Adjuvant therapy with two HER2-targeted drugs failed to improve disease-free survival (DFS) in early breast cancer compared with trastuzumab (Herceptin) monotherapy, results of a large international trial showed.
Concurrent administration of lapatinib (Tykerb ) and trastuzumab resulted in a nonsignificant 16% reduction in the hazard as compared with trastuzumab alone. Sequential treatment beginning with trastuzumab resulted in an even smaller reduction in the DFS hazard.
Patients treated with lapatinib had more diarrhea, rash, and hepatic toxic, further eroding any potential advantages, Martine Piccart-Gebhart, MD, of Institut Jules Bordet in Brussels, Belgium, and colleagues reported online in the Journal of Clinical Oncology.
The results contrast with those of a trial in the neoadjuvant setting, which showed an advantage for dual HER2 inhibition over trastuzumab alone.
"Positive results were eagerly anticipated, given the almost doubling of the pathologic complete response reported in the sister neoadjuvant trial ... which tested the combination of lapatinib and trastuzumab with paclitaxel," the authors said.
The trial provided a cautionary tale about moving therapy too quickly into the adjuvant setting, they continued. When planning for the trial began in 2007, investigators hypothesized that lapatinib would lead to a reduction in central nervous system (CNS) relapses, a better cardiotoxicity profile, and improved acceptance and reduced resource utilization associated with an oral medication.
"Since 2007, trials in advanced disease have suggested that lapatinib may have inferior progression-free survival to trastuzumab, neoadjuvant trials with relatively small numbers of patients have shown somewhat mixed results, and the importance of immunologic effects of trastuzumab has become clearer," they acknowledged.
Multiple clinical trials have shown that the addition of adjuvant trastuzumab to conventional chemotherapy reduces the risk of recurrent HER2-positive early breast cancer. Preclinical studies of lapatinib demonstrated improved signaling inhibition as compared with trastuzumab. Subsequently, a phase I trial of trastuzumab-lapatinib combination therapy demonstrated enhanced antitumor activity.
The accumulation of evidence provided the basis for a randomized phase III trial to compare combination strategies of trastuzumab and lapatinib versus trastuzumab alone. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial involved 8,381 women with early-stage HER2-positive breast cancer. Following surgery, the patients were randomized to one of four adjuvant treatment strategies, each continued for a year:
- Trastuzumab alone
- Lapatinib alone
- Concurrent lapatinib and trastuzumab
- Sequential trastuzumab and lapatinib
The trial had a primary endpoint of DFS, and trastuzumab alone served as the reference for comparison of the other three strategies. Enrollment in the lapatinib monotherapy arm ended prematurely after an interim analysis failed to demonstrate non-inferiority versus trastuzumab. After a median follow-up of 1.98 years, the interim analysis showed a DFS hazard of 1.52 for lapatinib versus trastuzumab (95% CI 1.23-1.88).
Analysis of the concurrent arm tested for superiority versus trastuzumab alone, and the sequential arm was evaluated for non-inferiority to trastuzumab monotherapy. Patients in all four arms were included in the safety analysis.
After a median follow-up of 4.5 years, patients treated with concurrent anti-HER2 therapy had a DFS hazard ratio of 0.84 versus trastuzumab alone (95% CI 0.70-1.02, P=0.048). The trial had a prespecified significance level of 0.025. Multivariable analysis did not yield substantially different results (HR 0.85, 95% CI 0.72-1.01). Subgroup analysis failed to identify any patient characteristics associated with greater benefit from combination therapy, the authors reported.
Analysis of data for sequential trastuzumab-lapatinib yielded a DFS hazard ratio of 0.96 (95% CI 0.80-1.15). A non-inferiority comparison yielded a hazard ratio of 0.93, which did not achieve statistical significance (95% CI 0.76-1.13, P=0.044). Multivariable analysis did not substantively change the outcome of the superiority comparison (HR 0.93, 95% C 0.79-1.10).
The 4-year overall survival was 95% for the concurrent- and sequential-therapy arms and 94% for trastuzumab alone.
Patients randomized to concurrent therapy had a 22% reduction in the hazard for first breast cancer recurrence (HR 0.78, 95% CI 0.64-0.94) and a 20% reduction in the hazard for distant recurrence (HR 0.80, 95% CI 0.65-0.98). The three treatment groups had similar rates of CNS recurrence as the first site of relapse.
All of the lapatinib-containing arms had higher rates of adverse events and serious adverse events, as compared with trastuzumab monotherapy. Concurrent lapatinib and trastuzumab was associated with the highest rate of toxicity-related discontinuations. The incidence of cardiac adverse events was low and occurred in a similar proportion of patients across all treatment groups (0.25% to 0.97%).
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