Neoadjuvant T-DM1 + pertuzumab tied to elevated risk of EFS events in HER2+ breast cancer
Neoadjuvant treatment with trastuzumab emtansine (T-DM1) plus pertuzumab led to an elevated risk of 3-year event-free survival (EFS) events in patients with HER2-positive breast cancer, according to a secondary analysis of the KRISTINE* trial presented at ASCO 2019.
This multicentre, open-label, phase III trial involved 444 patients with HER2-positive stage II–III breast cancer who were randomized 1:1 to receive neoadjuvant T-DM1 plus pertuzumab (T-DM1+P group, n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P group, n=221) every 3 weeks for six cycles. In the adjuvant phase, the T-DM1+P group continued treatment and the TCH+P group were only given trastuzumab + pertuzumab for 12 cycles. [ASCO 2019, abstract 500; J Clin Oncol 2019:JCO1900882]
At a median follow-up of 37 months, a higher risk of EFS events occurred in the T-DM1+P group than in the TCH+P group (31 vs 13 events, stratified hazard ratio [HR], 2.61, 95 percent confidence interval [CI], 1.36–4.98), which was due to more locoregional progression events prior to surgery (15 vs 0 events).
The patients with locoregional progression had lower HER2 expression and higher HER2 heterogeneity, which suggests that they may require conventional systemic chemotherapy combined with a HER2 blockade, said study lead author Dr Sara Hurvitz from the University of California, Los Angeles in Los Angeles, California, US.
Three events of noninvasive recurrence after surgery were reported in the T-DM1+P arm compared with none in the TCH+P arm.
Among patients who underwent surgery after six cycles of study-assigned therapy, the risk of 3-year invasive disease-free survival (IDFS) events was comparable between the two treatment groups (13 events in each arm, stratified HR, 1.11, 95 percent CI, 0.52–2.40).
Further analysis in patients who achieved pathologic complete response (pCR) revealed no difference in 3-year IDFS between treatment groups (96.7 percent [T-DM1+P] vs 97.5 percent [TCH+P], stratified HR, 0.99, 95 percent CI, 0.20–4.96). “The achievement of a pCR, regardless of treatment, was associated with a very high IDFS rate,” Hurvitz said.
However, the 3-year IDFS rate was poorer among patients who had residual disease, with no real difference detected between the T-DM1+P and TCH+P arms (89.4 percent vs 84.2 percent, stratified HR, 0.94, 95 percent CI, 0.38–2.33), said Hurvitz.
Over the study period, which included the neoadjuvant period when the TCH+P group received cytotoxic chemotherapy, TCH+P was associated with a higher rate of serious and grade ≥3 adverse events (AEs) compared with T-DM1+P (32.4 percent vs 13.5 percent [serious AEs] and 67.6 percent vs 31.8 percent [grade ≥3 AEs]).
However, when the neoadjuvant phase was excluded, the rates of serious and grade ≥3 AEs were higher in the T-DM1+P vs TCH+P arm (6.6 percent vs 4.7 percent [serious AEs] and 24.5 percent vs 9.9 percent [grade ≥3 AEs]).
A similar pattern for global health status and physical and cognitive functioning scales was observed in both treatment arms. However, impairments were observed, which was expected, when patients in the T-DM1+P arm also received adjuvant cytotoxic chemotherapy at around cycle 4 during the adjuvant phase, Hurvitz said.
“Overall, the observed worse EFS and similar IDFS associated with T-DM1+P might suggest the importance of selecting patients for a conventional chemotherapy-sparing neoadjuvant regimen … and must be confirmed in prospective studies, hopefully using biomarkers, said Hurvitz.
“The new results of the KRISTINE trial further reinforce the notion that the adjuvant setting can serve as a platform for risk stratification in clinical practice as well as for the development of new treatments for [patients with] HER2-positive breast cancer,” wrote Dr Antonio Wolff from The Johns Hopkins Kimmel Comprehensive Cancer Centre, Baltimore, Maryland, US, in an editorial. [J Clin Oncol 2019:JCO1901159]
*KRISTINE: A study evaluating trastuzumab emtansine plus pertuzumab compared with chemotherapy plus trastuzumab and pertuzumab for participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer