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Study results from the phase III TH3RESA clinical trial presented during the 38th San Antonio Breast Cancer Symposium (SABCS) held in San Antonio in December 2015, confirm that in patients with HER2-positive, metastatic breast cancer who had progressed despite treatment with a taxane or two or more forms of HER2-targeted therapy, including trastuzumab (Herceptin®; Genentech/Roche) and lapatinib (Tykerb®; Novartis), median overall survival (OS) increased by nearly 7 months for patients treated with ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche).

Hans Wildiers, MD, PhD
Photo 1.0: Hans Wildiers, MD, PhD on Friday December 11, 2015. during the San Antonio Breast Cancer Symposium being held at the Henry B. Gonzalez Convention Center in San Antonio, TX (USA). Courtesy: ©  SABCS 2015 MedMeetingImages/Todd Buchanan. Used with Permission.

TH3RESA demonstrated that after a median follow-up of 30.5 months, median overall survival was 22.7 months in the ado-trastuzumab emtansine arm with 404 participating patients vs. 15.8 months in the control arm, which included 198 participating patients (hazard ratio [HR] = 0.68; P = .0007). These results crossed pre-specified OS efficacy stopping boundary  which was an observed hazard ratio (HR) <0.75 or p<0.012. [1]

The updated study data, presented by Hans Wildiers, MD, PhD, Professor of Medical Oncology at KU Leuven,  Belgium, compared results with patients who received treatment of physician’s choice (TPC) which comprised HER2-directed regimens (83%) and single-agent chemotherapy (17%). [1] 

In this study, eligible patients were randomized 2:1 to receive ado-trastuzumab emtansine (3.6 mg/kg IV every 3 weeks) or TPC. Crossover from TPC to ado-trastuzumab emtansine following progressive disease was allowed from September 2012 onward.[1]

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Despite the fact that nearly half of all patients in the control group crossed over to receive ado-trastuzumab emtansine (93 patients (47%) had crossed at the data cutoff for this analysis), the statistically significant and clinically meaningful improved survival benefit compared to TPC was observed regardless of patient age, hormone-receptor status, visceral involvement, and number of prior treatment regimens. In addition to an increased median overall survival, patients receiving ado-trastuzumab emtansine also had reduced incidence of grade ≥3 adverse events. The safety profile was consistent with previous studies.

The researchers consider results important because they further solidifies the role of ado-trastuzumab emtansine in the treatment of previously treated HER2-positive advanced breast cancer. But what’s more, they are important because several breast cancer therapies that have shown to increase progression-free survival (PFS) do not increase overall survival (OS). Until now, this was an important unmet medical need requiring new treatment options.

Photo 2.0: …median overall survival (OS) increased by nearly 7 months for patients treated with ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche)…

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 DM1 to tubulin disrupts microtubule networks in the cell, which in turn causing cell cycle arrest and apoptotic cell death.[1]

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.

Following a recent change in the recommendations the National Comprehensive Cancer Network guidelines, which are widely used as the standard for cancer care, ado-trastuzumab emtansine is now included as a preferred treatment for patients with trastuzumab-exposed HER2-positive, metastatic breast cancer who’s disease has progressed following treatment with a combination of a taxane-based chemotherapy.

Because many patients have received second- or later-line treatment before this recommendation was put in place, TH3RESA was designed to establish whether or not ado-trastuzumab emtansine could benefit patients in later lines as well.

Neoadjuvant Chemotherapy
Another study, the phase II WSG-ADAPT trial,  investigated neoadjuvant treatment with ado-trastuzumab emtansine.[2][3]

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. [2]

A subgroup of the ADAPT study included patients with various breast cancer phenotypes including HER2-positive, HR-positive early breast cancer. This subgroup study enrolled a total of 376 patients with HER2-positive, hormone receptor–positive early breast cancer, randomizing them to 12 weeks of neoadjuvant treatment with one of three regimens: ado-trastuzumab emtansine, ado-trastuzumab emtansine plus endocrine therapy, or trastuzumab plus endocrine therapy. This was, in essentially all patients, followed by surgery and 1 year of trastuzumab.[2]

The results presented during SABCS in December 2015 demonstrated pathological complete response (pCR), a good surrogate marker of longer-term efficacy in the neoadjuvant drug treatment of breast cancer defined as the absence of invasive cancer in the breast and lymph nodes after treatment, was 41% for ado-trastuzumab emtansine alone, 41.5% for ado-trastuzumab emtansine plus endocrine therapy, and only 15.1% for trastuzumab plus endocrine therapy. [2]

The study showed a highly significantly improved pCR (P < .001) when ado-trastuzumab emtansine arm was compared to trastuzumab + endocrine therapy, however, the researchers involved in this study confirmed that the addition of endocrine to ado-trastuzumab emtansine did not further enhance patients benefit.

Data from the final analysis of the phase III EMILIA study, a randomized, open-label study of patients with centrally confirmed HER2-positive (IHC3+ and/or FISH amplification ratio ≥2.0), unresectable, locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane which were randomized 1:1 to ado-trastuzumab emtansine (3.6 mg/kg IV every 3 weeks) or capecitabine (1000 mg/m2 PO twice daily, days 1–14 every 3 weeks) plus lapatinib (1250 mg PO daily), demonstrated a significantly improved PFS (median 9.6 vs 6.4 months; HR=0.65; 95% CI, 0.55–0.77; p<0.0001) and OS (median 30.9 vs 25.1 months; HR=0.68; 95% CI, 0.55–0.85; p<0.0006) compared with treatment with capecitabine plus lapatinib.

The researchers involved in the final data analysis confirm that while median drug exposure was longer with ado-trastuzumab emtansine than capecitabine plus lapatinib, ado-trastuzumab emtansine was associated with fewer grade ≥3 AEs and AEs leading to dose reduction compared with capecitabine plus lapatinib (41% vs 57%).

This, according to EMILIA’s study researchers as well as other researchers and analysts, demonstrates that that treatment with ado-trastuzumab emtansine improved survival, even in the presence of treatment crossover, and reaffirms the ado-trastuzumab emtansine as the standard of care in patients with previously treated HER2-positive metastatic breast cancer.[4]

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