According to findings recently published online in the<em> Journal of Clinical Oncology, </em>12<em> </em>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.
Nadia Harbeck, MD, PhD
Nadia Harbeck, MD, PhD
According to findings recently published online in theJournal of Clinical Oncology,12weeks 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.
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<.001).
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= .005).
“Only 4 cycles of neoadjuvant T-DM1 in HER2-positive/HR-positive early breast cancer yield substantial pCR ratesquite 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 receptornegative 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-DM1containing 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 TrialEfficacy, 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.