Long-Term Outcomes in Patients with PET-Predicted Poor-Responsive HER2-Positive Breast Cancer Treated with Neoadjuvant Bevacizumab Added to Trastuzumab and Docetaxel: 5-Year Follow-Up of the Randomised AVATAXHER Study

Abstract

Background: The open-label, randomised Phase 2 AVATAXHER study demonstrated that early PET assessment identified patients with HER-2 positive breast cancer who responded poorly to standard neoadjuvant therapy (docetaxel plus trastuzumab). Adding bevacizumab to neoadjuvant therapy in PET-predicted poor-responders improved pathological complete response (pCR) rates (from 24·0% to 43·8%). We investigated whether the improved pCR rate translated into improved long-term outcomes. Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with a change in the maximum standardised uptake value (∆SUVmax) ≥70% received four further cycles of standard neoadjuvant therapy (PET responder group). PET-predicted poor-responders (∆SUVmax <70%) were randomised (2:1) to receive standard neoadjuvant therapy with (Group A) or without (Group B) bevacizumab for cycles 3-6. All patients received a single cycle of trastuzumab followed by surgery and 11 further cycles of adjuvant trastuzumab, with or without radiotherapy and hormonal therapy if hormone receptor positive cancer. Randomisation was open label using an adaptive minimisation method. Investigators and patients were aware of group assignment. Findings: One hundred and twenty-one patients completed the 5-year follow-up period (PET responder group, n=69; Group A, n=48; Group B, n=25). The 5-year estimated cumulative incidence of recurrence was 9·5% (95% CI: 4·4–20·0%) in PET responders, 9·8% (3·8-24·1%) in Group A, and 24·0% (11·6-45·8%) in Group B. Adding bevacizumab to neoadjuvant therapy increased the proportion of patients experiencing Grade ≥ 3/4 adverse events (Group A: 25·6%; Group B 12·5%) and serious adverse events (Group A: 18·6%; Group B 12·5%), but with no apparent effect on cardiac events. Interpretation: Adding bevacizumab to neoadjuvant docetaxel plus trastuzumab therapy may improve long-term outcomes in women with HER-2-positive breast cancer who are predicted to respond poorly to standard neoadjuvant therapy. Trial Registration: The study is registered with ClinicalTrials.gov (NCT01142778) and EudraCT (2009-013410-26). Funding Statement: Roche France. Declaration of Interests: BC reports personal fees and non-financial support from Roche Laboratories France, personal fees from Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories. JYP declares research funding received by his institution from Roche and Menarini Silicon Biosystems; honoraria received by his institution from Roche and Sanofi; and personal fees from Roche, Novartis, AstraZeneca, Pfizer, Amgen, Ipsen, Lilly, and Genomic Health TP is a member of scientific boards for Novartis, Lilly and Pfizer. TB reports personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Novartis, AstraZeneca, and Pfizer; and personal fees from Seattle Genetics, outside the submitted work. DC reports honorarium from Roche, Pfizer, Novartis, Sanofi, and AstraZeneca. GP acted as consultant for Chugai, Novartis and Shire (Takeda), with remunerations received by his institution. GP’s research team received grants for academic studies from Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma. AF and JD are full-time employees of Roche Pharma France. LA reports personal fees and non-financial support from Roche Laboratories France and Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories and Merck. M-AM-R, KK, J-MF, FLD, P-FD, PG, M-PC, CB, J-BP, GT, and AB-R declare no conflicts of interest. Ethics Approval Statement: The study was approved by the central Ethics Committee (Comite de Protection des Personnes) for all participating centres and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.