Background

One year of trastuzumab (T) with 12 weeks of paclitaxel (APT) is recommended for patients (pts) with small, node-negative (N0) HER2+ BC, although the data supporting this indication comes from a single-arm phase II trial. ALTTO was a large phase III study evaluating the addition of lapatinib (L) to T for early-stage HER2+ BC pts, and its large dataset provides a unique opportunity to delineate the outcomes of pts with HER2+ BC with pathological tumour size (pT)≤3cm/N0.

Methods

Pts were randomized to receive L alone, T alone, T combined with L (T+L) or T followed by L (T→L). L arm was closed earlier due to futility and 54% of its pts went on to receive T. Our primary endpoint was disease-free survival (DFS), with overall survival (OS) as a key secondary one. A multivariable Cox model for DFS adjusted for all clinicopathological features was fitted and 2-sided p-value<0.05 set for significance.

Results

Among 8381 pts, 2821 were eligible: 707 in L, 725 in T, 702 in T+L and 687 in T→L arm. Baseline characteristics were balanced among treatment arms. Median age was 52 years (y), with most pts having pT≤2 cm (64%), histologic grade 3 (56%), hormone receptor positivity (61%), and received an anthracycline-based CT (93%). At a median follow-up of 7y (IQR: [6.1-7.2 y]), 291 DFS events were observed, with 7y DFS rate of 88% (95% CI [87-89]). Multivariate analysis showed Asian ethnicity, adjuvant radiotherapy and concomitant CT to yield a protective effect, while L alone to be detrimental (table). As such, for pts under concomitant CT (N=1235), 96 DFS events occurred for 7y DFS rates of 84% (95% CI [77-90]), 91% (86-94), 93% (89-96), and 89% (83-93) in L, T, T+L, and T⟶L, respectively (p=0.038). With 102 deaths, 7y OS rate was 96% (95% CI [95-97]). Table: 221P

Multivariable Cox model for DFS adjusted for all clinicopathological variables and stratification factors

Conclusions

With most of its pts treated with anthracyclines, ALTTO shows that pts with pT≤3cm/N0 HER2+ BC treated with T and concomitant CT have long-term outcomes at best similar to that of those treated with APT, calling into question de-escalation of chemotherapy in this population.

Clinical trial identification

NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.

Legal entity responsible for the study

Breast International Group (BIG).

Funding

GSK/Novartis.

Disclosure

D. Eiger: Research grant/Funding (self), Research grant/Funding (institution), Funding for my ESMO Fellowship (2018-2019): Novartis; Research grant/Funding (institution): Roche/GNE; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Radius; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Synthon; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Pfizer. R. Caparica: Research grant/Funding (institution): Roche/GNE; Research grant/Funding (institution): Radius; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Synthon; Research grant/Funding (institution): Servier; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony: Boehringer-Ingelheim; Speaker Bureau/Expert testimony: Janssen-Cilag. S. Hultsch: Research grant/Funding (institution): GSK/Novartis. Y. Wang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. S. Chumsri: Research grant/Funding (self): Merck and Co.; Research grant/Funding (self): Array BioPharma; Advisory/Consultancy: Novartis; Advisory/Consultancy: Syndax Pharmaceuticals Inc.; Advisory/Consultancy: Puma Biotechnology; Advisory/Consultancy: Immunomedics. K. Pritchard: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Eisai; Advisory/Consultancy: Amgen; Advisory/Consultancy: Genomic Health Inc.; Advisory/Consultancy: Myriad Genetic Laboratories. M. Untch: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: AbbVie; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Daichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Lilly Germany; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Lilly International; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: MSD Mundipharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Myriad Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Odonate; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: PUMA Biotechnology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: F. Hoffmann-La Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: Sanofi Aventis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, Paid directly to my Institution: TEVA Pharmaceuticals. M. Bellet Ezquerra: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Travel/Accommodation/Expenses: Roche. D.D. Rosa: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Research grant/Funding (self): GSK; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Libbs; Advisory/Consultancy: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: Dr Reddy`s; Research grant/Funding (self), Travel/Accommodation/Expenses: Amgen. A. Moreno-Aspitia: Research grant/Funding (institution): Genentech; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Sermonix; Research grant/Funding (institution): Daiichi. M. Piccart: Honoraria (self), Scientific Board: Oncolytics; Honoraria (self), Research grant/Funding (institution), Scientific Board: Radius; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Camel-IDS; Honoraria (self): Crescendo Biologics; Honoraria (self): Debiopharm; Honoraria (self): G1 Therapeutics; Honoraria (self), Research grant/Funding (institution): Genentech; Honoraria (self): Huya; Honoraria (self): Immunomedics; Honoraria (self), Research grant/Funding (institution): Lilly; Honoraria (self): Menarini; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): Odonate; Honoraria (self): Oncolytics; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self): Seattle Genetics; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Synthon. U. Dafni: Advisory/Consultancy, Tumor Agnostic Evidence Working Group 2020: Roche. E. de Azambuja: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/GNE; Travel/Accommodation/Expenses: GSK/Novartis; Research grant/Funding (institution): Radius; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Synthon; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Pfizer. All other authors have declared no conflicts of interest.