NICE Recommends Roche’s Kadcyla as Adjuvant Therapy for HER2-Positive Early Breast Cancer Patients with Residual Disease

Compiled by Keke

On May 7, the UK National Institute for Health and Care Excellence (NICE) issued a draft guideline recommending Roche’s targeted anticancer drug Kadcyla (trastuzumab emtansine, also known as ado-trastuzumab emtansine) as an adjuvant treatment option for adults with HER2-positive early-stage breast cancer who have residual invasive disease in the breast or lymph nodes after receiving neoadjuvant taxane-based therapy and HER2-targeted treatment.

The purpose of neoadjuvant therapy is to reduce tumor size prior to surgery. Following this treatment, the tumor may sometimes shrink completely; however, patients may still harbor residual cancer after surgery (residual invasive disease). Alternatively, cancer cells may have spread to the axillary lymph nodes (lymph node-positive disease).

Adjuvant therapy aims to reduce the risk of postoperative cancer recurrence. In its draft guideline recommendations, NICE states that trastuzumab is an adjuvant treatment option for patients with either node-negative or node-positive disease. Currently, pertuzumab combined with trastuzumab and chemotherapy is an adjuvant treatment approach for node-positive cancer but is not indicated for node-negative disease. Trastuzumab emtansine can serve as an adjuvant treatment regimen for patients with either node-negative or node-positive disease.

Trastuzumab emtansine (brand name Kadcyla) is a HER2-targeted antibody-drug conjugate. In this conjugate, trastuzumab is a humanized anti-HER2 IgG1 antibody, and the small-molecule cytotoxin DM1 is a microtubule inhibitor. HER2 is a protein on the surface of cancer cells that promotes their growth and division. Upon binding to subdomain IV of the HER2 receptor, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, leading to the intracellular release of the cytotoxic catabolite DM1. The binding of DM1 to tubulin disrupts the intracellular microtubule network, resulting in cell cycle arrest and apoptotic cell death. Furthermore, in vitro studies have demonstrated that, similar to trastuzumab, trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity (ADCC), and suppresses the shedding of the HER2 extracellular domain in human breast cancer cells overexpressing HER2.

Clinical trial evidence demonstrates that, in patients with residual invasive cancer following neoadjuvant therapy and surgery, trastuzumab emtansine prolongs disease-free survival compared with trastuzumab monotherapy. It remains unclear whether trastuzumab emtansine extends overall survival, as final trial results have not yet been obtained.

However, indirect comparisons in patients with lymph node-positive disease suggest that trastuzumab emtansine prolongs the time to cancer progression compared with pertuzumab plus trastuzumab and chemotherapy. Although this conclusion is uncertain due to differences in patient characteristics between the two trials, NICE stated, following a cost-effectiveness assessment, that the drug could be included within the resource use scope of the UK National Health Service (NHS), and therefore recommended trastuzumab emtansine.

Meindert Boysen, Deputy Chief Executive of NICE and Director of the Centre for Health Technology Evaluation, stated: “Particularly welcome is the fact that trastuzumab emtansine can extend the time patients remain disease-free after surgery, potentially offering an additional treatment option to prevent cancer from fully recurring. Therefore, we are pleased to recommend the routine use of this adjuvant therapy in patients with HER2-positive early breast cancer following surgery.”

In the UK, approximately 7,000 patients with early-stage breast cancer are diagnosed as HER2-positive each year. According to NICE estimates, around 800 individuals annually are eligible for this newly recommended therapy.

It is reported that the average cost per patient for one course of treatment with trastuzumab deruxtecan, calculated at full price, is £51,000 (approximately $63,100). However, like all other pharmaceutical manufacturers whose drugs have been recommended for NHS coverage, Roche has provided a confidential discount applied to the list price of £51,000.

After more than four years of disagreement between Roche and NICE, Kadcyla finally received approval for an indication covering all patients with HER2-positive breast cancer who have undergone second-line treatment with Herceptin and taxane chemotherapy. In June 2017, NICE recommended that Kadcyla be routinely covered by the NHS to prevent recurrence during adjuvant therapy in patients with HER2-positive breast cancer after surgery. This means that breast cancer patients who still have residual tumor cells after neoadjuvant treatment with Roche’s Herceptin combined with chemotherapy will be able to use Kadcyla to prevent recurrence.

In May 2019, Kadcyla received FDA approval in the United States for inclusion in adjuvant treatment regimens for early-stage breast cancer. Subsequently, by the end of 2019, it also gained recommendations in the European Union and Canada. These approvals were based on the results of the Phase III KATHERINE clinical trial involving patients with early-stage breast cancer, which demonstrated that over a three-year period, Kadcyla prevented breast cancer recurrence in 88.3% of patients, compared to 77% for Herceptin.

Roche has three innovative drugs targeting the HER2 signaling pathway: Herceptin, Perjeta, and Kadcyla. Since the sensational news of “Herceptin losing patent protection” broke, Roche has been counting on Perjeta and Kadcyla to help the company continue achieving business growth.

This expectation was realized in the first quarter of this year, with the two drugs achieving sales of CHF 1.01 billion (approximately USD 1.04 billion) and CHF 428 million (approximately USD 441 million), respectively. Their combined total surpassed that of Herceptin, which recorded first-quarter sales of CHF 1.21 billion (approximately USD 1.25 billion), representing a 12% decline compared to the same period last year.

However, Roche’s HER2-targeted drug portfolio currently faces a formidable new challenger: Enhertu, an antibody-drug conjugate (ADC) co-developed by AstraZeneca and Daiichi Sankyo. Although Enhertu is currently approved only for breast cancer patients who have failed at least two prior treatment regimens, researchers are conducting a head-to-head comparative study against Kadcyla in the second-line setting, aiming to demonstrate the superiority of Enhertu. Reportedly, Enhertu’s sales reached $30 million in the first quarter of this year.

Reference Source:

1、NICE draft guidance recommends new treatment option for people with early breast cancer

2、Roche's Kadcyla wins NICE backing in early breast cancer use