1. De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial.
- Author
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Nitz U, Gluz O, Graeser M, Christgen M, Kuemmel S, Grischke EM, Braun M, Augustin D, Potenberg J, Krauss K, Schumacher C, Forstbauer H, Reimer T, Stefek A, Fischer HH, Pelz E, Zu Eulenburg C, Kates R, Wuerstlein R, Kreipe HH, and Harbeck N
- Subjects
- Antibodies, Monoclonal, Humanized, Female, Hormones therapeutic use, Humans, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Paclitaxel, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Neoadjuvant Therapy
- Abstract
Background: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype., Methods: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m
2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment., Findings: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group)., Interpretation: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing., Funding: Roche, Bayer., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests UN reports research funding paid to their institution from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, and Sanofi; consulting fees from Genomic Health and Roche; honoraria from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis, Pfizer, Roche/Genentech, and Teva; payment for expert testimony from Genomic Health; travel support from Genomic Health, Pfizer, and Roche; participation on a data safety monitoring board or advisory board at Roche, Seagen, and Exact Sciences (all outside the submitted work); and a co-director position at the West German Study Group. OG reports consulting fees from Celgene, Genomic Health/Exact Sciences, Lilly, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, and Molecular Health; honoraria from Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, and AstraZeneca; payment for expert testimony from Genomic Health; and travel support from Roche (all outside the submitted work); and a co-director position at the West German Study Group. MG reports consulting fees from AstraZeneca and travel support from Daiichi Sankyo, all outside of the submitted work. SK reports research funding from Roche and Novartis; consulting fees from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health/Exact Science, Lilly, MSD, Novartis, Seagen, Pfizer, pfm Medical, Roche, Somatex, and Gilead; travel support from Roche and Daiichi Sankyo; and other financial or non-financial interests for non-continuing medical education services from Somatex, Roche, Novartis, and Lilly (all outside of the submitted work); and a co-director position at the West German Study Group. MB reports consulting fees from AstraZeneca, Exact Sciences, Novartis, Puma, and Roche; honoraria from AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva, and MSD; and travel support from AstraZeneca, Celgene, Medac, Novartis, Roche, and Daiichi Sankyo (all outside the submitted work). KK reports honoraria from Roche, RG Gesellschaft für Information und Organisation, Reuter Medico Consulting, and bsh medical communications (all outside the submitted work). HF reports honoraria from Roche and iOMEDICO (lecture); and travel support from Celgene and Amgen (all outside of the submitted work). TR reports research funding from Else Kröner-Fresenius-Stiftung and German Cancer Aid; consulting fees from Pfizer; honoraria from Pfizer, AstraZeneca, Novartis, Lilly, and Roche; and other financial or non-financial interests from Pfizer (all outside the submitted work). HHF reports consulting fees and honoraria from Roche Pharma, AstraZeneca, Pfizer, and Genomic Health (all outside of the submitted work). RK reports consulting fees from AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Sandoz, and Seattle Genetics; and honoraria from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Zodiac Pharma (all paid to immediate family members and outside the submitted work); and a co-director position at the West German Study Group. RW reports consulting fees, honoraria, and travel support from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Eisai, Exact Sciences/Genomic Health, Gilead, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Tesaro Bio, Teva, Veracyte and Viatris; and other financial or non-financial interests from FomF (Forum for medical education in Germany), Aurikamed, Clinsol, and Pomme Med (all outside the submitted work). HHK reports honoraria for lectures from Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, and Pfizer; and participation in a data safety monitoring board or advisory board at Roche Pharma, Genomic Health, and AstraZeneca (all outside the submitted work). NH reports research funding paid to institution from Lilly, MSD, Novartis, Pfizer, and Roche/Genentech; honoraria for lectures or consulting from Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Sandoz, and Seagen (all outside the submitted work). All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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