KRISTINE Trial Demonstrates TCH+P Still Best Choice for HER2+ Breast Cancer

Josh Bilenker, MD, CEO of Loxo Oncology

Sara A. Hurvitz, MD

Phase III results of the KRISTINE trial demonstrated that patients with HER2-positive early breast cancer had a significantly higher pathological complete response (pCR) rate when they received the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P) versus trastuzumab emtansine (T-DM1) plus pertuzumab (T-DM1+P).

While the TCH+P regimen was also associated with a higher rate of breast conserving surgery, researchers reported that T-DM1+P had a notably better safety profile and that health-related quality of life and physical functioning were maintained longer.

“Neoadjuvant TCH+P achieved a superior pCR rate compared with T-DM1+P and was associated with a higher breast-conserving-surgery rate,” said Sara A. Hurvitz, MD, General Internal Medicine, Hematology & Oncology, UCLA Medical Center. “However, neoadjuvant T-DM1+P had a more favorable safety profile, with lower incidence of grade 3 or greater adverse events, serious adverse events, and adverse events leading to treatment discontinuation.”

T-DM1 and pertuzumab bind to different HER2 domains and have marked antitumor activity in HER2-positive breast cancer. KRISTINE, results of which were presented at the 2016 ASCO Annual Meeting, shows the first phase III data for a neoadjuvant regimen that omits standard chemotherapy for HER2-positive breast cancer.

From June 2014 to June 2015, researchers at 68 centers in 10 countries enrolled 444 patients with centrally confirmed HER2-positive breast cancer greater than 2 cm in size. Patients were randomly assigned to receive T-DM1+P or the TCH+P regimen. Both regimens were given every 3 weeks for 6 cycles. At the end of the first cycle, patients underwent a core needle biopsy of the tumor for biomarker endpoints.

After 6 cycles, patients received standard of care surgery, and after surgery, they went on to receive 12 more doses of HER2-directed therapy according to the arm they were in. Patients in the T-DM1+P arm who had significant residual disease at the time of the surgery were encouraged to receive standard chemotherapy before receiving a maintenance therapy regimen.

Baseline characteristics were well distributed to 2 treatment arms by age, world region, estrogen receptor (ER)/progesterone receptor (PR) status, and stage.

The pCR rate in the breast and lymph nodes was 56% in the TCH+P arm and 44% in the T-DM1+P arm. This 11% difference was statistically significant, said Hurvitz, favoring the TCH+P arm.

In patients with ER- and PR-negative breast cancer, TCH+P yielded a pCR of 73% in breast and lymph nodes compared with 54% in the T-DM1+P arm.

In hormone receptor (HR)—positive breast cancer, the pCR was 44% in the TCH+P arm and 35% in the T-DM1+P arm, also favoring TCH+P. Over 60% of patients had HR-positive breast cancer, Hurvitz noted.

A preplanned, subgroup analysis showed that the benefits seen with TCH+P tended to favor all subgroups (age, world region, clinical stage at diagnosis and HR status). In addition, more women in the TCH+P underwent breast-conserving surgery (52.6% vs 41.7%, P = .0228).

In contrast, neoadjuvant T-DM1+P was associated with longer maintenance of patient-reported health-related quality of life and physical functioning, said Hurvitz. Neoadjuvant T-DM1+P also had a more favorable safety profile with a lower rate of grade 3/4 adverse events (AEs) (13% vs. 64%), serious AEs (5% vs. 29%), and AEs leading to treatment discontinuation (3% vs. 9%).

Cardiac event rates were unusual and were similar in the 2 treatment arms. Grade 3/4 AEs occurring in at least 3% of patients in either treatment arm included febrile neutropenia, neutropenia, diarrhea, and cytopenias, all of which were more common in the traditional chemotherapy arm compared with the T-DM1+P regimen.

Biomarker data and longer-term follow-up will be reported at a later date, said Hurvitz. In addition, there are several studies evaluating the use of T-DM1 in the early stage setting, including the KATHERINE and KAITLIN trials.

Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). J Clin Oncol 34, 2016 (suppl; abstr 500).