Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial

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 participants: This 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 (18F-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.

Results: Overall, 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 18F-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 relevance: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.

Trial registrations: ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Foukakis reported receiving grants and personal fees from Pfizer (institutional); and personal fees from Novartis, Veracyte, Exact Sciences, Affibody, and Wolters Kluwer outside the submitted work. Dr Bosch reported serving on the advisory boards for Pfizer and Novartis; and receiving grants from Roche outside the submitted work. Dr Lindman reported receiving grants from Roche; and personal fees from Lilly, Daiichi, and Novartis outside the submitted work. Dr Hartman reported receiving personal fees from Roche, Novartis, Eli Lilly, Pfizer, and Merck; and grants from Cepheid; and being cofounder of Stratipath AB outside the submitted work. Dr Bergh reported receiving grants from AstraZeneca (institutional), Merck (institutional), Amgen (institutional), Bayer (institutional), Roche (institutional), Pfizer (institutional), and Sanofi (institutional); and payment to Asklepios Medicin Hb from UpToDate outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Patient Flow in the Trial (CONSORT)

In the group of patients randomized to receive standard treatment, 2 patients withdrew consent and 2 received a diagnosis of disseminated disease after randomization and before the start of treatment. One patient receiving treatment with trastuzumab emtansine received all preoperative treatment but withdrew consent before surgery and underwent surgery elsewhere.

Figure 2.. Subgroup Analysis of Baseline Clinical and Tumor Characteristics at Baseline in Relation to Pathologic Complete Response

Odds ratios (ORs) were estimated using logistic regression. ERBB 2+ indicates intermediate expression of ERBB2 (formerly HER2); ERBB 3+, marked expression of ERBB2; ER, estrogen receptor; PR, progesterone receptor; and TIL, tumor-infiltrating lymphocyte.

Figure 3.. Event-Free Survival After a Median Follow-up of 40.4 Monthsa

Events were defined as progression during neoadjuvant therapy, local-regional or distant recurrence, contralateral breast cancer, any other malignant neoplasm, or death of any cause, whatever appears first. One patient in the investigational group withdrew consent shortly before surgery and has, therefore, been excluded from the analysis. aRange, 2.2-66.5 months.