Neoadjuvant T-DM1 Shows Promising pCR Rates in HER2+/HR+ Early Breast Cancer

Nadia Harbeck, MD, PhD

Chemotherapy-free neoadjuvant treatment with trastuzumab emtansine (T-DM1; Kadcyla) demonstrated a pathological complete response (pCR) rate of 40.5% in patients with HER2+ and HR+ early breast cancer, according to findings from the phase II ADAPT trial presented at the 2015 ASCO Annual Meeting.

"After 12 weeks without systemic chemotherapies we observed more than a 40% pCR in both the breast and nodes in our T-DM1-treated HER+/HR+ patients," said lead investigator Nadia Harbeck, MD, PhD, head of the Breast Center, Oncological Therapy and Clinical Trials Unit, University of Munich, Germany. "We did see very low overall toxicity, and did not detect any new safety signals."

The ADAPT trial is a large umbrella trial that has enrolled 5000 patients with various breast cancer phenotypes. In the arm of the trial presented at ASCO, 376 patients with HER2+ and HR+ breast cancer were randomized to receive neoadjuvant T-DM1 at 3.6 mg/kg with or without endocrine therapy or trastuzumab plus endocrine therapy. Treatment was administered for 4 cycles followed by surgery and 1-year of standard adjuvant chemotherapy plus trastuzumab.

The primary endpoint of the study was pCR between each of the T-DM1 arms in comparison with the trastuzumab plus endocrine therapy arm. For this evaluation, pCR was defined as no invasive carcinoma in the breast and lymph nodes (ypT0).

In January 2015, an independent data and safety monitoring board analyzed results from an interim analysis of 130 patients. As a result of the high-level of efficacy seen in the T-DM1 arms, the board recommended that the study should be stopped.

Of the 130 patients analyzed, more than half were premenopausal (range, 45.8%-60%). The majority of tumors were larger than 2 centimeters (range, 45.9%-57.8%) and a third of patients were node positive (range, 27.1%-37.8%). Three-fourths of patients across all three arms had G3 disease.

"As you can see from the baseline characteristics, this was not a low-risk population," said Harbeck.

The pCR rate was found to be substantially higher in the T-DM1 arms compared with trastuzumab plus endocrine therapy (P <.001). In the T-DM1 alone arm (n = 37), the pCR rate was 40.5%. In the T-DM1 plus endocrine therapy arm (n = 48), the pCR rate was 45.8%. In the trastuzumab plus endocrine therapy arm (n = 45), the pCR rate was just 6.7%.

In an exploratory analysis of the T-DM1 arms it was found that pCR rates differed substantially between pre- and post-menopausal patients. In premenopausal patients (n = 22), single-agent T-DM1 demonstrated a 27% pCR rate versus 60% in those who were postmenopausal. A substantial difference between was not observed between the two groups in the combination arm (45.5% vs 46.2%).

"In the premenopausal patients, adding endocrine therapy increased pCR from 27% to about 46%, whereas this was not the case in the postmenopsaul patients," Harbeck said. "This is an interim analysis and these are low numbers, but these need to be followed-up because in the postmenopausal patients we did see a slight decrease when endocrine therapy was added."

Similar pCR rates to the ADAPT trial have been seen across several studies for patients with HER2+/HR+ early breast cancer. However, these trials generally assessed 12 to 24 weeks of chemotherapy with either single or dual HER2 inhibition. Additionally, the definition of pCR varied, with only a few defining the endpoint as ypT0.

In the NSABP B-41 trial, the pCR rate in patients with HER2+/HR+ early breast cancer treated with chemotherapy plus trastuzumab was 46%. In those who received chemotherapy with trastuzumab plus lapatinib, the pCR rate was 55%. Similarly, in the GeparSepto trial, the pCR rate with epirubicin, cyclophosphamide, nab-paclitaxel, pertuzumab, and trastuzumab was 56%. Without nab-paclitaxel, the pCR rate was 50%.

"It's obviously always difficult to make these cross-study comparison," Harbeck noted. "But, I don't think it is unreasonable to assume that our pCR rates in the ADAPT trial after only 4 cycles of T-DM1 compare quite well to other trials where patients got 24 weeks of aggressive chemotherapy plus dual blockade."

Across all arms of the ADAPT trial there were only 16 serious adverse events in 13 patients. The most common all-grade adverse events with single-agent T-DM1 were thrombocytopenia (30%), aspartate aminotransferase increase (19%), alanine aminotransferase increase (22%), and infections and infestations (11%).

"We had no problems administering the study medications for all 4 cycles. There were no grade 4 adverse events reported," Harbeck said. "Only 7 of the serious adverse events were related to the study medication, and mostly they were labeled serious because patients had to undergo unplanned hospitalization."

In the T-DM1 combination arm, some of the adverse events seen with single-agent T-DM1 were less frequent. The most common all-grade adverse events in this arm were thrombocytopenia (15%), infections and infestations (15%), aspartate aminotransferase increase (10%), and alanine aminotransferase increase (6%).

"In our study, there was a lower frequency of higher grade events associated with T-DM1," Harbeck explained. "These were all treatment-naive patients, before they started T-DM1. In all other trials reported so far, patients had extensive pretreatment, including chemotherapy."

Moreover, a prospective trial will be needed to compare single-agent T-DM1 to chemotherapy plus dual HER2 blockade. Given the single-agent activity, further assessment is warranted; based on findings from the study, it could be possible to explore lower doses of T-DM1, Herbeck suggested. Modifications to the ADAPT trial are planned, to further assess T-DM1 in patients with HER+/HR+ breast cancer.

Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 506).