by Dr. C.H. Weaver M.D. updated 12/2019
The precision cancer medicine Kadcyla® (trastuzumab emtansine) significantly reduces the risk of breast cancer recurring in women with HER 2-positive breast cancer including women with early stage or advanced disease.
HER2 is a protein involved in normal cell growth. Approximately 25% of breast cancers over-express (make too much of) the HER2 protein, and this over-expression contributes to cancer cell growth and survival. HER2 targeted therapies such as Herceptin (trastuzumab) have dramatically improved outcomes for women with HER2-positive breast cancer, but researchers continue to explore new approaches to treatment.
Kadcyla combines Herceptin and a chemotherapy drug (DM1) that interferes with cancer cell growth. Kadcyla delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy. Kadcyla has already been approved or the treatment of more advanced HER2-positive breast cancer.(1-4,8)
The FDA has approved Kadcyla for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant Herceptin and chemotherapy and for the treatment of patients with metastatic HER2-positive breast cancer who previously received Herceptin and a taxane, either alone or in combination.
ATEMPT - Kadcyla for Early Stage Breast Cancer
The results of a clinical trial evaluating the side effects of Kadcyla suggest that chemotherapy may not be required to treat early stage HER2 positive cancer. The ATEMPT trial was designed to determine whether adjuvant Kadcyla treatment is more tolerable than the Taxol-Herceptin combination regimen and whether the use of adjuvant Kadcyla is associated with a clinically acceptable disease-free-survival. Initial study findings were presented at the December 2019 San Antonio Breast Cancer Symposium.
The ATEMPT clinical trial included 512 patients with stage I HER2-positive breast cancer who were treated with Kadcyla for 17 cycles or Taxol for 12 weeks followed by Herceptin for 39 weeks and directly compared.
After a median follow-up of 3 years 97.5% of Kadcyla treated patients survived without evidence of cancer recurrence compared to 93.2% of Taxol – Herceptin treated patients. These initial trial results suggest that women with early stage HER2-positive breast cancer may be able to avoid treatment with chemotherapy altogether. (7)
KATHERINE Clinical Trial - Neoadjuvant Treatment
The KATHERINE clinical trial evaluated women with HER2-positive ESBC who did not achieve a pathological complete response to neoadjuvant treatment. Neoadjuvant treatment is given before surgery with the goal of providing immediate treatment and to shrink the cancer for easier surgical removal. In the KATHERINE clinical trial nearly 1500 women were treated with either Kadcyla or Herceptin as an adjuvant therapy in patients with residual cancer in the breast and/or axillary lymph nodes following neoadjuvant treatment with Herceptin and taxane-based chemotherapy and directly compared.
Overall 77% of patients who received Herceptin compared to 88.3% of patients who received Kadcyla were alive without evidence of cancer progression 3 years from treatment. This represents an absolute increased improvement of 11% for patients treated with Kadcyla.
TH3RESA Clinical Trial in Advanced HER2-Positive Breast Cancer
Patients with metastatic, HER2-positive breast cancer who received a combination antibody/chemotherapy drug in a phase 3 clinical trial survived longer, on average, than patients receiving other treatments. Researchers from Dana-Farber Cancer Institute reported the findings at the San Antonio Breast Cancer Symposium.
The TH3RESA trial, which enrolled more than 600 participants in the U.S. and overseas, compared survival times in patients randomized to treatment with the conjugate drug Kadcyla (T-DM1) to those randomized to treatment of their physician’s choice. All patients had metastatic breast cancer that tested positive for the human epidermal growth factor receptor 2 (HER2) protein – a feature in about 20 percent of all breast cancers – and had previously been treated with chemotherapy as well as the HER2-targeted drugs trastuzumab and lapatinib.
The investigators found that those in the T-DM1 group lived a median of 22.7 months vs. 15.8 months for those in the treatment of physician’s choice group – a 44 percent improvement. (The treatment of physician’s choice consisted either of drug regimens that targeted HER2 or single-agent chemotherapy.) The survival benefit associated with T-DM1 was consistent across all patient subgroups, regardless of age, degree of metastasis, number of prior treatments, and type of treatment of physician’s choice.
The incidence of severe side effects deemed severe or greater was also lower in the T-DM1 group – 40 percent, compared to 47.3 percent for those in the treatment of physician’s choice group.
Kadcyla combines trastuzumab, an antibody that latches onto the HER2 protein and blocks it from receiving growth signals, and emtansine, a potent chemotherapy drug that disrupts the way cells grow. By attaching the emtansine to trastuzumab, T-DM1 delivers the emtansine directly to the HER2-positive cancer cells. This essentially makes emtansine into a targeted drug that is highly effective at killing HER2+ cancer cells, but largely avoids damaging normal cells.
“This is an important trial because it demonstrates that even in patients whose cancer has progressed on multiple other HER2-targeted therapies, treatment with T-DM1 substantially extends patient survival compared to other drugs,” said the study’s senior author, Ian Krop, MD, PhD, Senior Physician in the Susan F. Smith Center for Women’s Cancers at Dana-Farber. “In addition, T-DM1 causes fewer serious side effects than other treatments. Based on this study and others, T-DM1 should be considered the standard of care for patients whose cancer has progressed on a HER2-targeted treatment.”(5)
PIK3CA Cancer Respond Well
Researchers have also evaluated whether tumor mutations in the PIK3CA gene affect treatment response because patients with this mutation typically do not respond as well to other HER2-targeted therapies as their counterparts without the mutation. Analysis has revealed that PIK3CA mutation status did not diminish treatment response. Women with the highest tumor HER2 levels benefit the most from the drug Kadcyla, regardless of PIK3CA mutation status. Measuring HER2 levels may help physicians individualize treatment among this population.
T-DM1 Benefits Women With Advanced HER2-Positive Breast Cancer
Among women with advanced, previously treated, HER2-positive breast cancer, trastuzumab emtansine (T-DM1)—an investigational drug that combines Herceptin® (trastuzumab) and a chemotherapy drug—resulted in better progression-free survival than standard treatment. The results of this Phase III clinical trial were presented at the 2012 Annual Meeting of the American Society of Clinical Oncology.
Approximately 20-25% of breast cancers overexpress (make too much of) the HER2 protein. HER2-targeted therapies such as Herceptin have dramatically improved outcomes for women with HER2-positive breast cancer, but researchers continue to explore new approaches to treatment.
T-DM1 links Herceptin with a chemotherapy drug (DM1). T-DM1 delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy.
To evaluate T-DM1 for the treatment of advanced, HER2-positive breast cancer, researchers conducted a Phase III clinical trial known as EMILIA. The study enrolled close to 1000 women with locally advanced or metastatic HER2-positive breast cancer that had progressed (worsened) in spite of previous chemotherapy and Herceptin. Study participants were treated with either T-DM1 or a standard treatment. The standard treatment consisted of Xeloda® (capecitabine) plus Tykerb® (lapatinib).
- Survival without cancer progression was 9.6 months among women in the T-DM1 group and 6.4 months among women in the Xeloda and Tykerb group.
- Two-year overall survival was 65.4% among women in the T-DM1 group and 47.5% among women in the Xeloda and Tykerb group. The difference between the groups in overall survival was not statistically significant, suggesting that it could have occurred by chance alone. Another analysis is planned for later in the study, and will provide additional information about the effect of T-DM1 on overall survival.
- Compared with women treated with Xeloda and Tykerb, women treated with T-DM1 were less likely to experience side effects such as diarrhea, hand-foot syndrome, and vomiting. The most common serious side effects of T-DM1 were low platelet counts and changes in liver function tests.
These results suggest that T-DM1 may be safe and effective for the treatment of advanced, previously treated, HER2-positive breast cancer.
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- <a href="https://www.roche.com/media/releases/med-cor-2018-10-15.ht">https://www.roche.com/media/releases/med-cor-2018-10-15.ht</a>
- Geyer CE, Huang CS, Mano MS, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE. Oral presentation at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX.
- Minckwitz GV, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1814017
- Dana-Farber Cancer Institute. (2015). Conjugate drug extends survival in patients with advanced HER2-positive breast cancer. [Press release].
- Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC). Presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. Abstract LB-63.
- Tolaney SM, Trippa L, Barry W, et al. TBREAST CANCERRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-05.
- FDA Approves Genentech's Kadcyla for Adjuvant Treatment of People With HER2-Positive Early Breast Cancer With Residual Invasive Disease After Neoadjuvant Treatment. Genentech. Published April 3, 2019. <a href="https://bit.ly/2UYWOVN.">https://bit.ly/2UYWOVN.</a> Accessed April 3, 2019.
- Blackwell KL, Miles D, Gianni L et al. Primary results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. Paper presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012;Chicago,IL. Abstract LBA1.