No Advantage to Dual HER2 Blockade in Early-Stage Breast Cancer

TON Web Exclusives - Breast Cancer

Five-year results from the phase 3 ALTTO trial indicated that 1 year of dual adjuvant HER2 blockade is still not significantly superior to single-agent trastuzumab in preventing breast cancer recurrence in women with HER2-positive early-stage disease.1 However, the trial results do offer the possibility that patients with HER2-positive, estrogen receptor (ER)-negative breast cancer may derive additional benefit from 2 HER2-targeted agents.

“Dual HER2 blockade as provided in this trial did not lead to better disease-free survival [DFS] or overall survival [OS],” said lead investigator Alvaro Moreno-Aspitia, MD, Department of Hematology/Oncology, Mayo Clinic, Rochester, Minnesota. “An interesting hypothesis-generating observation is that tumors that are HER2-positive and hormone receptor–negative may have different biologic behavior and so patients with this profile may benefit from dual HER2 blockade. This has been observed also in several of the neoadjuvant trials.”

In the 5-year analyses of ALTTO, the hazard ratios for single-agent trastuzumab versus lapatinib added to trastuzumab (whether sequential or in combination) were similar and did not confer a decided advantage in terms of DFS. The prespecified 5-year analyses were presented at the 2017 meeting of the American Society of Clinical Oncology (ASCO).

ALTTO enrolled 8381 patients with HER2-positive early-stage breast cancer at 946 sites in 44 countries. Patients were randomized to 1 of 4 treatment groups: trastuzumab daily for 52 weeks (as the control arm); lapatinib daily for 52 weeks; trastuzumab daily for 12 weeks followed by a washout period of 6 weeks and then lapatinib for 34 weeks; or lapatinib daily for 52 weeks plus trastuzumab daily for 52 weeks. In addition, based on physician and patient preference, 3 modalities of chemotherapy were offered. In design 1, anthracycline-based chemotherapy was provided for 12 to 18 weeks, followed by anti-HER2 therapy for 52 weeks. In design 2, anthracycline was provided for 9 to 12 weeks followed by a taxane for 12 weeks with concurrent anti-HER2 therapy for 52 weeks. In design 2B, docetaxel and carboplatin were provided for 18 weeks with concurrent anti-HER2 therapy for 52 weeks.

The lapatinib alone arm ended in 2011 because of futility of treatment, and was not included in the updated analysis at ASCO 2017. The primary end point was DFS. The results of the primary analysis were presented in 2014.2

Since the primary analysis in 2014,2 with 5-year follow-up of DFS, there were 20.3 DFS events per 1000 patient-years in the arms receiving trastuzumab and lapatinib compared with 21.4 events per 1000 patient-years in the trastuzumab alone (control) arm.

After 6 years of follow-up, DFS was 85% in the trastuzumab/lapatinib concurrent cohort versus 82% in the trastuzumab alone arm, for a hazard ratio of 0.86, which did not achieve statistical significance (95% confidence interval [CI], 0.74-1.00). The DFS in the sequential trastuzumab/lapatinib arm was 84% (hazard ratio, 0.93; 95% CI, 0.81-1.08). “So at this time, as noted in the primary analysis, there’s no benefit on the primary end point in regards to dual HER2 blockade as provided in this clinical trial,” Dr Moreno-Aspitia said.

“In terms of OS, there’s absolutely no benefit to dual HER2 blockade over single agent trastuzumab,” he continued. “However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer term follow-up.”

The 6-year OS was 93% for trastuzumab and lapatinib administered concurrently, 92% for trastuzumab followed by lapatinib, and 91% for the control arm. The hazard ratios for OS were 0.86 for concurrent trastuzumab/lapatinib versus control and 0.88 for trastuzumab followed by lapatinib versus control, neither of which was statistically significant, as the 95% CIs crossed 1.0.

For women with ER-negative tumors, the trastuzumab/lapatinib combination did appear to confer benefit on the primary end point, noted Dr Moreno-Aspitia. In this cohort, the 6-year DFS rate was 84% for trastuzumab and lapatinib administered concurrently (hazard ratio, 0.80; P = .053), 82% for sequential trastuzumab and lapatinib (hazard ratio, 0.97; P = .990), and 80% for trastuzumab alone.

There were no major changes in terms of adverse events from the earlier analysis, and cardiac toxicity rates remained low.

Correlative studies are ongoing, and final efficacy analysis is to be reported when all patients have been followed for at least 10 years.

References
1. Moreno-Aspitia A, Holmes EM, Jackisch C, et al. Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer. J Clin Oncol. 2017;35(suppl):Abstract 502.
2. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol. 2014;32:5s(suppl):Abstract LBA4.

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Last modified: August 22, 2017