T-DM1 after Pertuzumab plus Trastuzumab: Treatment Sequence-Induced Selection Bias in HER2-Positive Metastatic Breast Cancer

Simple Summary Real-world data studies suggest trastuzumab emtansine (T-DM1) may be less effective following pertuzumab treatment in patients with metastatic breast cancer. However, the short time frame between pertuzumab and T-DM1 approvals may have biased these studies toward selecting pertuzumab-experienced patients with more aggressive disease. Our study assessed the impact of this selection bias on time to next treatment or death and other outcomes. Among T-DM1-treated patients, prior pertuzumab use was more frequent in the most recent years; however, no concomitant changes in outcomes were observed. The examination of pertuzumab-experienced patients over time showed that those entering the T-DM1 cohort earliest had more aggressive disease and poorer outcomes than patients entering the study in the most recent years, who had outcomes similar to those of pertuzumab-naive patients. This study demonstrates that such selection bias should be accounted for when assessing treatment sequences. Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H +/- P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnosis to T-DM1 initiation increased from 10 to 14 months (2013-2019), and median TTNT increased from 4.4 to 10.2 months (2013-2018). Over time, prior H + P prevalence significantly increased with no observable impact on T-DM1 effectiveness. Drug approval timing should be considered when assessing treatment effectiveness within a sequence.