Background

We previously reported the biologic and clinical activity of HER3-DXd in Part A of SOLTI TOT-HER3 in patients (pts) with HR+/HER2- early breast cancer (BC) after a single dose of 6.4 mg/kg (Prat A. et al, ESMO BREAST 2022). Here, we present the main efficacy and safety results of TOT-HER3 Part B.

Methods

In Part B of this window of opportunity trial, 2 cohorts of pts with treatment-naïve HER2- primary operable BC, ≥1 cm by US or MRI were recruited. Pts received a single dose of HER3-DXd 5.6 mg/kg. Primary objective was the variation in tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) score between pre- and post-treatment tumors. Associations of baseline clinical and biological features with CelTIL changes and overall response rate (ORR) by US were explored.

Results

Thirty-seven pts with HER2- BC were recruited (HR+ n=20; TNBC n=17). Mean age was 53 (30-81); 20 (54%) were pre-menopausal; mean tumor size was 21 mm (range 10-81 mm); and median Ki67 was 30% (12-95%). In response to treatment with HER3-DXd CelTIL score increased and decreased in 21 (57%) and 16 (43%) pts, respectively. Overall, a statistically significant change in CelTIL was observed between paired samples overall (p=0.046) and in TNBC (p=0.016), but not in HR+ (p=0.793). ORR by US in all patients was 32% (35% in TNBC and 30% in HR+). The absolute change in CelTIL was associated with ORR (AUC=0.693; p=0.049). Baseline ERBB3 levels were not associated with CelTIL change or ORR. HER3-DXd induced high expression of immune-related genes (e.g., PD1, CD8 and CD19), and suppressed proliferation-related genes. Thirty-one (84%) patients reported AEs at any grade. Most common AEs were nausea, fatigue, alopecia, diarrhea, constipation and vomiting. Grade 3 treatment-related nausea occurred in 1 patient. No ILD events were reported.

Conclusions

A single dose of HER3-DXd was associated with clinical response and significant biological changes in HER2- tumors, irrespective of baseline ERBB3 levels. The safety profile was consistent with that previously reported. Additional correlative analysis will be presented on site.

Clinical trial identification

EudraCT 2019-004964-23. NCT04610528, First posted: October 30, 2020.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Daiichi Sankyo Inc.

Disclosure

M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. M. Margeli Vila: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, MSD, Gilead, Lilly, Pierre Fabre; Financial Interests, Personal, Other, Travel expences: Gylead; Financial Interests, Institutional, Invited Speaker, I have received research funding for my institution from Pfizer: Pfizer. J.M. Cejalvo: Financial Interests, Institutional, Invited Speaker: Pfizer, Novartis. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichi, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, AstraZeneca, Daiichi, Seagen, Esteve, Roche. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. S. Esker, P. Fan, A. Santhanagopal: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. O. Martínez-Sáez: Financial Interests, Personal, Advisory Board: Reveal. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. R. Sanchez Bayona: Financial Interests, Personal, Invited Speaker: Novartis, Lilly Oncology, GSK Oncology, AstraZeneca, Seagen, Clovis Oncology; Financial Interests, Personal, Other, Travel and accommodation: Pfizer; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: SOLTI; Financial Interests, Personal, Other, Medical Monitor in HARMONIA Trial: Novartis. C. Falato: Financial Interests, Personal, Expert Testimony, Study results presentation for educational purposes: Daiichi Sankyo. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. All other authors have declared no conflicts of interest.

Background

HER3 plays a key oncogenic role in breast cancer, being associated with poor prognosis and resistance to PI3K/AKT/mTOR inhibitors (inh) and endocrine therapy (ET). HER3-DXd is an anti-HER3 monoclonal antibody conjugated to a topoisomerase I inh by a peptide-based cleavable linker, which showed activity in HER3-expressing ABC (NCT02980341). ICARUS-BREAST01 (NCT04965766) is an ongoing multi-center, single-arm, phase II study in pts with HR+ and HER2- ABC, unselected for HER3 expression, who progressed on CDK 4/6 inh, any line of targeted/ET and 1 line of chemotherapy for ABC.

Methods

Enrolled pts receive HER3-DXd 5.6 mg/kg IV every 3 weeks and undergo tumor biopsy at baseline, on-treatment and end of treatment (EoT); 100 pts are planned; enrollment on HER3 IHC expression level was removed by amendment on Apr 21^st, 2022. Primary endpoint is confirmed objective response rate; secondary: progression-free survival; duration of response; clinical benefit rate; overall survival and safety. We report the 3-months response rate (3m-RR) of patients included before Sept 15 2022 and safety data up to Nov 4 2022, based on data cut-off [DCO] of Jan 23, 2023. Multiplex imaging mass cytometry, DNA sequencing, circulating tumor cells (CTC) and association with treatment response will be presented.

Results

At DCO, 85 pts were included in the study and 56 were evaluable for this analysis. Pts and treatment characteristics are reported in the table. Among the 56 pts: 16 had partial response, 30 stable disease, 10 progressive disease. The 3 m-RR was 28.6% [95%CI: 18.4-41.5]. Most common any-grade adverse events (AEs) were: fatigue (89.3%), nausea (76.8%); most frequent grade ≥3 AEs was fatigue (14.0%). Confirmed ILD: 1 G1 (1.8%).

Table: 189O

Conclusions

HER3-DXd showed early signs of activity and a manageable safety profile in pts with HR+ HER2- ABC. Results on biomarkers analysis will also be presented.

Clinical trial identification

NCT04965766.

Legal entity responsible for the study

Gustave Roussy.

Funding

Daiichi Sankyo.

Disclosure

B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen; Financial Interests, Institutional, Advisory Board: Exact science, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Invited Speaker: AstraZeneca, Seagen, MSD, Daiichi; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi, MSD. F. Dalenc: Non-Financial Interests, Principal Investigator: Roche, AstraZeneca, Gilead, Novartis. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. M. Benderra: Financial Interests, Invited Speaker: Novartis, Lilly, AstraZeneca, MSD, GSK, Gilead; Financial Interests, Other: Pfizer, Novartis, Lilly, AstraZeneca. D. Sellami: Financial Interests, Full or part-time Employment: Daiichi Sankyo S. Michiels: Financial Interests, Personal, Other, Statistical advice: Roche; Financial Interests, Personal, Other, DSMB member: Sensorion, Servier, Biophytis, Yuhan, IQVIA, Kedrion. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: MedImmune, Gilead, Relay Therapeutics; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.

Background

IMpassion031 met its primary objective, significantly improving pathological complete response (pCR) rate with atezo added to neoadjuvant CT in pts with eTNBC (58% vs 41% with CT alone in the intent-to-treat [ITT] population; 17% difference, 1-sided p=0.0044) [Mittendorf 2020]. Benefit from atezo was seen regardless of PD-L1 status.

Methods

Pts with untreated stage II/III eTNBC and a primary tumour >2 cm were randomised 1:1 to placebo or atezo 840 mg q2w + neoadjuvant CT (nab-paclitaxel 125 mg/m² qw for 12 wk, then doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² q2w for 8 wk). After surgery, pts randomised to atezo received open-label atezo 1200 mg q3w for 11 cycles. Pts without pCR could have standard adjuvant systemic therapy (± atezo). Stratification factors were disease stage (II vs III) and PD-L1 status (IC <1% vs ≥1% by SP142). Secondary efficacy endpoints included event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the ITT and PD-L1+ populations.

Results

After ∼39 mos’ median follow-up, EFS, DFS and OS numerically favoured atezo consistently across key clinical subgroups (Table). Among pts without pCR, 14/70 (20%) in the atezo arm vs 33/99 (33%) in the placebo arm received additional adjuvant systemic therapy, most often capecitabine (4/70 [6%] vs 26/99 [26%]). In exploratory analyses, pCR was highly prognostic for long-term outcome. Exploratory ctDNA analyses showed clearance in most pts (including all ctDNA-evaluable pts with pCR) at surgery. Positive ctDNA at/after surgery was associated with poor prognosis. There were no new safety signals or treatment-related deaths with atezo. Table: 031

Conclusions

The significant pCR benefit with the addition of atezo to CT for eTNBC translated into numerically improved EFS, DFS and OS. Long-term safety results are consistent with previous reports.

Clinical trial identification

NCT03197935, EudraCT 2016-004734-22, Japan Pharmaceutical Information Center JapicCTI-173630.

Editorial acknowledgement

Jennifer Kelly (Medi-Kelsey Ltd.), funded by F. Hoffmann-La Roche Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

C.H. Barrios: Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: GSK; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Novartis; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Pfizer; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Roche; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Eisai; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Bayer; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: MSD; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: AstraZeneca; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Zodiac; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Lilly; Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: Sanofi; Financial Interests, Personal, Advisory Board, Consultation: Boehringer; Financial Interests, Personal, Advisory Board, Scientific Presentations Consulting Ad Board: Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Virtual App: Thummi; Financial Interests, Personal, Stocks/Shares, Clinical Research Company: Medisr; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Pfizer; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering Committee: Novartis; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Amgen; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering Committee: Astra Zeneca; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: GSK; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering Committee: Roche; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Lilly; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Sanofi; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Merk; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Biomarin; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: BMS; Financial Interests, Institutional, Research Grant, Research Funding to the Institution Steering Committee: Daiichi; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Medivation; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Exelixis; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Merck KGaA; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Shangai Henlius Biothech; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Polyphor; Financial Interests, Institutional, Research Grant, Research Funding to the Institution: Pharma Mar; Financial Interests, Institutional, Invited Speaker, Research funding to the Institution: Nektar; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Regeneron; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Janssen; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: OBI Pharma; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Seagen; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Checkpoint Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Novocure; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Aveo Oncology; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Takeda; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Celgene; Financial Interests, Institutional, Invited Speaker, Research funding to the institution Steering committee: Myovant; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: TRIO; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: PPD; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Syneos health; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: DOCS; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Labcorp; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: IQIVIA; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Parexel; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Nuvisan; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: PSI; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Medplace; Non-Financial Interests, Invited Speaker, Member of Executive Board: BIG International Group; Non-Financial Interests, Leadership Role, Latin American Cooperative Oncology Group: LACOG; Non-Financial Interests, Other, Chair, International Educational Steering Group: ASCO; Non-Financial Interests, Advisory Role, Member Compliance Committee: ESMO. N. Harbeck: Financial Interests, Personal, Other, Consulting: Gilead; Financial Interests, Personal, Other, Consulting: Sandoz; Financial Interests, Personal, Other, Consulting: Seagen; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Amgen; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: AstraZeneca; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Gilead; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Eli Lilly; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Merck Sharp and Dohme; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Novartis; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Pierre-Fabre; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Pfizer; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Roche; Financial Interests, Personal, Invited Speaker, Lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: Seagen; Financial Interests, Personal, Leadership Role, Chair of data safety monitoring board: Roche; Financial Interests, Personal, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Leadership Role: ESMO. H.A. Zhang: Financial Interests, Personal, Advisory Role: Roche/Genentech. S. Saji: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Chugai; Non-Financial Interests, Invited Speaker: Japan Breast Cancer Research Group; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Sanofi; Non-Financial Interests, Invited Speaker: Japanese Breast Cancer Society; Non-Financial Interests, Invited Speaker: Japanse Society of Medical Oncology; Non-Financial Interests, Invited Speaker: Breast International Group. K.H. Jung: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Board: Bixink; Financial Interests, Personal, Advisory Board: Everest Medicine; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Takeda Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. A. Koehler: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Research Grant: German Breast Group; Financial Interests, Personal, Other, Travel/accommodation expenses: Stada. J. Sohn: Financial Interests, Personal, Stocks/Shares, Immediate Family Member: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Astra Zeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Seagen. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal and Institutional, Invited Speaker: Chugai; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Personal and Institutional, Invited Speaker: Amgen; Financial Interests, Personal and Institutional, Invited Speaker: Sanofi; Financial Interests, Personal and Institutional, Invited Speaker: Lilly; Financial Interests, Personal and Institutional, Invited Speaker: Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Bayer; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer; Financial Interests, Personal and Institutional, Invited Speaker: Kyowa Hakko Kirin; Financial Interests, Personal and Institutional, Invited Speaker: Behringer; Financial Interests, Personal and Institutional, Invited Speaker: Nihon Kayaku. M.L. Telli: Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Arvinas; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Biothera; Financial Interests, Institutional, Research Grant: Calithera Biosciences; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Hummingbird Biosciences; Financial Interests, Institutional, Research Grant: Medivation; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: OncoSec; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Vertex; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Aduro Biotech; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Blueprint Medicines; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: G1 Therapeutics; Financial Interests, Personal, Advisory Role: Guardant; Financial Interests, Personal, Advisory Role: Immunomedics; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Natera; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: OncoSec; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: RefleXion; Financial Interests, Personal, Advisory Role: Sanofi. J. Boileau: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AbbVie; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Bristol-Myers-Squibb; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Advisory Board: Vifor Pharma; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Mundi Pharma; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: McCann Health; Financial Interests, Institutional, Advisory Board: Roularta; Financial Interests, Institutional, Advisory Board: Teva; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Institutional, Advisory Board: Gilead; Financial Interests, Personal, Other, Consultancy: Gilead; Financial Interests, Personal, Other, Consultancy: Novartis; Financial Interests, Personal, Other, Consultancy: MSD; Financial Interests, Personal, Other, Consultancy: Roche; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Invited Speaker: Medscape; Financial Interests, Personal, Advisory Board: Astra Zeneca; Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Personal, Invited Speaker: Focus Patient; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Gilead Sciences; Financial Interests, Personal, Ownership Interest: Need Inc.; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Invited Speaker: MSD; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Leadership Role, Vice President: Belgian Society of Medical Oncology BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Leadership Role: EORTC Breast Cancer Task Force Steering Committee Member; Non-Financial Interests, Institutional, Product Samples, Drug provision for academic research: Gilead Sciences; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. M. Dieterich: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. Z.J.F. Assaf, E. Shearer-Kang, L. Molinero, S.Y. Chui: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. T. Xu: Financial Interests, Personal, Full or part-time Employment: Roche. M. Liste Hermoso: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: Roche. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. All other authors have declared no conflicts of interest.

Background

For most HER2-positive early breast cancer (EBC) patients (pts), neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy is standard of care. To improve the balance between toxicity burden and treatment outcomes, chemotherapy de-escalation has been a major focus in recent years. Among other immunogenic properties, anthracyclines can trigger an immunogenic cell death that engages the adaptive immune system. Within the ABCSG-52 trial we investigated a chemotherapy de-escalation immunotherapy regimen in HER2-positive EBC.

Methods

Pts with previously untreated, histologically confirmed HER2-positive EBC (clinical prognostic stage cT1c-4a-d, N0–3,M0) were randomized 1:1 to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1200mg atezolizumab (TP+A) or TP alone. Afterwards, all pts received 4 cycles of TP+A in combination with epirubicin (part 2). The primary endpoint was pathological complete response (pCR; ypT0/Tis ypN0) in the overall study population. A pCR rate of ≥ 40% was considered as a positive trial result.

Results

Overall, 58 pts were randomized to TP-A (n=29) or TP (n=29) in 9 Austrian study centers. Median age was 57 (range 33-82), 16 pts (27.6%) had hormone-receptor (HR)-negative and 42 (72.4%) had HR-positive tumors. 45 pts (77.6%) had stage ≤ IIA and 13 (22.4%) ≥ IIB. In 35 pts a pCR was observed (60.3%; 95%CI 47.5% - 71.9%), 19 (65.5%) in the TP-A group and 16 (55.2%) in TP group (Δ 10.3%; 95%CI -14.7% - 35.4%). Residual cancer burden (RCB) class 0 or I was seen in 44 out of 55 pts (80%) with valid RCB assessment. Treatment emergent adverse events (AEs) grade ≥ 3 were reported in 17 pts (29.3%), 9 in TP-A group (31.0%) and 8 (27.6%) in TP group. No AEs of special interest (immune-related AEs, cardiac disorders grade ≥ 2, or infusion-related reactions) grade ≥ 3 were detected. Outcome according to PD-L1 expression status is currently analyzed and will also be presented at the meeting.

Conclusions

For HER2-positive EBC, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is highly effective and safe and merits further investigation.

Clinical trial identification

EudraCT 2019-002364-27.

Legal entity responsible for the study

Austrian Breast and Colorectal Cancer Study Group (ABCSG).

Funding

Academic group WITH funding from a pharma: Austrian Breast and Colorectal Cancer Study Group (ABCSG); Provision of IMP and financial support by Roche Austria GmbH.

Disclosure

G. Rinnerthaler: Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Pfizer, Roche, Seagen; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche; Financial Interests, Personal, Other, Travel grant: Amgen, Daiichi Sankyo, Eli Lilly, Gilead, Merck, Pfizer, Roche; Non-Financial Interests, Member: Austrian Society for Haematology and Medical Oncology (OeGHO). D. Egle: Financial Interests, Personal, Advisory Board: AstraZeneca, Gilead, Pfizer, Novartis, Lilly, Seagen, Pierre-Fabre, MSD; Financial Interests, Personal, Invited Speaker: Roche, Sirius Medical; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo. R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen, Roche, Novartis, Eli Lilly, Pierre-Fabre, Daiichi, Gilead, MSD, Pfizer, Eisai, Gruenenthal; Financial Interests, Personal, Advisory Board: Daiichi, AstraZeneca, Roche, Novartis, Eli Lilly, Pierre-Fabre, MSD, Gilead, Seagen, Eisai, Gruenenthal; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Invited Speaker, Drug support for investigator initiated trial: MSD. A.L. Petzer: Financial Interests, Personal, Advisory Board: Novartis, Amgen, Celgene-BMS, Daiichi Sankyo, AstraZeneca, Seagen, Roche, Pfizer; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo. M. Balic: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, MSD, Pierre Fabre, Pfizer, Roche, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eli Lilly, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Gilead; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker, Steering Committee Member, Coordinating PI, Advisory role: Roche; Financial Interests, Institutional, Invited Speaker: Roche, Austrian Breast and Colorectal Cancer Study Group, MSD, Qiagen, Amgen, Pierre Fabre, Novartis, Pfizer, Gilead. E. Petru: Financial Interests, Personal, Advisory Board, Attendance fees: AstraZeneca, Eisai, Lilly, GSK; Financial Interests, Personal, Invited Speaker, Lecture fees: AstraZeneca, EISAI, Lilly, GSK; Financial Interests, Personal, Advisory Board, Fees: MSD, Novartis, Pharma Mar, Roche, Seagen, Pierre Fabre, Daiichi Sankyo, Gilead; Financial Interests, Personal, Invited Speaker, Fees: MSD, Novartis, Roche, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Invited Speaker, Fees to institution: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Patient Fees: Roche; Financial Interests, Institutional, Invited Speaker, Fees: Lilly, GSK, Novartis, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Fees: Seagen, Pierre Fabre. C.F. Singer: Financial Interests, Personal, Other, consultancy: Amgen; Financial Interests, Personal, Advisory Board, Advisory Function: Novartis; Financial Interests, Personal, Advisory Board, Advisory Role: Roche; Financial Interests, Personal, Other, Study Support: Pfizer; Financial Interests, Personal, Advisory Board, Advisory, Speaker Honoraria, Study Support: AstraZeneca; Financial Interests, Personal, Invited Speaker, Study Coordinator: Amgen; Non-Financial Interests, Principal Investigator, Study: Amgen, AstraZeneca; Non-Financial Interests, Project Lead, Register: Pfizer. V. Bjelic-Radisic: Non-Financial Interests, Principal Investigator, PI of the EORTC Follow Up 16-17 study PI of EORTC QLQ BR Update study: EORTC. S.P. Gampenrieder: Financial Interests, Personal, Invited Speaker: Novartis, BMS, AstraZeneca, Pfizer, Lilly, Seagen, Daichi Sankyo, Janssen; Financial Interests, Personal, Advisory Board: Novartis, Lilly, AstraZeneca, MSD, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Funding: Roche; Other, Travel grant: Roche, Novartis, Pfizer, Celgene, Daiichi Sankyo, Janssen. Z.A. Bago-Horvath: Financial Interests, Personal, Advisory Board, Advisory Board Trastuzumab Deruxtecan: AstraZeneca, Daichi Sanyo; Financial Interests, Personal, Advisory Board, Advisory Board Sacituzumab Govitecan: Gilead; Financial Interests, Personal, Other, Travel support: Roche; Financial Interests, Personal, Invited Speaker, Speaker at CME Lectures: MSD; Non-Financial Interests, Institutional, Product Samples, Reagents: Roche. M. Filipits: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Eli Lilly, Biorad, Merck, Novartis. M.I. Gnant: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Novartis, Pierre Fabre; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Eli Lilly, Menarini-Stemline; Financial Interests, Personal, Expert Testimony: Veracyte; Financial Interests, Invited Speaker: Pfizer; Other, Spouse is employed by Sandoz: Sandoz. R. Greil: Financial Interests, Personal, Advisory Board: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Personal and Institutional, Funding: Celgene, Roche, Merck, Takeda, AstraZeneca Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo. All other authors have declared no conflicts of interest.