Results from the German phase II ADAPT study (WSG-ADAPT), showed that neoadjuvant ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche) is effective in the treatment of HER2-positive, hormone receptor (HR)-positive breast cancer, with or without endocrine therapy. The trial compared this therapy with the treatment of trastuzumab (Herceptin®; Genetech/Roche) and endocrine therapy.[1][2]

The results of an interim analysis of the ADAPT study were presented by the researchers during the 51 Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 29 – June 2, 2015 in Chicago, Illinois (ASCO, abstract 506).[3]

Unique trial
The ADAPT study is one of the first new generation (neo)adjuvant clinical trials dealing with the individualization of (neo)adjuvant decision-making in the treatment of early breast cancer. The “umbrella” study, with approximately 5,000 participating patients (n = 4,936) with early primary breast cancer (BC) aged between 18 and 75 years old, aims to establish early predictive surrogate markers for therapy response under a short, 3-week, induction treatment (using the baseline diagnostic and repeat core biopsy following induction) in order to maximally individualize and optimize therapy and avoid a patient’s exposure to unnecessary toxicity as a result of ineffective or over-/undertreatment in luminal tumors. The study has now been closed because efficacy was reached. [4]

A subgroup of the ADAPT study included patients with various breast cancer phenotypes including HER2-positive, HR-positive early breast cancer. This substudy enrolled a total of 376 patients at 48 sites. The results of the interim analysis presented at this year’s ASCO meeting included 130 of the patients enrolled in the substudy. Participating patients with HER2+ and HR+ breast cancer were randomized to receive either (neo)adjuvant ado-trastuzumab emtansine mono therapy (N = 37), ado-trastuzumab emtansine with endocrine therapy (n = 48), or trastuzumab with endocrine therapy (n = 45) at 3.6 mg/kg.  This treatment was administered in 4 cycles and followed by surgery + 1-year treatment of the standard adjuvant chemotherapy + trastuzumab.

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Ado-trastuzumab emtansine
Ado-trastuzumab emtansine, a conjugated version of the humanized anti-HER2 IgG1, trastuzumab, to a small molecule cytotoxin microtubule inhibitor DM1. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor mediated internalization and subsequent lysosomal degradation. This results in intracellular release of DM1-containing cytotoxic catabolites. The binding of DMl to tubulin disrupts microtubule networks in the cell, which in turn causing cell cycle arrest and apoptotic cell death.[5]

The drug is used as a single-agent for the treatment of patients with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane – either separately or in combination.

Trial results
In the ADAPT study, researchers noted, after only 12 weeks of treatment, a clinical meaningful rate of pathologic complete response (pCR), defined as no invasive tumor in breast and lymph nodes (ypT0), of 40.5% with ado-trastuzumab emtansine alone, 45.8% with ado-trastuzumab emtansine and endocrine therapy, and only 6.7% with trastuzumab and endocrine therapy (P < 0.001 for both ado-trastuzumab emtansine groups vs. trastuzumab).  Ongoing biomarker analyses included PI3K mutations and intrinsic subtypes.

Menopausal status
The treatment results with ado-trastuzumab emtansine differed by menopausal status. The researchers noted that of the 130 patients analyzed, a significantly larger number was premenopausal (range 45.8%-60%). The majority of tumors encountered were larger than 2 centimeters (range, 45.9%-57.8%) while a third of participating patients were node positive (range, 27.1%-37.8%).  About 75% of patients across all three of the arms had G3 disease.

The analysis showed that more postmenopausal women benefitted when ado-trastuzumab emtansine monotherapy was used compared with premenopausal women. They also noted that adding endocrine therapy did not noticably change the treatment outcome.

Adverse Events
Overall, the researchers observed low overall toxicity with 16 serious adverse events in 13 patients and only 7 grade 3 adverse events related to the study medications. Interestingly, they noticed that in treatment-naive patients, some of the adverse events seen in single-agent use of  ado-trastuzumab emtansine were less frequent in the combination arm.

The most common all-grade adverse events in  were thrombocytopenia (30%), alanine aminotransferase increase (22%), aspartate aminotransferase increase (19%) and infections and infestations (11%). All participating patients recovered completely

The data presented during this year’s ASCO are, at this time, only an interim analysis. Experts are eagerly looking forward to the complete data analysis, which is expected to be presented during a future meeting. The complete data analysis will offer a more robust picture of the trial results of this unique study.