Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer

Abstract

IMPORTANCE Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown.OBJECTIVE To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTSThis randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis.INTERVENTIONS Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose ( 18 F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles.MAIN OUTCOME AND MEASURES Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. RESULTSOverall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18 F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). CONCLUSIONS AND RELEVANCEIn this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.

Neoadjuvant Treatment with HER2-Targeted Therapies in HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis

“…Of the 3010 studies identified, 32 published studies [5,[10][11][12], including 21 RCTs [10,11,29,31,32,34,35,[38][39][40][43][44][45][46][47][48][49][50][51]53,54], were eligible for inclusion within this analysis (Figure 1). Among these, four anti-HER2 medicines (i.e., T, L, P, T-DM1) were evaluated in 11 regimens (i.e., TC, LC, PC, PT, T-DM1P, PTC, LTC, T-DM1LC, T-DM1PC, PTC_T-DM1P, T-DM1) along with chemotherapy alone (see Table S1).…”

“…The individual study characteristics are presented in Table 1. Twelve RCTs were comprised of two arms, for which TC vs. C was the most common treatment comparison (5 RCTs) [30,32,34,35,45], followed by TC vs. LC (2 RCTs) [12,46], with the remainder comprising unique comparisons [10,[49][50][51]54]. Eight RCTs included three arms with seven RCTs comparing TC vs. LC vs. LTC [31,40,43,44,47,48,53]; a single RCT compared PTC vs. T-DM1PC vs. PTC_T-DM1P [11], while one trial comprised four arms that compared TC vs. PC vs. PT vs. PTC [38].…”

“…Twenty-one studies reported grade 3 and 4 adverse events that were included in the analysis of SAE [10,31,32,35,40,[45][46][47][48]53,54].…”

“…Of the 21 RCTs, 10 reported DFS [5,11,12,30,33,37,42,52,54,56], but only seven studies [5,12,37,42,52,54,56] provided KM curves from which IPD could be simulated. The follow-up time ranged from 36 to 168 months, with a median of 48 months.…”

Post-Neoadjuvant Treatment Strategies in Breast Cancer

“…For systemic therapy, this has been addressed in patients with HER2-positive disease. The PREDIX HER2-trial compared docetaxel, trastuzumab and pertuzumab to T-DM1 and found similar rates of pathologic complete response and event-free survival in both arms [ 20 , 21 ]. Results on survival outcomes are pending.…”