Adverse events that occur early in the treatment of HER2-positive advanced breast cancer with ado-trastuzumab emtansine (T-DM1) and require dose interruptions or reductions are not associated with changes to long-term survival outcomes, according to a new analysis published in Breast Cancer Research and Treatment.
“T-DM1 is generally well tolerated, but when adverse events occur, dose adjustments… may be required, and the effect of those dose adjustments on survival outcomes is currently unknown,” wrote study authors led by Ethan Tang, PhD, of Flinders University in Adelaide, Australia.
The new study included a total of 893 patients in the EMILIA and TH3RESA trials who received T-DM1 for advanced HER2-positive breast cancer.
Within the first 4 months of T-DM1 treatment, 266 of the patients had disease progression, death or were lost to follow-up and were thus not included in this analysis. Of the remaining patients, 467 had no changes to their T-DM1 dosage within those four months, 86 had a dose interruption, 53 had a dose reduction, and 21 withdrew from the therapy because of adverse events.
The researchers found no associations between the need to interrupt or reduce the dosage within four months and survival outcomes through the follow-up period (more than 48 months for overall survival (OS), and more than 36 months for progression-free survival [PFS]). For dose interruptions, the hazard ratio (HR) for OS compared to patients who had no dose change was 1.15 (95% CI, 0.85–1.55); for dose reductions, the HR was 0.75 (95% CI, 0.49–1.14).
Results were similar with regard to PFS, with an HR for dose interruptions of 1.13 (95% CI, 0.87–1.48) and for dose reductions of 0.90 (95% CI, 0.62–1.31). The authors noted that it would be reasonable to assume that the patients who required withdrawal from the drug completely would have poorer survival outcomes, but this is relatively infrequent in trials to date, including in this cohort.
“This indicates that patients requiring T-DM1 dose interruptions/reductions who survive to 4 months without progression are unlikely to be subsequently affected in regard to OS/PFS,” they concluded. “In clinical practice, this allows for evidence-based counseling to this particular population of patients that their dose adjustment is not associated with poorer survival outcomes.”
The results are encouraging given relatively high rates of dose changes in previous trials. For example, results of the KAMILLA study published earlier this year found that while only 4.3% of patients required a dose interruption to T-DM1, 22.5% of patients required a dose reduction. A total of 12.6% of that cohort discontinued the therapy due to an adverse event.
In an editorial that accompanied the TH3RESA and EMILIA trials’ final results in 2017, Filippo Montemurro, MD, of the Candiolo Cancer Institute in Candiolo, Italy, wrote that the safety profile of T-DM1 “seems to be favorable,” which the new analysis underscores.
“In particular in EMILIA, the drug tested resulted in more manageable and fewer complex toxic effects than did lapatinib and capecitabine,” he wrote. “In TH3RESA, trastuzumab emtansine was associated with a reduced treatment exposure-adjusted rate of grade 3 and 4 adverse events compared with various different treatment options.”