Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial

Abstract

Background: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting.

Methods: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm.

Results: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]).

Conclusions: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial.

Trial registration number: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

Conflict of interest statement

D.E.: funding for his ESMO fellowship (2018–2019) provided by Novartis; research grant for his institute: Roche/GNE, Radius, Astra-Zeneca, Lilly, MSD, Novartis, Synthon, Servier, and Pfizer; N.F.P.: honoraria: MundiPharma, Astrazeneca; travel grants: Novartis, Astrazeneca, MundiPharma, Roche; D.A.T.: none; A.M.A.: none; M.P.: Board Member (Scientific Board): Oncolytics, Radius; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, Seattle Genetics; Research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon; Speakers bureau/stock ownership: none; F.H.: research grant for her Institute (for the conduct of the ALTTO trial): GSK, Novartis; O.W.: employee of Novartis Pharma AG; S.C.: Research grant from Merck & Co. and Array BioPharma. Consultation/Advisory Board from Novartis, Syndax Pharmaceuticals Inc., Puma Biotechnology, and Immunomedics Incs.; A.D.: Research funding from GSK during the study; J.R.K.: none; H.G.: received honoraria as speaker from AstraZeneca, Roche, BMS, and Novartis; I.L.: none; R.J.R.: none; M.S.E.: ownership or stock/financial holdings: none; Book royalties: Elsevier and Peoples Medical Publishing House; Consulting agreements with Boehringer-Ingelheim, Bayer, Merck, and Daiichi Sankyo; T.S.: none; E.A.: honoraria and advisory board: Roche/GNE; travel grants: Roche/GNE, GSK/Novartis; co-principal investigator of the LORELEI trial (NCT02273973); research grant for his institute: Roche/GNE, Radius, Astra-Zeneca, Lilly, MSD, Novartis, Synthon, Servier, and Pfizer.

Figures

Fig. 1. Cumulative incidence of CEs over time, per arm of treatment.

There is a non-statistical difference of −1.4% in the rate of CE on T + L arm (7.9%) vs T arm (9.3%), with a multivariate OR of 0.85 [(95% CI, 0.68–1.05); p = 0.139]. The rates of CEs at the 6th month are 4.1% and 4.7% on T + L arm and T arm, respectively, increasing to 6.1% and 7.8% at the 12th month, and to a lesser extent to 6.6% and 8.2% at the 18th month, respectively.

Fig. 2. Mean left ventricular ejection fraction (mLVEF) over time according to treatment arm.

After a minor decrement from screening to week 13 (T + L arm: 64.5–62.5%, T arm: 64.5–62.8%, respectively), mLVEF becomes stable in both treatment arms until the end of treatment (T + L arm: 62.0%, T arm: 62.2%).

Fig. 3. Cumulative incidence of CEs over time, according to number of cardiac risk factors.

At 6, 12 and 18 months from randomisation, patients with 0–1 risk factors have an incidence of CE of 1.3%, 2.1% and 2.1%, respectively. Patients with 2–3 risk factors, at the same time-points, have an incidence of CE of 4.5%, 7.2% and 7.7%, respectively. For those with 4 risk factors, the incidences are 9.2%, 14.0% and 14.0%, respectively. Note that any given patient could have accumulated up to 4 risk factors, instead of the 5 identified, since none was exposed both to doxorubicin and epirubicin.