Lilly, Novartis, Exact Sciences; Financial Interests, Institutional, Other: Seagen. P. Aftimos: Financial Interests, Personal, Other: Boehringer Ingelheim, Macrogenics, Amcure, Synthon, Servier, G1 Therapeutics, Novartis, Radius, Deloitte, Menarini, Gilead; Non-Financial Interests, Personal, Other, Travel Grant: Roche; Non-Financial Interests, Institutional, Other, Travel Grant: Amgen, MSD, Pfizer. J. Huober: Financial Interests, Personal, Other: Gilead, Seagen, Roche, MSD, AbbVie, Eisai; Financial Interests, Personal and Institutional, Research Grant, Grant: Lilly; Financial Interests, Personal and Institutional, Research Grant, Grant, Travel, Other: Novartis; Financial Interests, Personal, Other, Travel, Other: Pfizer, Daiichi; Financial Interests, Institutional, Research Grant, Grant: Hexal; Financial Interests, Institutional, Research Grant, Grant, Travel: BMS. M. Untch: Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Amgen GmbH, AstraZeneca, Celgene GmbH, Daiichi Sankyo, Eisai, Lilly Int., MSD Merck, Myriad Genetics, Pfizer GmbH, Roche Pharma AG, Sanofi Aventis Deutschland GmbH, Novartis, Clovis Oncology; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: BMS, Lilly Deutschland, Pierre Fabre, Seattle Genetics, Seagen, GSK, Gilead. M. Balic: Financial Interests, Institutional, Research Grant, Grants: ABCSG; Financial Interests, Institutional, Research Grant, Grant, Consulting fees, Payment or honoraria for lectures, Support for attending meetings, travel, Data safety board or advisory board: AstraZeneca, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche; Financial Interests, Institutional, Research Grant, Grant, Consulting fees, Payment or honoraria for lectures, Data safety board or advisory board: Daiichi Sankyo, Seagen; Financial Interests, Institutional, Research Grant, Grant, Consulting fees, Payment or honoraria for lectures: Samsung. M. Reinisch: Financial Interests, Personal, Other: AstraZeneca, Novartis, Roche, Pfizer, Somatex, Daiichi Sankyo, Lilly MSD. J. Blohmer: Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Honoraria: Amgen, AstraZeneca, Novartis; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Travel, Accommodations, Expenses, Honoraria: Pfizer, Roche; Financial Interests, Personal, Other, Honoraria: MSD Oncology, Lilly, Gilead Sciences, Eisai Germany, Seattle Genetics, Daiichi Sankyo/AstraZeneca, Exact Sciences, Molecular Health. S. Loibl: Financial Interests, Institutional, Research Grant, Grant, Other: AbbVie, AstraZeneca, Celgene; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Amgen, Bayer, BMS; Non-Financial Interests, Institutional, Advisory Board, Honorarium for Ad Board & Lecture, Medical Writing: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Eirgenix, GSK, Lilly, Merck; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Immunomedics/Gilead; Non-Financial Interests, Institutional, Advisory Board, honorarium for Ad Board & Lectures, Medical Writing, Grant, Other: Novartis, Pfizer, Roche; Financial Interests, Institutional, Advisory Board, Honorarium for Ad Board & Lecture, Other: Pierre Fabre, prIME/Medscape; Non-Financial Interests, Institutional, Advisory Board, Honorarium for Ad Board, Medical Writing, Other: Puma, Seagen; Financial Interests, Institutional, Advisory Board, honorarium for Lecture, Other: Samsung; Other, Institutional, Other, Patent Pending: EP14153692.0, EP21152186.9; Other, Institutional, Other, Patent Issued: EP15702464.7; Other, Institutional, Other, Patent Pending, GeparNuevo: EP19808852.8; Other, Institutional, Royalties, Patent Issued, Royalties: Digital Ki67 Evaluator. All other authors have declared no conflicts of interest.

Background

T-DXd is an anti-HER2 antibody-drug conjugate that has demonstrated high antitumor activity in HER2-positive and HER2-low metastatic breast cancer (mBC). We aimed to unravel the mechanism of action and resistance to T-DXd in patients from DAISY trial.

Methods

DAISY is a phase II clinical trial (NCT04132960) that assessed T-DXd efficacy in mBC according to HER2-expression (HER2-positive, HER2-low, and HER2-negative). Bystander effect and T-DXd uptake were analyzed by immunohistochemistry (IHC) (HER2, gH2AX, and T-DXd) on tumor biopsies at baseline and on-treatment (n=10 patients). T-DXd immune effects were explored by multiplex immunofluorescence (CD3, CD4, CD8, CD68, FoxP3, PD-1, PD-L1, CK/SOX10 antibodies) on tumor biopsies at baseline and on-treatment (Day 22 or 43, n=31 patients). Mechanisms of resistance were analyzed on tumor samples at baseline (n=118) and at progression by whole exome sequencing (n=24) and IHC (n=25). The predictive value of HER2 spatial distribution was investigated by artificial intelligence (AI) using weakly supervised and clustering algorithms on HER2-positive slides images at baseline (n=61).

Results

Molecular analyses showed that cancer cells expressing low levels of HER2, but not HER2-null cells, uptake T-DXd (p=0.053). In the whole population (n=31), a decrease of PDL1-positive cells was associated with a best objective response (BOR) (p=0.008). No modulation of T cells and macrophages was observed (p=0.6 and p=0.9 respectively). A decrease of PDL1 expression was detected in HER2-positive mBC (n=18; p=0.02). Clustering algorithms identified a cluster associated with a lower BOR (p=0.007), whose features identified by AI included a high percentage of HER2-negative cells currently under investigation. At progression, a decrease of HER2 expression was observed in 13/25 (52%) patients (p=0.07). DNA sequencing and final AI results will be available at the meeting.

Conclusions

A correlation between HER2 expression and T-DXd uptake in cancer cells was observed in on-treatment biopsies. T-DXd did not modulate intratumoral lymphocytes but decreased PDL1 expression. WES analyses at baseline and progression samples will be presented on-site.

Legal entity responsible for the study

The authors

Funding

Unicancer and Daiichi Sankyo

Disclosure

V. Dieras: Financial Interests, Personal, Advisory Board, Travel Expenses: Roche, Novartis, Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Invited Speaker, Travel Expenses: Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Principal Investigator, Travel Expenses: Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Principal Investigator: AbbVie; Non-Financial Interests, Personal, Advisory Board: Eisai, Pierre Fabre Oncologie. E. Deluche: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Fresenius Kabi, Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, scientific events: Lilly, GSK; Financial Interests, Personal, Other, funding for conference travel: AstraZeneca-Daiichi, Roche, Amgen. B. Pistilli: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, Pfizer; Financial Interests, Personal, Other, Consulting Fees: Myriad, Pierre Fabre; Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, Novartis, Puma; Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Novartis, Puma; Financial Interests, Personal, Other, Attending Meetings and/or Travel: AstraZeneca, Pierre Fabre, MSD; Financial Interests, Institutional, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche. D. Tran: Non-Financial Interests, Institutional, Full or part-time Employment, Full-time: DIEP T. N. TRAN. N. Droin: Non-Financial Interests, Institutional, Full or part-time Employment, Part-time: Nathalie Droin. M. Kobayashi, T. Kakegawa: Other, Personal, Full or part-time Employment, Employee of Daiichi Sankyo RD Novare, which belongs to Daiichi Sankyo Group. Daiichi Sankyo Group is developing T-DXd: Daiichi Sankyo RD Novare. M. Lacroix-Triki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Daiichi Sankyo. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.