In early May 2019, the United States Food and Drug Administration (FDA) approved ado-trastuzumab emtansine (Kadcyla®, Genentech/Roche; T-DM1) for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

All patients considered for treatment should be selected based on an FDA-approved companion diagnostic for ado-trastuzumab emtansine. FDA also approved both the Ventana Medical Systems, Inc. PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and the INFORM HER2 Dual ISH DNA Probe Cocktail assay as companion diagnostic devices for selecting these patients.

(Ado-) trastuzumab emtansine also know as T-DM1 (Kadcyla®; Genentech/Roche) is a human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate that comprises the humanized anti-HER2 IgG1 (antibody) trastuzumab linked to the anti-mitotic agent mertansine (a maytansine derivative; also known as the maytansinoid DM1). The antibody-drug conjugate combines two strategies: the anti-HER2 activity of trastuzumab, and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor which interferes with mitosis and promotes apoptosis. The linker in trastuzumab emtansine is a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation). Emtansine refers to the MCC-DM1 complex.

“This approval is a significant treatment advance for HER2-positive early breast cancer. By working closely with the FDA and participating in the Real-Time Oncology Review pilot program, we are able to make ado-trastuzumab emtansine available for people with residual invasive disease after neoadjuvant therapy much sooner than anticipated,” noted Sandra Horning, MD, chief medical officer and head of Global Product Development.

“With every step forward in reducing the risk of disease recurrence, we come closer to the goal of helping each person with early breast cancer have the greatest opportunity for cure,” Horning said.

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Treatment consideration
The goal in treating early breast cancer is to provide women with the best chance for a cure, which may involve treatment before and after surgery as part of a comprehensive treatment approach.

While researchers are bringing us come closer to the goal to reach a cure with each advance made, many people still have a disease recurrence in the long term. Neoadjuvant treatment is given before surgery and is designed to shrinking tumors and helping to improve surgical outcomes. Adjuvant treatment is given after surgery and aims to eliminate any remaining cancer cells in the body to help reduce the risk of the cancer returning.

Basis for approval
Approval of this indication was based on the KATHERINE study (NCT01772472), a randomized, multicenter, open-label trial of 1,486 patients with HER2-positive early breast cancer.

In this trual, breast tumor samples were required to demonstrate HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using Ventana’s PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays. Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment per local guidelines. Patients were randomized (1:1) to receive ado-trastuzumab emtansine 3.6 mg/kg intravenously or trastuzumab 6 mg/kg intravenously on day 1 of a 21-day cycle for 14 cycles.

The trial’s primary endpoint was invasive disease-free survival (IDFS), defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. After a median follow-up of 40 months, the trial demonstrated a statistically significant improvement in IDFS in patients who received ado-trastuzumab emtansine compared with those who received trastuzumab (HR 0.50; 95% CI: 0.39, 0.64; p<0.0001). Overall survival data were not mature at the time of the IDFS analysis.

Adverse events
The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.

Recommended dose
The recommended ado-trastuzumab emtansine dose is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) for a total of 14 cycles for patients with EBC, unless there is disease recurrence or unacceptable toxicity.

Unique approval process
The FDA rapidly reviewed and approved the application under the FDA’s Real-Time Oncology Review (RTOR) and Assessment Aid pilot programs, leading to an approval 12 weeks after completing the submission. Ado-trastuzumab emtansine is the first Genentech medicine approved under the RTOR pilot program, which is exploring a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. For this indication, ado-trastuzumab emtansine was also granted Breakthrough Therapy Designation, which is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.

ado-trastuzumab emtansine is the only antibody-drug conjugate approved for the treatment of HER2-positive metastatic breast cancer. Genentech licenses technology for ado-trastuzumab emtansine under an agreement with ImmunoGen.

Clinical trials
A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE) | NCT01772472

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