Background

Intermediate biopsies during neoadjuvant treatment might offer opportunities for prediction of pathological complete response (pCR) and patient outcome, which could be a basis for de-escalation of treatment. However, their relevance for clinical decisions is not clear.

Methods

We evaluated intermediate biopsies that were taken during neoadjuvant treatment from 297 patients with invasive breast cancer from three prospective, randomized trials (GeparQuattro, -Quinto, -Sixto). We evaluated the presence of invasive breast cancer, tumor-infiltrating lymphocytes (TILs) and Ki-67 expression and compared the results to pre-treatment samples. We explored the association of residual cancer in the intermediate biopsies as well as dynamics in Ki-67 and TILs with pCR rates and disease-free survival.

Results

Of the 297 tumors, 87 (29%) samples were triple-negative (TNBC), 138 (46%) HR+/HER2- and 72 (24%) HER2+. We found invasive tumor cells in 70% of biopsies, with significant differences between the subtypes (HR+/HER2-: 84%; TNBC: 62%, HER2+: 51%; p<0.001). In the complete cohort, 8% of patients with invasive tumor cells in intermediate biopsies achieved a pCR after completion of treatment (pCR rate in patients with residual tumor: TNBC: 19%, HR+/HER2: 3%; HER2+: 11%). If no residual cancer was present, pCR rate was 50% in the complete cohort (TNBC: 48%, HR+/HER2-: 27%; HER2+: 66%). An increase in TILs from baseline biopsy to intermediate biopsy was associated with a higher probability of pCR in the overall study cohort (p=0.001). A similar or increased Ki-67 was associated with a low probability of pCR in the overall study cohort (p=0.004) and with a shorter disease-free survival in patients with TNBC (p=0.04).

Conclusions

Intermediate biopsies can identify patients that are unlikely to achieve a pCR after therapy. After further validation, this may be useful for adaptation of treatment. For translational biomarker research, intermediate biopsies are useful tool to study mechanisms of therapy resistance and biomarker discovery. Additional studies will be needed to demonstrate if standardized sampling procedures can further improve response prediction through intermediate biopsies.

Legal entity responsible for the study

German Breast Group.

Funding

Has not received any funding.

Disclosure

M. Untch: Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Amgen GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: AstraZeneca; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: BMS; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Celgene GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Daiichi Sankyo; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Eisai; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Lilly Deutschland; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Lilly Int.; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: MSD Merck; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Myriad Genetics; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Pfizer GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Roche Pharma AG; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Sanofi Aventis Deutschland GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Novartis; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Pierre Fabre; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Clovis Oncology; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Seatlle Genetics; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Seagen; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: GSK; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Gilead. T. Karn: Other, Personal, Other, Patent pending: EP18209672. M. van Mackelenbergh: Financial Interests, Institutional, Other, Honoraria: Amgen; Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Novartis; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Pierre Fabre; Financial Interests, Institutional, Other, Honoraria: Lilly; Financial Interests, Institutional, Other, Honoraria: Genomic Health; Financial Interests, Institutional, Other, Honoraria: Molecular Health; Financial Interests, Institutional, Other, Honoraria: Roche; Financial Interests, Institutional, Other, Honoraria: Gilead; Financial Interests, Institutional, Other, Honoraria: Seagen; Financial Interests, Institutional, Other, Honoraria: GSK. J. Huober: Financial Interests, Personal, Other, personal fees: Gilead; Financial Interests, Personal, Other, personal fees: Seagen; Financial Interests, Personal and Institutional, Research Grant, Grant, personal fees: Lilly; Financial Interests, Personal and Institutional, Research Grant, Grant, Travel, personal fees: Novartis; Financial Interests, Personal, Other, Travel, personal fees, Other: Pfizer; Financial Interests, Personal, Other, Travel, personal fees, Other: Daiichi; Financial Interests, Personal, Other, personal fees: Roche; Financial Interests, Personal, Other, personal fees: MSD; Financial Interests, Personal, Other, personal fees: AbbVie; Financial Interests, Personal, Other, personal fees: Eisai; Financial Interests, Institutional, Research Grant, Grant: Hexal; Financial Interests, Institutional, Research Grant, Grant, Travel, Other: BMS. W.D. Schmitt: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Funding: Myriad Genetics. F. Marmé: Financial Interests, Personal, Other, Personal Fees: Roche/Genentech; Financial Interests, Personal, Other, Personal Fees: AstraZeneca; Financial Interests, Personal, Other, Personal Fees: Pfizer; Financial Interests, Personal, Other, Personal Fees: Tesaro; Financial Interests, Personal, Other, Personal Fees: Novartis; Financial Interests, Personal, Other, Personal Fees: Amgen; Financial Interests, Personal, Other, Personal Fees: PharmaMar; Financial Interests, Personal, Other, Personal Fees: Genomic Health; Financial Interests, Personal, Other, Personal Fees: CureVac; Financial Interests, Personal, Other, Personal Fees: EISAI; Financial Interests, Personal, Other, Persona Fees: BMS; Financial Interests, Personal, Other, Personal Fees: Clovis Oncology; Financial Interests, Personal, Other, Personal Fees: GSK; Financial Interests, Personal, Other, Personal Fees: MSD; Financial Interests, Personal, Other, Personal Fees: Seagen; Financial Interests, Personal, Other, Personal Fees: Myriad Genetics; Financial Interests, Personal, Other, Personal Fees: Pierre Fabre; Financial Interests, Personal and Institutional, Research Grant, Personal Fees: Gilead/Immunomedics; Financial Interests, Personal, Other, Persona fees: Janssen-Cilag. E. Stickeler: Financial Interests, Personal, Other, personal fees: Roche; Financial Interests, Personal, Other, personal fees: Gilead; Financial Interests, Personal, Other, personal fees: MSD; Financial Interests, Personal, Other, personal fees: Lilly; Financial Interests, Personal, Other, personal fees: Pfizer; Financial Interests, Personal, Other, personal fees: Seagen; Financial Interests, Personal, Other, personal fees: PharmaMar. H. Tesch: Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Novartis; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Roche; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: GSK; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Seagen; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Pfizer; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Lilly; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: AstraZeneca; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Daiichi; Financial Interests, Institutional, Other, Consulting fees, honoraria for lectures, presentations: Exact Science. P.A. Fasching: Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant, Grant, Institutional Funding: BioNTech; Financial Interests, Personal and Institutional, Advisory Board, Advisory Board, Invited Speaker, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Grant, Institutional Funding: Cepheid; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Advisory Board: Hexal; Financial Interests, Personal, Advisory Board, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Gilead. A. Schneeweiss: Financial Interests, Personal and Institutional, Research Grant, Research Grant, Travel expenses, Honoraria: BMS; Financial Interests, Personal and Institutional, Research Grant, Research Grant, Expert testimony, Travel expenses, Honoraria: Roche; Financial Interests, Institutional, Research Grant, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant, Research Grant: Molecular Partner; Financial Interests, Personal, Expert Testimony, Expert testimony, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria, Travel expenses: Pfizer; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Tesaro; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Other, Honoraria: Seagen; Financial Interests, Personal, Other, Honoraria: Gilead. V. Müller: Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: Amgen; Financial Interests, Personal, Invited Speaker, speaker honoraria: AstraZeneca; Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: Eisai; Financial Interests, Personal, Invited Speaker, speaker honoraria: Pfizer; Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: MSD; Financial Interests, Personal and Institutional, Invited Speaker, speaker and consultancy honoraria, Institutional research support: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, speaker and consultancy honoraria, Institutional research support: Roche; Financial Interests, Personal, Invited Speaker, speaker honoraria: Teva; Financial Interests, Personal and Institutional, Invited Speaker, speaker honoraria, Institutional research support: Seagen; Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: GSK; Financial Interests, Personal, Invited Speaker, speaker and consultancy honoraria: Gilead; Financial Interests, Personal, Advisory Role, consultancy honoraria: Genomic Health; Financial Interests, Personal, Advisory Role, consultancy honoraria: Hexal; Financial Interests, Personal, Advisory Role, consultancy honoraria: Pierre Fabre; Financial Interests, Personal, Advisory Role, consultancy honoraria: ClinSol; Financial Interests, Personal, Advisory Role, consultancy honoraria: Lilly; Financial Interests, Institutional, Other, Institutional research support: Genentech. S. Loibl: Financial Interests, Institutional, Research Grant, Grant, Other: AbbVie; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Amgen; Financial Interests, Institutional, Research Grant, Grant, Other: AstraZeneca; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Bayer; Financial Interests, Institutional, Advisory Board, honorarium for Ad Boards, Other: BMS; Financial Interests, Institutional, Research Grant, Grant, Other: Celgene; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Eirgenix; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: GSK; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Immunomedics/Gilead; Financial Interests, Institutional, Advisory Board, honorarium for Ad Boards, Other: Lilly; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Other: Merck; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Novartis; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Pfizer; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board & Lecture, Other: Pierre Fabre; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board & Lecture, Other: prIME/Medscape; Non-Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Medical Writing, Other: Puma; Financial Interests, Institutional, Advisory Board, honorarium for Lecture, Other: Samsung; Non-Financial Interests, Institutional, Advisory Board, honorarium for Ad Board, Medical Writing, Other: Seagen; Non-Financial Interests, Institutional, Advisory Board, honorarium for Ad Boards & Lectures, Medical Writing, Other: Roche; Other, Institutional, Other, Patent Pending, Immunsignature in TNBC: EP14153692.0; Other, Institutional, Other, Patent Pending, Signature for CDK 4/6 Inhibitor: EP21152186.9; Other, Institutional, Other, Patent Issued, Predicting response to an Anti-HER2 containing therapy: EP15702464.7; Other, Institutional, Other, Patent Pending, GeparNuevo: EP19808852.8; Other, Institutional, Royalties, Patent Issued, Royalties, VM Scope GmbH: Digital Ki67 Evaluator. 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; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Molecular Health; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Merck; Financial Interests, Personal and Institutional, Advisory Role, Consulting or Advisory Role, Research Funding: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Lilly; Financial Interests, Institutional, Research Grant, Research Funding: Myriad Genetics; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: VMScope digital pathology software; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2015114146A1; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2010076322A1; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2020109570A1. All other authors have declared no conflicts of interest.

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

PENELOPE-B is a phase III study investigating the role of PAL + ET vs placebo + ET in HR+, HER2- early BC pts with high risk of relapse after neoadjuvant chemotherapy (NACT). Invasive disease-free survival was not improved with PAL + ET (Loibl JCO 2021). Estradiol (E2), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) values might be influenced by post-NACT PAL. Changes in hormones for pts treated with CDK4/6 inhibitors + ET are not well explored.

Methods

616 pts were premenopausal at baseline (BL, investigator-defined). Pts with serum samples at BL and at least before cycle (C) 7 or at end of treatment (EOT) were considered (N=576). 576 pts provided blood samples at BL, 526 before C7, 541 at EOT. Centrally assessed FSH>12.4 IU/l and E2<52.2 ng/L were defined as postmenopausal; fertile level of AMH as ≥0.22 ng/mL (central lab cut-offs). Analysed subgroups were pre- vs postmenopausal FSH/E2 at BL, age ≤40 vs >40 yrs, gonadotropin-releasing hormone analogue (GnRHa) use vs no.

Results

Median age was 43 (19-56) yrs; 46.8% pts had BMI <25, 53.2% ≥25. Hormone values are shown below. At BL, 41.6% of pts in the placebo vs 41.3% in the PAL arm had premenopausal hormone levels. Of these, 9.1 vs 13.5% (p=0.387) had postmenopausal hormone levels at C7. In pts ≤40 yrs 29.2 vs 29.5% at BL (p=1.000), 18.1 vs 23.4% at C7 (p=0.472) had postmenopausal values. More pts >40 yrs (BL 75.3%, C7 69.8%) vs ≤40 yrs (29.4, 20.7%) and without GnRHa (80.3, 72.2%) vs with (15.9, 12.1%) had postmenopausal hormone levels. Median AMH was under the detection limit at all time points. At BL 91.8 vs 93.6% had non-fertile levels of AMH (p=0.426), 94.4 vs 96.5% at C7 (p=0.298), without difference in subgroups. EOT analysis will be presented at the meeting. Table: 60MO

Conclusions

PAL does not influence FSH, E2 and the ovarian reserve significantly when added to ET after NACT.

Clinical trial identification

NCT01864746.

Legal entity responsible for the study

German Breast Group.

Funding

Funding and drug were provided by Pfizer.

Disclosure

F. Marmé: 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; Financial Interests, Personal and Institutional, Research Grant, Grant: Gilead/immunomedics. Y. Liu: Financial Interests, Institutional, Stocks/Shares: Pfizer. M. Martin Jimenez: Financial Interests, Institutional, Research Grant, Grant: Roche; Financial Interests, Institutional, Research Grant, Grant, Consulting/Advisory Fees: Puma; Financial Interests, Institutional, Research Grant, Grant, Consulting/Advisory Fees, Speakers’ Honoraria: Novartis; Financial Interests, Institutional, Advisory Role, consulting/advisory fees, speakers’ honoraria: AstraZeneca, Amgen, Roche, Genentech, Eli Lilly, Pfizer; Financial Interests, Institutional, Advisory Role, consulting/advisory fees: Taiho Oncology, PharmaMar, 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, Advisory Role, Research Funding: Myriad Genetics; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: VMScope Digital Pathology Software, WO2015114146A1, WO2010076322A1, WO2020109570A1. T. Karn: Other, Personal, Other, Patent pending: EP18209672. M. van Mackelenbergh: Financial Interests, Institutional, Other, Honoraria: Amgen, AstraZeneca, Roche, Pfizer, Novartis, Lilly, Pierre Fabre, Genomic Health, Molecular Health, Gilead, Seagen, GSK. 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. V. Müller: Financial Interests, Personal, Invited Speaker, Speaker and Consultancy Honoraria: Amgen, Daiichi Sankyo, MSD, GSK, Gilead; Financial Interests, Personal, Invited Speaker, Speaker Honoraria: AstraZeneca, Eisai, Pfizer, Teva; Financial Interests, Personal and Institutional, Invited Speaker, Speaker and Consultancy Honoraria: Novartis, Roche; Financial Interests, Personal and Institutional, Invited Speaker, Speaker Honoraria: Seagen; Financial Interests, Personal, Advisory Role, Consultancy Honoraria: Genomic Health, Hexal, Pierre Fabre, ClinSol, Lilly; Financial Interests, Institutional, Other, Other: Genentech. E. Stickeler: Financial Interests, Personal, Other, Personal Fees: Roche, Gilead, MSD, Lilly, Pfizer, Seagen, PharmaMar. S. Loibl: Financial Interests, Institutional, Research Grant, honorarium for Ad Boards: AbbVie, Celgene; Financial Interests, Institutional, Advisory Board, honorarium for Ad Board: Amgen, Bayer, BMS, Eirgenix, GSK, Lilly, Merck; Financial Interests, Institutional, Research Grant, honorarium for Ad Boards & Lectures, Grant, Other: AstraZeneca; Non-Financial Interests, Institutional, Research Grant, honorarium for Ad Board & Lecture, Medical Writing: Daiichi Sankyo, Roche; Non-Financial Interests, Institutional, Research Grant, honorarium for Ad Board, Medical Writing: Immunomedics/Gilead; Non-Financial Interests, Institutional, Research Grant, honorarium for Ad Board, Medical Writing: Novartis, Pfizer; Financial Interests, Institutional, Invited Speaker, honorarium for Ad Board & Lecture: Pierre Fabre, prIME/Medscape; Non-Financial Interests, Institutional, Invited Speaker, honorarium for Ad Board, Medical Writing: Puma; Financial Interests, Institutional, Invited Speaker, honorarium for Lecture: Samsung; Non-Financial Interests, Institutional, Invited Speaker, honorarium for Ad Boards, Medical Writing: Seagen; 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

GeparX (NCT02682693) investigated efficacy and safety of adding Dmab to standard NACT and two different nP schedules for primary BC. Addition of Dmab to NACT did not improve pCR rates. nP weekly (q1w) significantly increased pCR rate compared to d1,8 q3w schedule, but was associated with higher toxicity (Blohmer et al. Cancer Res 2020). Here we present QoL.

Methods

Patients (pts) were randomized to receive or not receive Dmab 120mg s.c. q4w for 6 cycles and to either nP 125mg/m² q1w or d1,8 q3w for 4 cycles, followed by 4x epirubicin/cyclophosphamide (q2w/q3w). QoL was assessed at baseline (BL), after nP, at end of treatment and 90 days (d) post-surgery (PS) using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane) questionnaire, FACT-Taxane Trial Outcome Index (TOI), FACT-G total score, and FACT-Taxane total score scales. Higher mean scores indicate better functioning and QoL. Mixed models including BL value as a random effect and treatment, time, and treatment by time interaction as fixed effects were used to compare the QoL scores based on the safety set. Primary endpoint was the mean score change from BL to 90d PS.

Results

Between 02/2017 and 03/2019, 780 pts were randomized and started treatment, of whom 768 were eligible for QoL analyses. BL parameters were well balanced. Questionnaire completion response remained >70% throughout the trial. Addition of Dmab did not change the QoL scores at any time point. Pts receiving nP q1w reported significantly lower mean scores of physical/functional well-being and FACT-G total score (p<0.001) compared to pts receiving nP d1,8 q3w. The decreased well-being with nP q1w partly persists 90d PS. The mean scores of additional concerns, FACT-Taxane TOI and FACT-Taxane total scores significantly differed favouring nP d1,8 q3w in all post-BL assessments (p<0.001). Social/family and emotional aspects were not affected by the regime.

Conclusions

nP q1w led to a significantly higher pCR rate but is associated with decreased QoL compared to nP d1,8 q3w, which is consistent with the higher toxicity reported for nP q1w. Benefit and risks need to be discussed with the pts.

Clinical trial identification

NCT02682693.

Legal entity responsible for the study

German Breast Group.

Funding

GeparX was financially supported by Amgen and BMS (Celgene).

Disclosure

M. Reinisch: Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Somatex; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: MSD. J. Blohmer: Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Honoraria: Amgen; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Honoraria: Novartis; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Travel, Accommodations, Expenses, Honoraria: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role, Travel, Accommodations, Expenses, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: MSD Oncology; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Other, Honoraria: Gilead Sciences; Financial Interests, Personal, Other, Honoraria: Eisai Germany; Financial Interests, Personal, Other, Honoraria: Seattle Genetics; Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo/AstraZeneca; Financial Interests, Personal, Other, Honoraria: Exact Sciences; Financial Interests, Personal, Other, Honoraria: Molecular Health. T. Link: Financial Interests, Personal, Other, Personal Fees: Pfizer; Financial Interests, Personal, Other, Personal Fees: Roche; Financial Interests, Personal, Other, Personal Fees: Tesaro; Non-Financial Interests, Personal, Other, Personal Fees: MSD; Financial Interests, Personal, Other, Personal Fees: Amgen; Non-Financial Interests, Personal, Other, Personal Fees: Clovis; Non-Financial Interests, Institutional, Other: Celgene; Financial Interests, Personal, Other, Personal Fees: Novartis; Financial Interests, Personal, Other, Personal Fees: Lilly; Non-Financial Interests, Personal, Other, Personal Fees: GSK; Financial Interests, Personal, Other, Personal Fees: Myriad; Financial Interests, Personal, Other, Personal Fees: Eisai; Non-Financial Interests, Institutional, Other: Daiichi Sankyo; Financial Interests, Personal, Other, Personal Fees: Gilead. M. Untch: Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Amgen GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: AstraZeneca; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: BMS; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Celgene GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Daiichi Sankyo; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Eisai; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Lilly Deutschland; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Lilly Int.; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: MSD Merck; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Myriad Genetics; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Pfizer GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Roche Pharma AG; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Sanofi Aventis Deutschland GmbH; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Novartis; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Pierre Fabre; Non-Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Clovis Oncology; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Seatlle Genetics; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Seagen; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: GSK; Financial Interests, Personal and Institutional, Other, All fees to the institution/employer: Gilead. P.A. Fasching: Financial Interests, Personal, Invited Speaker, Advisory Board, Invited Speaker: Novartis; Financial Interests, Institutional, Funding, Grant, Institutional Funding: BioNTech; Financial Interests, Personal and Institutional, Research Grant, Advisory Board, Invited Speaker, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker, Advisory Board, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Advisory Board, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker, Advisory Board, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker, Advisory Board, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Institutional Funding: Cepheid; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Advisory Board: Hexal; Financial Interests, Personal, Advisory Board, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Advisory Board, Advisory Board, Invited Speaker: Gilead. A. Schneeweiss: Financial Interests, Personal, Research Grant, Research Grant, Travel expenses, Honoraria: BMS; Financial Interests, Personal, Research Grant, Research Grant, Expert testimony, Travel expenses, Honoraria: Roche; Financial Interests, Institutional, Research Grant, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant, Research Grant: Molecular Partner; Financial Interests, Personal, Expert Testimony, Expert testimony, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria, Travel expenses: Pfizer; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Tesaro; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Other, Honoraria: Gilead; Financial Interests, Personal, Other, Honoraria: Seagen. P. Wimberger: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Roche Pharma GmbH; Financial Interests, Institutional, Research Grant: GSK. S. Seiler: Financial Interests, Institutional, Research Grant, Grant: Amgen; Financial Interests, Institutional, Research Grant, Grant: BMS; Financial Interests, Personal, Other, Presentations: AbbVie. J. Huober: Financial Interests, Personal, Other: Gilead; Financial Interests, Personal, Other: Seagen; 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; Financial Interests, Personal, Other, Travel, Other: Daiichi; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: AbbVie; Financial Interests, Personal, Other: Eisai; Financial Interests, Institutional, Research Grant, Grant: Hexal; Financial Interests, Institutional, Research Grant, Grant, Travel, Other: BMS. M. Thill: Non-Financial Interests, Personal, Other, Personal Fees: Amgen; Financial Interests, Personal, Other, Personal Fees: AstraZeneca; Non-Financial Interests, Personal, Other, Personal Fees: BMS; Financial Interests, Personal, Other, Personal Fees: Daiichi Sankyo; Financial Interests, Personal, Other, Personal Fees: Eisai; Non-Financial Interests, Personal and Institutional, Research Grant, Trial funding, Grant, Personal Fees: Exact Sciences; Financial Interests, Personal, Other, Personal Fees: Lilly; Financial Interests, Personal, Other, Personal Fees: MSD; Financial Interests, Personal, Other, Personal Fees: Hexal; Financial Interests, Personal, Other, Personal Fees: Novartis; Financial Interests, Personal, Other, Personal Fees: Pfizer; Non-Financial Interests, Personal, Other, Manuscript support, Other: PFM Medical; Non-Financial Interests, Personal, Other, Personal Fees: Roche; Financial Interests, Personal, Other, Personal Fees: Tesaro; Financial Interests, Personal, Other, Manuscript support, Other: Clovis; Financial Interests, Personal, Other, Personal Fees: Seagen; Financial Interests, Institutional, Research Grant, Grant, Trial funding: Endomagnetics; Financial Interests, Personal, Other, Personal Fees: Norgine; Non-Financial Interests, Institutional, Other: RTI Surgical; Non-Financial Interests, Institutional, Other, Manuscript support, Other: Clearcut; Financial Interests, Personal, Other, Personal Fees: Becton and Dickinson; Financial Interests, Personal, Other, Manuscript support, Other: Servier; Financial Interests, Personal, Other, Personal Fees: Gilead Sciences; Financial Interests, Personal, Other, Personal Fees: Sysmex; Non-Financial Interests, Personal, Other, Personal Fees: Neodynamics; Financial Interests, Personal, Other, Personal Fees: GSK; Financial Interests, Personal, Other, Personal Fees: Vifor; Financial Interests, Personal, Other, Personal Fees: Organon; Financial Interests, Personal, Other, Personal Fees: Viatris; Financial Interests, Personal, Other, Manuscript support, Other: Vifor. C. Jackisch: Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Celgene; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Exact Sciences; Financial Interests, Institutional, Other: Seagen. K. Rhiem: Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Amgen. C. Hanusch: Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: AstraZeneca. 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; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Molecular Health; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Merck; Financial Interests, Personal and Institutional, Advisory Role, Consulting or Advisory Role, Research Funding: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Lilly; Financial Interests, Institutional, Funding, Research Funding: Myriad Genetics; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: VMScope digital pathology software; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2015114146A1; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2010076322A1; Other, Personal, Royalties, Patents, Royalties, Other Intellectual Property: WO2020109570A1. S. Loibl: Financial Interests, Institutional, Advisory Board, Grant, Other: AbbVie; Financial Interests, Institutional, Advisory Board, Other: Amgen; Financial Interests, Institutional, Advisory Board, Grant, Other: AstraZeneca; Financial Interests, Institutional, Advisory Board, Other: Bayer; Financial Interests, Institutional, Advisory Board, Other: BMS; Financial Interests, Institutional, Advisory Board, Grant, Other: Celgene; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board, Other: Eirgenix; Financial Interests, Institutional, Advisory Board, Other: GSK; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Immunomedics/Gilead; Financial Interests, Institutional, Advisory Board, Other: Lilly; Financial Interests, Institutional, Advisory Board, Other: Merck; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Novartis; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Pfizer; Financial Interests, Institutional, Advisory Board, Other: Pierre Fabre; Financial Interests, Institutional, Advisory Board, Other: prIME/Medscape; Non-Financial Interests, Institutional, Advisory Board, Medical Writing, Other: Puma; Financial Interests, Institutional, Other, honorarium for Lecture: Samsung; Non-Financial Interests, Institutional, Advisory Board, honorarium for Ad Boards, Medical Writing: Seagen; Non-Financial Interests, Institutional, Research Grant, Grant, Medical Writing, Other: Roche; Other, Institutional, Other, Patent Pending, Immunsignature in TNBC: EP14153692.0; Other, Institutional, Other, Patent Pending, Signature for CDK 4/6 Inhibitor: EP21152186.9; Other, Institutional, Other, Patent Issued, Predicting response to an Anti-HER2 containing therapy: EP15702464.7; Other, Institutional, Other, Patent Pending, GeparNuevo: EP19808852.8; Other, Institutional, Royalties, Patent Issued, Royalties, VM Scope GmbH: Digital Ki67 Evaluator. All other authors have declared no conflicts of interest.

Background

This analysis evaluated the cost effectiveness of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery compared with neoadjuvant chemotherapy for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The analysis was conducted from a US third-party public healthcare payer perspective.

Methods

A multi-state transition model including four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death was developed to simulate patients’ disease course over lifetime. Efficacy and safety data were derived from the KEYNOTE-522 randomized clinical trial. The model Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, in 2021 values) for drug acquisition/administration, adverse events, disease management and subsequent therapies were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.

Results

In the base-case scenario, pembrolizumab plus chemotherapy followed by pembrolizumab resulted in an expected gain of 3.37 life-years (LYs) and 2.90 QALYs and an incremental cost of $US79,046 compared with chemotherapy alone. The incremental cost per QALY gain was $US27,285/QALY and the incremental cost per LY gain was $US23,489/LY, which were lower than all cost-effectiveness thresholds cited in the literature. Sensitivity analyses showed the results to be robust over plausible values of key model inputs.

Conclusions

Compared with neoadjuvant chemotherapy, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery is projected to be a cost-effective option for high-risk eTNBC in the US.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Hecal; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Invited Speaker: Cepheid; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.V.; Non-Financial Interests, Member: Translational Research in Oncology; Non-Financial Interests, Member: Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, C. Le Bailly De Tilleghem, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. W. Xue, Z. Zhou: Financial Interests, Institutional, Funding: Merck. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax; Financial Interests, Personal, Advisory Board: Carrick Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Gilead Sciences; Financial Interests, Personal, Advisory Board: Ontada; Financial Interests, Personal, Advisory Board: Pierre Fabre Pharmaceuticals; Financial Interests, Personal, Advisory Board: Samsung Bioepis; Financial Interests, Personal, Advisory Board: Sanofi.

Background

Pembrolizumab in combination with chemotherapy showed significantly longer progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone and manageable safety as first-line treatment in patients with locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1-positive (Combined Positive Score [CPS]≥ 10) tumors in the KEYNOTE-355 (KN355) trial. The objective of this analysis was to gain insights on the clinical benefits and risks of pembrolizumab in terms of quality-adjusted survival among patients in the trial.

Methods

KN355 is a double-blind, randomized, controlled, global phase III trial. This analysis was based on the final analysis of KN355. The Quality-adjusted Time without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare the treatment arms. Survival time of each patient was partitioned into three health states: time before disease progression with toxicity (TOX), time before disease progression without toxicity (TWiST), and disease progression until death. Toxicities considered in the analysis were grade 3+ adverse events (AEs). Mean utility scores for the three health states were estimated using EQ-5D-3L data collected in the KN355 trial. Q-TWiST calculated as the utility-weighted sum of the mean health state durations. The published criterion for a ‘clearly clinically important’ improvement in Q-TWiST is 15% of mean OS in a study.

Results

Patients randomized to pembrolizumab plus chemotherapy had 5.44 months longer mean PFS, which consisted of 3.03- and 2.41-months gains in TOX and TWiST, respectively, compared to those randomized to chemotherapy alone with 44 months of follow-up. The improvement in Q-TWiST was 3.71 months (P=0.003, about 18% of mean OS). Results showed an increase in trend for the Q-TWiST improvement of pembrolizumab over time.

Conclusions

Despite higher risks for AEs, pembrolizumab combined with chemotherapy showed statistically significant and clinically meaningful improvement in quality-adjusted survival compared to chemotherapy alone as first-line treatment for PD-L1-positive mTNBC.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hecal, Lilly, Pierre Fabre, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Lilly, Seagen; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck.

C. Le Bailly De Tilleghem: Financial Interests, Personal, Full or part time Employment: MSD.

J. O’Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, prIME Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi.

Background

In DESTINY-Breast03 (NCT03529110), T-DXd showed superior progression-free survival by BICR vs T-DM1 (HR, 0.28 [95% CI, 0.22-0.37]; P < 0.001) and manageable safety in pts with HER2+ MBC. PRO measures incorporate pts’ perspective in clinical trials to assess effect of treatment on health-related quality of life (QoL). Here, PROs and hospitalization rate for T-DXd vs T-DM1 (May 21, 2021, data cutoff) are reported.

Methods

Pts with HER2+ (IHC 3+ or IHC 2+/ISH+) MBC whose disease progressed on or after trastuzumab and a taxane were assigned 1:1 to T-DXd or T-DM1. PRO endpoints were assessed before infusion on day 1 of the first 3 21-day cycles, then every 2 cycles, at end of treatment, at 40-days’ follow-up, then every 3 months until end of follow-up; endpoints included European Organization for Research and Treatment of Cancer QoL questionnaires (EORTC QLQ-C30; primary variable: global health status [GHS]/QoL scale score) and the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analog scale (VAS). Analyses included change from baseline (CFB) and time to definitive deterioration (TDD). Hospitalization-related endpoints were also measured.

Results

Compliance for questionnaires was >97% at baseline and >80% for cycles 3-29. QLQ-C30 baseline GHS scores recorded for T-DXd (n = 253) and T-DM1 (n = 260) were similar. At end of treatment, mean CFB was not meaningfully different vs baseline (<10-point CFB) in both arms. Median TDD of QLQ-C30 GHS was 9.7 mo for T-DXd vs 8.3 mo for T-DM1 (HR, 0.88 [95% CI, 0.70-1.11]), and all prespecified QLQ-C30 subscales presented longer TDD with T-DXd, including emotional functioning (HR, 0.69 [95% CI, 0.53-0.89]) and pain (HR, 0.75 [95% CI, 0.59-0.95]). Median TDD of EQ-5D-5L VAS was 13.2 mo for T-DXd vs 8.5 mo for T-DM1 (HR, 0.77 [95% CI, 0.61-0.98]). With T-DXd vs T-DM1, 18 pts (6.9%) vs 19 pts (7.2%) were hospitalized; median time to first hospitalization was 219.5 vs 60.0 days, respectively.

Conclusions

The improved efficacy and manageable toxicity reported previously for T-DXd, together with this evidence of maintained or improved QoL supports the overall benefit of T-DXd for pts with HER2+ MBC.

Clinical trial identification

NCT03529110.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Marianna B. Johnson, PhD, and Eileen McIver, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc., AstraZeneca.

Disclosure

G. Curigliano: Financial Interests, Personal, Other, Honoraria: BMS, Pfizer, Novartis, Lilly, Roche, AstraZeneca, Daiichi Sankyo, Exact Sciences, Seagen, Gilead, Celcuity; Financial Interests, Personal, Advisory Board, Honoraria: BMS, Pfizer, Novartis, Lilly, Roche, AstraZeneca, Daiichi Sankyo, Exact Sciences, Seagen, Gilead, Celcuity; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Lilly, Roche, AstraZeneca, Daiichi Sankyo, Exact Sciences, Seagen; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Other, Travel expenses, including accommodations: Pfizer, Roche; Financial Interests, Institutional, Research Grant: BMS, Pfizer, Novartis, Lilly, Roche, AstraZeneca, Daiichi Sankyo, Exact Sciences, Seagen, Gilead, Celcuity; Financial Interests, Personal, Officer: ESMO, LILT, EUSOMA; Financial Interests, Personal, Other: National Health Council. K. Dunton: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. M. Rosenlund: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. M. Janek: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. J. Cathcart: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Liu: Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo, Inc.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.A. Fasching: Financial Interests, Personal, Other, Honoraria: Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia, Sanofi Aventis, Gilead; Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia, Sanofi Aventis, Gilead; Financial Interests, Institutional, Research Grant: Cepheid, BioNTech; Financial Interests, Personal, Officer: TRIO. H. Iwata: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Chugai, AstraZeneca, Sanofi, Lilly, MSD, Pfizer; Financial Interests, Personal, Research Grant: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer.

Background

LUCY interim findings confirmed the clinical effectiveness of olaparib 300 mg twice daily in patients with metastatic breast cancer (mBC) in a real world setting. Findings were consistent with the OlympiAD trial of olaparib vs chemotherapy of physician’s choice. We report results of the final planned analysis.

Methods

Eligible adults had germline (g) or somatic (s) BRCA1- and/or BRCA2-mutated (BRCAm), HER2-negative mBC and had received taxane and/or anthracycline in early or metastatic settings and ≤2 previous lines of chemotherapy for mBC. Pts with hormone receptor-positive (HR+) mBC had previously completed ≥1 line of endocrine therapy (ET) in any setting or were unsuitable for further ET. Primary endpoint: investigator-assessed progression-free survival (PFS; gBRCAm cohort). Overall survival (OS) and safety were secondary endpoints. Final analysis was planned at 130 OS events (gBRCAm). Results are in all pts (gBRCAm and sBRCAm). Prespecified subgroups (gBRCAm only): HR status (HR+ vs triple-negative breast cancer [TNBC]); line of therapy (1st line vs 2nd line+).

Results

During 2018, 255 pts were enrolled (252 gBRCAm, 3 sBRCAm; median [m] age: 45.0 [range 22–75] years; 98.4% female). mPFS: 8.2 months (95% CI 7.0–9.2; 208 events, 81.6%). mOS: 24.9 months (95% CI 21.1–27.9; 142 events, 55.7%). OS rate at 30 months: 41.7% (95% CI 35.2–48.1). Treatment-related adverse events (AEs, >10% pts): nausea (47.8%), anaemia (34.5%), asthenia (20.8%), fatigue (18.0%), vomiting (17.6%), neutropenia (15.3%) and diarrhoea (11.0%). Grade ≥3 AEs (17.6% pts) included anaemia (11.8%). Few pts (4.3%) discontinued treatment due to an AE. Post study therapies will be reported.

Conclusions

The benefit of olaparib was similar across HR status and treatment lines. mOS was longer than reported in OlympiAD. No new safety signals were observed. These results strongly support olaparib as a chemotherapy-free alternative for gBRCAm, HER2-negative mBC. Table: 174P

Subgroup analyses (full analysis set)

Editorial acknowledgement

Medical writing assistance was provided by Elizabeth Gandhi, PhD of PharmaGenesis Cambridge, Cambridge, UK, with funding from AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Legal entity responsible for the study

AstraZeneca.

Funding

This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J. Balmana: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MedSir. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Hecal; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Invited Speaker: Cepheid; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.V.; Non-Financial Interests, Member: Translational Research in Oncology; Non-Financial Interests, Member: Deutsche Gesellschaft für Senologie e.v. 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. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; 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. S. Aksoy: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche. C.V. Timcheva: Financial Interests, Personal, Invited Speaker, Presentation during national scientific conference: Roche Bulgaria; Financial Interests, Personal, Advisory Board, Discussion on the place of CDK4/6 inhibitors in the treatment of metastatic breast cancer: Eli Lilly; Financial Interests, Personal, Advisory Board, The role of PARP inhibitors in the treatment of breast and ovarian cancer: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: Parexel; Financial Interests, Personal and Institutional, Invited Speaker, Pi for several clinical trials perforing in the hospital: Roche; Financial Interests, Personal and Institutional, Invited Speaker, PI for some clinical trials performing in the hospital: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, PI for the clinical trial performing in the hospital: I3Research; Non-Financial Interests, Principal Investigator, Investigator initiated trial on metastatic CRC: Merck; Non-Financial Interests, Member, Created in 2012, Head of BAMO until 2020: Bulgarian Association for Medical Oncology (BAMO). T. Park-Simon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pizer; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis. E. John: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca. K. Baria: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G. Walker: Financial Interests, Institutional, Other, I work as a consultant to the company: AstraZeneca. K.A. Gelmon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Ayala; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: BMS. All other authors have declared no conflicts of interest.

Background

Gaps in RW evidence exist regarding pts’ and health-care professionals’ (HCPs) perspectives on SEs impacting QOL. Previously, RW survey results showed disconnects between pts with ABC and HCPs on the importance of QOL discussions (Cardoso, SABCS 2021). Here, we examine how SEs impacting QOL in pts with ABC are perceived.

Methods

The survey was designed by a committee of oncologists, nurses, advocates, and pts. After ethical approval, data were collected from July 2020 to May 2021 via a cross-sectional online survey of oncologists, nurses, and pts with HR+/HER2− ABC in 7 countries. HCPs and pts were surveyed on the impact of SEs on QOL and HCP interactions. Observations were assessed using a 4-point Likert scale.

Results

The survey was completed by 467 pts and 502 HCPs. Most pts and HCPs believed fear of progression (76% & 92%, respectively) and pain (73% & 96%) had a moderate/severe impact on QOL. The most common SEs experienced by pts since starting ABC tx or their current tx were fatigue (73% & 64%) and pain (64% & 42% [back pain]). Fatigue relieved by rest was believed to have a moderate/severe impact on QOL more so by pts (78%) than HCPs (40%). Most pts did not discuss SEs with HCPs (79% for fatigue, 74% for pain) until these were moderate/severe. Pts reported that insomnia (83%), anxiety (82%), back pain (78%), fatigue (77%), and diarrhea (71%) had a moderate/severe impact on their QOL. Pts were least willing to live with back pain (52%), fatigue (42%), diarrhea (41%), and loss of appetite (41%) even if tx was working. In pts on a CDK4/6i, 83% experienced ≥ 1 moderate/severe SE, with insomnia (85%), diarrhea (75%), back pain (75%), and fatigue (74%) having a moderate/severe impact on QOL.

Conclusions

Pts with ABC and HCPs were generally aligned on SEs that severely impacted QOL, but HCPs may undervalue the impact of mild SEs on pts. Fatigue and pain were the most common SEs experienced by pts. In pts on a CDK4/6i, insomnia, diarrhea, back pain, and fatigue had a moderate/severe impact on QOL. These data support close monitoring, early intervention, and when indicated, prophylaxis of SEs that may greatly impact QOL in pts with ABC.

Editorial acknowledgement

Medical writing support was provided by Shashank Tandon at MediTech Media, funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

F. Cardoso: Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Astellas/Medivation; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Celgene; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: EISAI; Financial Interests, Personal, Other: GE Oncology; Financial Interests, Personal, Other: Genentech; Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: Macrogenics; Financial Interests, Personal, Other: Medscape; Financial Interests, Personal, Other: Merck-Sharp; Financial Interests, Personal, Other: Merus; Financial Interests, Personal, Other: Mylan; Financial Interests, Personal, Other: Mundipharma; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Pierre Fabre; Financial Interests, Personal, Other: prIME Oncology; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Sanofi; Financial Interests, Personal, Other: Samsung Bioepis; Financial Interests, Personal, Other: Teva; Financial Interests, Personal, Other: Seagen; Financial Interests, Personal, Other: Debiopharm; Financial Interests, Personal, Other: Gilead; Financial Interests, Personal, Other: Iqvia; Financial Interests, Personal, Other: Touchime; Other, Personal, Writing Engagements, Medical Writer Support: Novartis. J. Rihani: Financial Interests, Personal, Invited Speaker, For participating in various Novartis (sponsored) events, i.e. giving talks, a member in committees and on patient engagement panels: Novartis. D. Aubel: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. J. de Courcy: Financial Interests, Institutional, Other, Adelphi Real World received payment from Novartis to conduct the study: Novartis; Financial Interests, Institutional, Other, Adelphi Real World received payment from Novartis to conduct the study: Adelphi Real World. N. Harbeck: Financial Interests, Personal, Other, Consulting: Novartis; Financial Interests, Personal, Invited Speaker, Lectures: Novartis; Financial Interests, Personal, Invited Speaker, Lectures: Lilly; Financial Interests, Personal, Other, Consulting: Lilly; Financial Interests, Personal, Invited Speaker, Lectures: AstraZeneca; Financial Interests, Personal, Other, Consulting: AstraZeneca; Financial Interests, Personal, Invited Speaker, Lectures: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Lectures: MSD; Financial Interests, Personal, Other, Consulting: MSD; Financial Interests, Personal, Invited Speaker, Lectures: Pierre Fabre; Financial Interests, Personal, Other, Consulting: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Lectures: Roche; Financial Interests, Personal, Other, Consulting: Roche; Financial Interests, Personal, Invited Speaker, Lectures: Sandoz/Hexal; Financial Interests, Personal, Other, Consulting: Sandoz/Hexal; Financial Interests, Personal, Invited Speaker, Lectures: Seattle Genetics; Financial Interests, Personal, Other, Consulting: Seattle Genetics; Non-Financial Interests, Personal, Member of the Board of Directors, Co-Director WSG: West German Study Group. H.S. Rugo: Financial Interests, Institutional, Research Grant, Grant - Institution: Plexxikon; Financial Interests, Institutional, Research Grant, Grant - Institution: Macrogenics; Financial Interests, Institutional, Research Grant, Grant - Institution: OBI Pharma; Financial Interests, Institutional, Research Grant, Grant - Institution: Eisai; Financial Interests, Institutional, Research Grant, Grant - Institution: Pfizer; Financial Interests, Institutional, Research Grant, Grant - Institution: Novartis; Financial Interests, Institutional, Research Grant, Grant - Institution: Eli Lilly; Financial Interests, Institutional, Research Grant, Grant - Institution: GlaxoSmithKline; Financial Interests, Institutional, Research Grant, Grant - Institution: Genentech; Financial Interests, Institutional, Research Grant, Grant - Institution: Celsion; Financial Interests, Institutional, Research Grant, Grant - Institution: Merck; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: Novartis; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: Roche/Genentech; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: OBI Pharma; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: Bayer; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Genomic Health. P.A. Fasching: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Funding, Institutional Funding: BioNTech; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Institutional, Funding, Institutional Funding: Cepheid; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Hexal; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Advisory Board: Gilead.

S. Haftchenary: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares, Stock ownership: Novartis. P. Pathak: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares, Stock ownership: Novartis. All other authors have declared no conflicts of interest.

Background

The MONALEESA-3 (NCT02422615) final protocol-specified OS analysis and an exploratory OS analysis with extended follow-up demonstrated significant OS benefit with RIB + FUL vs placebo (PBO) + FUL as 1L or second-line (2L) treatment (tx). At the time of these analyses, the median (m) OS was 53.7 vs 41.5 mo for RIB vs PBO in the intent-to-treat (ITT) population. Although the mOS was not reached in the RIB arm for 1L pts, the mOS in 2L pts was 39.7 vs 33.7 mo for RIB vs PBO. We report an exploratory analysis of OS with additional follow-up, allowing further characterization of long-term OS benefits of RIB in the 1L setting.

Methods

Postmenopausal pts with HR+/HER2− ABC were randomized 2:1 to receive RIB + FUL or PBO + FUL. Updated OS in the 1L setting (pts with de novo disease or relapse >12 mo from completion of [neo]adjuvant endocrine therapy) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were also evaluated.

Results

At the data cutoff (January 12, 2022), the median follow-up for 1L pts was 70.8 mo; 16.5% and 8.6% of pts remained on tx in the RIB and PBO arms, respectively. An OS benefit was observed with 1L RIB vs PBO (mOS, 67.6 vs 51.8 mo; HR, 0.67; 95% CI, 0.50-0.90). The OS rate at 5 years was 56.5% vs 42.1% for RIB vs PBO, respectively. PFS2 (HR, 0.64) and CFS (HR, 0.62) favored RIB vs PBO. In pts who discontinued study tx, 81.8% and 89.7% received subsequent antineoplastic therapy, while 16.7% vs 35.0% received a subsequent cyclin-dependent kinase 4/6 inhibitor in the RIB vs PBO arms. Results in the ITT and 2L populations were generally consistent with the previous analysis.

Conclusions

This exploratory analysis of 1L RIB + FUL in MONALEESA-3 reports the longest mOS thus far (67.6 mo—a 15.8-mo improvement vs PBO and a relative reduction in risk of death of 33%) in a 1L population in a Phase III clinical trial in ABC. These impressive results in the 1L setting further support the use of RIB + ET in HR+/HER2− ABC.

Clinical trial identification

NCT02422615.

Editorial acknowledgement

Medical writing support was provided by Casey Nielsen at MediTech Media, funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

P.A. Fasching: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Seagen, Roche, Gilead; Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia, Sanofi Aventis, Gilead; Financial Interests, Institutional, Funding, Institutional Funding: Biontech, Cepheid; Financial Interests, Personal, Research Grant: Pfizer. S. Chia: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Hoffman La Roche, Eli Lilly; Financial Interests, Institutional, Funding, My institution received funds for participation in clinical trials by: Novartis, Pfizer, Hoffman La Roche, Eli Lilly. G. Jerusalem: Financial Interests, Personal, Other, Grants, Personal Fees & Non-Financial Support: Novartis, Roche, Pfizer; Financial Interests, Personal, Other, Personal Fees & Non-Financial Support: Lilly, Amgen, BMS, AstraZeneca; Financial Interests, Personal, Other, Personal Fees: AbbVie, Daiichi Sankyo, Seagen; Non-Financial Interests, Personal, Other, Non-Financial Support: Medimmune, Merck KGaA. M. De Laurentiis: Financial Interests, Personal, Speaker’s Bureau, Speaker's Honoraria: Pfizer, Novartis, Roche, AstraZeneca, Eisai, Eli Lilly, Pierre Fabre; Financial Interests, Personal, Advisory Board, Advisory Board Honoraria: Pfizer, Novartis, Roche, AstraZeneca, Eisai, Eli Lilly, MSD, Pierre Fabre. S. Im: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, Hanmi, Pfizer, Novartis; Non-Financial Interests, Personal, Other, Travel support: Novartis; Financial Interests, Personal, Advisory Role, Participation in advisory meetings: Eisai, Amgen, Roche, Lilly, GSK, MSD; Financial Interests, Personal, Other: Daewoong Pharm. K. Petrakova: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Roche, Pfizer. G.V. Bianchi: Financial Interests, Personal, Advisory Role: Roche, Eli Lilly, Novartis, Seagen, AstraZeneca/Daichi Sankyo, MSD. M. Martin Jimenez: Financial Interests, Personal, Speaker’s Bureau, Speaker Honoraria: Lilly, Pfizer; Financial Interests, Personal, Advisory Board, Honoraria for Participation in Advisory Boards: Lilly, Pfizer, AstraZeneca, Novartis, Roche-Genentech, GlaxoSmithKline, PharmaMar, Taiho Oncology; Financial Interests, Personal, Research Grant: Novartis, Roche-Genentech. A. Nusch: Financial Interests, Personal, Advisory Role, Consulting/Advisory role: Novartis, Amgen; Financial Interests, Personal, Funding, Research Funding: Novartis; Other, Personal, Travel/Accommodation/Expenses: Novartis; G.S. Sonke: Financial Interests, Institutional, Other, Institutional Reimbursement for Patient Accrual: Novartis; Financial Interests, Institutional, Other, Institutional Reimbursement for Education and Steering Committee Activities: Novartis; Financial Interests, Institutional, Other, Institutional research support: Merck, AstraZeneca, Roche. J.T. Beck: Financial Interests, Institutional, Research Grant, Institutional funding for doing research: AbbVie, Alliance, Argenx, Ascentage Pharma Group, AstraZeneca, Biodesix, Bio-Thera, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech-Roche, Hutchison, Immunomedics, Gilead, MT Group Merck, Nektar, Pfizer, Polynoma, Seattle Genetics, Serono-EMD, Tesaro, TG Therapeutics, Daiichi Sankyo, Exact Sciences, Boehringer Ingelheim, Laekna, Novocure, Mirati Therapeutics, Tarveda Therapeutics, Sumitomo Dainippon Pharma Oncology (formerly Boston Bio), Elpiscience Biopharma, Takeda, Vaccinex, Vincerx Pharma, Ultimovacs, Mersana. J.P. Zarate, Y. Wang, A. Chakravartty, C. Wang: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. D. Slamon: Non-Financial Interests, Personal, Member of the Board of Directors: Biomarin; Non-Financial Interests, Personal, Other, Travel expenses: Biomarin, Pfizer, Novartis; Financial Interests, Personal, Stocks/Shares: Pfizer, Amgen, Seattle Genetics; Financial Interests, Personal, Other, Research funding: Pfizer, Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, Consulting: Novartis, Eli Lilly. All other authors have declared no conflicts of interest.

Background

This analysis evaluated the cost effectiveness of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery compared with neoadjuvant chemotherapy for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The analysis was conducted from a US third-party public healthcare payer perspective.

Methods

A multi-state transition model including four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death was developed to simulate patients’ disease course over lifetime. Efficacy and safety data were derived from the KEYNOTE-522 randomized clinical trial. The model Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, in 2021 values) for drug acquisition/administration, adverse events, disease management and subsequent therapies were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.

Results

In the base-case scenario, pembrolizumab plus chemotherapy followed by pembrolizumab resulted in an expected gain of 3.37 life-years (LYs) and 2.90 QALYs and an incremental cost of $US79,046 compared with chemotherapy alone. The incremental cost per QALY gain was $US27,285/QALY and the incremental cost per LY gain was $US23,489/LY, which were lower than all cost-effectiveness thresholds cited in the literature. Sensitivity analyses showed the results to be robust over plausible values of key model inputs.

Conclusions

Compared with neoadjuvant chemotherapy, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery is projected to be a cost-effective option for high-risk eTNBC in the US.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Hecal; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Invited Speaker: Cepheid; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.V.; Non-Financial Interests, Member: Translational Research in Oncology; Non-Financial Interests, Member: Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, C. Le Bailly De Tilleghem, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. W. Xue, Z. Zhou: Financial Interests, Institutional, Funding: Merck. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax; Financial Interests, Personal, Advisory Board: Carrick Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Gilead Sciences; Financial Interests, Personal, Advisory Board: Ontada; Financial Interests, Personal, Advisory Board: Pierre Fabre Pharmaceuticals; Financial Interests, Personal, Advisory Board: Samsung Bioepis; Financial Interests, Personal, Advisory Board: Sanofi.

Background

Pembrolizumab in combination with chemotherapy showed significantly longer progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone and manageable safety as first-line treatment in patients with locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1-positive (Combined Positive Score [CPS]≥ 10) tumors in the KEYNOTE-355 (KN355) trial. The objective of this analysis was to gain insights on the clinical benefits and risks of pembrolizumab in terms of quality-adjusted survival among patients in the trial.

Methods

KN355 is a double-blind, randomized, controlled, global phase III trial. This analysis was based on the final analysis of KN355. The Quality-adjusted Time without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare the treatment arms. Survival time of each patient was partitioned into three health states: time before disease progression with toxicity (TOX), time before disease progression without toxicity (TWiST), and disease progression until death. Toxicities considered in the analysis were grade 3+ adverse events (AEs). Mean utility scores for the three health states were estimated using EQ-5D-3L data collected in the KN355 trial. Q-TWiST calculated as the utility-weighted sum of the mean health state durations. The published criterion for a ‘clearly clinically important’ improvement in Q-TWiST is 15% of mean OS in a study.

Results

Patients randomized to pembrolizumab plus chemotherapy had 5.44 months longer mean PFS, which consisted of 3.03- and 2.41-months gains in TOX and TWiST, respectively, compared to those randomized to chemotherapy alone with 44 months of follow-up. The improvement in Q-TWiST was 3.71 months (P=0.003, about 18% of mean OS). Results showed an increase in trend for the Q-TWiST improvement of pembrolizumab over time.

Conclusions

Despite higher risks for AEs, pembrolizumab combined with chemotherapy showed statistically significant and clinically meaningful improvement in quality-adjusted survival compared to chemotherapy alone as first-line treatment for PD-L1-positive mTNBC.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hecal, Lilly, Pierre Fabre, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Lilly, Seagen; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck.

C. Le Bailly De Tilleghem: Financial Interests, Personal, Full or part time Employment: MSD.

J. O’Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, prIME Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi.