Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study

Abstract

Purpose: The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.

Methods: Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).

Results: Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.

Conclusion: Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

Trial registration: ClinicalTrials.gov NCT02131064.

FIG 1.

Patient disposition. EFS, event-free survival; IDFS, invasive disease-free survival; TCH+P, docetaxel, carboplatin, and trastuzumab plus pertuzumab; T-DM1+P, trastuzumab emtansine plus pertuzumab.

FIG 2.

(A) Kaplan-Meier analysis of event-free survival in the intention-to-treat population. Event-free survival was defined as the time from random assignment to disease progression (including local progression before surgery), disease recurrence (local, regional, distant, ipsilateral noninvasive, or contralateral [invasive or noninvasive]), or death from any cause. (B-D) Kaplan-Meier analysis of invasive disease-free survival in the intention-to-treat population who underwent surgery according to (B) treatment arm, (C) pathologic complete response (pCR) status, and (D) treatment arm and pCR status. Invasive disease-free survival was defined as the time from surgery to the first documented occurrence of ipsilateral invasive local recurrence, ipsilateral locoregional invasive recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. TCH+P, docetaxel, carboplatin, and trastuzumab plus pertuzumab; T-DM1+P, trastuzumab emtansine plus pertuzumab.

FIG 3.

Patient-reported outcomes during the overall study period for patients in the intention-to-treat population. Graphs depict mean change from baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire−C30 for domains of (A) global health status, (B) physical functioning, (C) cognitive functioning, and (D) diarrhea. Baseline is defined as neoadjuvant cycle 1, day 1. TCH+P, docetaxel, carboplatin, and trastuzumab plus pertuzumab; T-DM1+P, trastuzumab emtansine plus pertuzumab.