medwireNews: In patients with early-stage breast cancer, shorter durations of adjuvant trastuzumab therapy are noninferior to the standard 1-year schedule with regard to disease-free survival (DFS), suggests an individual patient data meta-analysis.
The researchers point out in JAMA Network Open that “[t]he choice of 1-year duration of adjuvant trastuzumab was somewhat arbitrary without strong preclinical or clinical rationale.”
And “[a]lthough trastuzumab is a well-tolerated drug,” they note that “it is associated with cardiac dysfunction.”
The team analyzed individual data on 11,376 patients extracted from five randomized controlled trials (RCTs) that compared shorter durations (9–12 weeks and 6 months) of trastuzumab with 1-year administration, and estimated 5-year DFS rates of 85.42% and 87.12%, respectively. This translated into a hazard ratio (HR) of 1.14, which met the prespecified margin for noninferiority of 1.30 (the median of the margins across the included trials).
Trial-level estimates, based on data from six RCTs including a total of 11,603 participants, “closely matched” these findings, at an HR for DFS of 1.15, note the study authors.
However, an analysis for superiority demonstrated that DFS was significantly better with the 1-year regimen than with shorter durations, at an HR of 0.87, although the researchers point out that the trials were only “explicitly planned to prove the noninferiority of shorter durations of trastuzumab.”
The same patterns were seen for overall survival (OS), such that shorter durations were noninferior to 1 year of trastuzumab in the individual patient data analysis, with corresponding 5-year OS rates of 92.39% and 93.46%, and an HR of 1.17. This was identical to the HR for OS from trial-level estimates. And again, tests for superiority showed significantly better OS with 1 year of trastuzumab than shorter durations (HR=0.86).
The researchers report “more favorable” HRs for DFS for the three trials that investigated 6 months of trastuzumab than the three evaluating 9–12 weeks, at 1.10 and 1.27, respectively, relative to 1-year administration. The findings were similar for OS, with corresponding HRs of 1.14 and 1.25, and suggest that “abbreviating trastuzumab duration to 6 months may be a more appropriate strategy,” they add.
Notably, the rate of congestive heart failure was significantly lower among patients who received shorter durations of trastuzumab than those who received it for a year, at 3.9% versus 6.9% (relative risk [RR]=0.53]. And there was also a trend towards a reduction in the incidence of asymptomatic left ventricular ejection fraction decline with the shorter durations, at 5.0% and 7.0%, respectively (RR=0.71).
“[D]espite the higher cardiac toxic effects, longer duration of trastuzumab was associated with lower all-cause mortality compared with shorter durations,” which “is likely a reflection of the reversibility of trastuzumab-associated cardiac toxic effects,” say Sudeep Gupta (Tata Memorial Centre, Mumbai, India) and fellow investigators.
Noting that “[t]he absolute survival differences between the 2 groups are small,” the team observes that “shorter durations could be therapeutically appropriate in situations of toxic effects or resource constraints, especially among patients with clinically low-risk disease.”
And Gupta et al conclude that “a shorter duration of adjuvant trastuzumab may be the preferred option for patients with low-risk disease or a predisposition to cardiac toxic effects.”
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JAMA Netw Open 2020; 3: e2011777