Nadia Harbeck, MD, PhD
Twelve weeks of neoadjuvant T-DM1 (ado-trastuzumab emtansine; Kadcyla) with or without endocrine therapy induced superior pathologic complete response (pCR) compared with trastuzumab (Herceptin) plus endocrine therapy in patients with HER2-positive/HR-positive early breast cancer, according to findings recently published online in the Journal of Clinical Oncology.
In the prospective, neoadjuvant phase II ADAPT trial conducted by the West German Study Group, pCR was 41.0% for patients assigned to T-DM1 alone and 41.5% for those who received T-DM1 and endocrine therapy. In contrast, 15.1% of patients assigned to trastuzumab and endocrine therapy had a pCR (P
Early response was defined as a ≥30% decrease in the Ki-67 level after a single therapy cycle. Two-thirds of patients who responded were early responders. Of those, 35.7% achieved a pCR compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24-4.19; P
“Only 4 cycles of neoadjuvant T-DM1 in HER2-positive/HR-positive early breast cancer yield substantial pCR rates—quite comparable to standard chemotherapy plus trastuzumab (or even to dual HER2 blockade). T-DM1 may be an efficient and safe alternative for patients who are not suited for systemic chemotherapy in this setting; the addition of endocrine therapy does not seem to play a crucial role,” first author Nadia Harbeck, MD, University of Munich, and coinvestigators wrote.
“Our trial results add to the existing evidence that HER2-positive early breast cancer may require approaches that differ regarding the treatment of the luminal (HR-positive) and the nonluminal (HR-negative) subtypes, “added Harbeck et al.
Investigators enrolled 375 patients with early HER2-positive/HR-positive breast cancer at 48 centers from October 2012 to March 2015. The intent-to-treat population included 119 patients randomly assigned to T-DM1 (3.6 mg/kg body weight every 3 weeks for 4 cycles; Arm A), 127 randomly assigned to T-DM1 (same regimen) plus endocrine therapy (Arm B), and 129 randomly assigned to trastuzumab (loading dose of 8 mg/kg and then 6 mg/kg every 3 weeks for 3 more cycles) plus endocrine therapy (Arm C).
The median ages in the arms ranged from 50 to 51.5 years, and investigators said the characteristics were well balanced between the 3 groups. Rate of cT1 tumors was 50.4%, 48.8%, and 46.5%, in arms A, B, and C, respectively; cN0 tumor rates were 71.4%, 75.6%, and 70.5%, respectively. Progesterone receptor–negative tumors in the arms were 17.6%, 15.7%, and 16.3%, prospectively.
Rates of near pCR (ypT1a or ypT0/is) were 52.9% in arm A, 52.9% in arm B, and 19.3% in arm C. Rates of total pCR (ypT0, ypN0) were 32.5% in arm A, 34.1% in arm B, and 10.1% in arm C. ypT0/is rates were 42.4% in arm A, 43.4% in arm B, and 19.2% in arm C.
Postmenopausal women assigned to T-DM1 alone had a pCR rate of 44.1% versus 37.9% for premenopausal women. The rates were 45.0% versus 38.1% and 16.7% versus 13.6% for the T-DM1 plus endocrine therapy and the trastuzumab plus endocrine therapy groups, respectively.
Although these pCR rates were numerically higher in postmenopausal women, the difference was not statistically significant overall (P
= .3) or within treatment arms (Arm A, P
=.57; Arm B, P
= .47; Arm C, P
= .8). None of the premenopausal patients received a gonadotropin-releasing hormone analog and an aromatase inhibitor.
T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Investigators observed 17 therapy-related serious adverse events (AEs; Group A, 5.3%; Group B, 3.1%), including 4 serious AEs that were grade 3 or greater (2 each in Arms A and B) and 1 each for ALT increase, corneal cyst, hypertensive crisis, and hypersensitivity reaction. All patients recovered without sequelae.
In the T-DM1–containing arms, 7.5% of patients experienced at least one grade ≥3 AE compared with 4.1% in Arm C (P
= .26). Increases in transaminases were the most common AE (112 observed in 103 patients).
“In summary, no new safety signals for T-DM1 were detected, and overall toxicity was favorable in all 3 treatment arms,” Harbeck et al wrote.
Harbeck N, Gluz O, Christgen M, et al. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor–Positive Phase II Randomized Trial—Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET [published online July 6, 2017]. J Clin Oncol. doi:10.1200/JCO.2016.71.9815.