Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial

Abstract

Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear.

Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab.

Design, setting, and participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries.

Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year.

Main outcomes and measures: The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety.

Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group.

Conclusions and relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.

Trial registration: ClinicalTrials.gov Identifier: NCT00593697.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Joensuu is an advisor of Neutron Therapeutics, has a co-appointment at Orion Pharma, has received consultation fees from Orion Pharma, and has Orion Pharma, Faron Pharmaceuticals, and Sartar Therapeutics stock ownership interest. Dr Wildiers has received honoraria from Amgen and Novartis, has a consulting role with Roche, Amgen, Novartis, Celldex, Pfizer, and PUMA, and has received research funding from Roche and compensation for traveling from Roche, Pfizer, and PUMA. Dr Huovinen has acted as an advisor with Teva Pharmaceuticals, Amgen, AstraZeneca, and Roche. Dr Utriainen has a consulting role with Roche, Pfizer, AstraZeneca, Teva Pharmaceuticals, and Amgen. Drs Granstam-Björneklett and Ritchie have a consulting role with Pfizer. Dr Tanner is in the speakers’ bureau of Roche and Pfizer, has received compensation for traveling from Roche, Pfizer, and Ratiopharm, and received consultation fees from Roche, Amgen, Pfizer, and Ratiopharm. Mr Huttunen is an employee of 4Pharma Ltd. Dr Kellokumpu-Lehtinen has a consulting role with Sanofi, Pfizer, Roche, and Bristol-Myers Squibb, and has received compensation for traveling from Roche, Astellas Pharma, Sanofi, and Bayer. Dr Lindman has acted as an advisor for AstraZeneca, Novartis, Pfizer, Amgen, and Daiichi Sankyo, and is in the speakers’ bureau of Servier, Amgen, Celgene, AstraZeneca, and Roche. No other disclosures are reported.

Figures

Figure 1.. CONSORT Diagram

The numbers of individuals screened for eligibility and the reasons for exclusion were not captured.

Figure 2.. Kaplan-Meier Estimates of Survival Outcomes

Figure 3.. Disease-Free Survival in Prespecified Subgroups