Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2–positive Breast Cancer

Three-Year Outcomes From the Phase III KRISTINE Study

Sara A. Hurvitz, MD; Miguel Martin, MD; Kyung Hae Jung, MD; Chiun-Sheng Huang, MD, PhD; Nadia Harbeck, MD, PhD; Vicente Valero, MD; Daniil Stroyakovskiy, MD; Hans Wildiers, MD, PhD; Mario Campone, MD, PhD; Jean-François Boileau, MD, MSc; Peter A. Fasching, MD; Karen Afenjar, MS; Gonzalo Spera, MD, MSc; Vanesa Lopez-Valverde, PhD; Chunyan Song, MD; Peter Trask, PhD, MPH; Thomas Boulet, MS; Joseph A. Sparano, MD; W. Fraser Symmans, MD; Alastair M. Thompson, FRCSEd, MD; Dennis Slamon, MD, PhD


J Clin Oncol. 2019;37(25):2206-2216. 

In This Article

Abstract and Introduction


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.


Current standard-of-care neoadjuvant regimens for the treatment of human epidermal growth factor receptor 2 (HER2) –positive breast cancer consist of conventional systemic chemotherapy plus trastuzumab-based therapy.[1] Pathologic complete response (pCR) rates with conventional systemic chemotherapy plus HER2 blockade have ranged from 25% to 65%,[2–8] with dual HER2-targeted regimens producing increased pCR rates compared with trastuzumab alone.[5,6] pCR in the breast and nodes is associated with prolonged event-free survival (EFS) and overall survival (OS) in patients with HER2-positive breast cancer.[9]

Despite the pCR benefits of dual HER2-targeted neoadjuvant therapy, approximately 15% of patients will experience disease relapse or death within 3 to 5 years.[10,11] In addition, these regimens are accompanied by toxicities that are associated with conventional systemic chemotherapy, such as neutropenia and febrile neutropenia.[4,5,10] Improving outcomes and safety among patients with HER2-positive early breast cancer remain important goals when developing neoadjuvant and adjuvant therapies.

The KRISTINE study is a phase III, randomized, multicenter, open-label study that evaluated a neoadjuvant regimen in which conventional systemic chemotherapy is replaced with trastuzumab emtansine (T-DM1), an antibody–drug conjugate that provides targeted delivery of chemotherapy to HER2-overexpressing cells, as well as HER2 blockade,[12] and is associated with a lower incidence of adverse events (AEs) that are typically observed with conventional chemotherapy.[13,14] KRISTINE compared neoadjuvant T-DM1 plus pertuzumab (T-DM1+P) with conventional systemic chemotherapy—docetaxel plus carboplatin—plus dual HER2-targeted blockade—trastuzumab and pertuzumab—in patients with HER2-positive breast cancer. As reported previously, the T-DM1–based regimen led to a statistically significantly lower pCR rate in the breast and nodes (ypT0/is, ypN0) than the conventional systemic chemotherapy–based regimen (44.4% v 55.7%; difference of 11.3 percentage points [95% CI, −20.5 to −2.0] P = .016); however, fewer grade 3 or greater (13.0% v 64.4%) and serious AEs (4.9% v 28.8%) were observed with the T-DM1–based regimen in the neoadjuvant phase.[12] Here, we report the final results, which include 3-year efficacy, safety, and patient-reported outcomes (PROs) from KRISTINE.