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Original Investigation
June 24, 2021

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

Author Affiliations
  • 1Breast Cancer Center, Karolinska University Hospital, Stockholm, Sweden
  • 2Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
  • 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 4Department of Oncology, South Hospital, Stockholm, Sweden
  • 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
  • 6Department of Pathology, Skåne University Hospital, Lund, Sweden
  • 7Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
  • 8Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden
  • 9Department of Oncology, Southern Älvsborg Hospital, Borås, Sweden
  • 10Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden
  • 11Department of Radiation Sciences, Oncology Unit, Umeå University Hospital, Umeå, Sweden
  • 12Department of Oncology, Sundsvall Hospital, Sundsvall, Sweden
  • 13Department of Oncology, Örebro University Hospital, Örebro, Sweden
  • 14Department of Oncology, St Göran Hospital, Stockholm, Sweden
  • 15Department of Radiology, Karolinska University Hospital, Stockholm, Sweden
  • 16Department of Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden
  • 17Central Trial Office, Clinical Trial Unit, Karolinska University Hospital, Stockholm, Sweden
JAMA Oncol. 2021;7(9):1360-1367. doi:10.1001/jamaoncol.2021.1932
Key Points

Question  Is the efficacy of the present standard combination of docetaxel, trastuzumab, and pertuzumab different from that of trastuzumab emtansine as neoadjuvant therapy for ERBB2-positive breast cancer?

Findings  In this primary analysis of the randomized phase 2 PREDIX HER2 trial, combination docetaxel, trastuzumab, and pertuzumab had similar pathologic complete response when compared with trastuzumab emtansine.

Meaning  In selected patients with ERBB2 (formerly HER2)-positive breast cancer, neoadjuvant treatment can be de-escalated with trastuzumab emtansine monotherapy.


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

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