In 2012, an estimated 2,975,314 women were living with breast cancer, representing about 12% of all new cancer cases and 25% of all cancers in women. Globally, breast cancer is the most frequently diagnosed cancer among women in 140 of 184 countries worldwide. According to recent statistics from the World Cancer Research Fund International, worldwide breast cancer incidence has increased by more than 20% since 2008. In the same period, mortality rates have increased by 14%. [1]
One out of five of women diagnosed with breast cancer have a type of cancer where the protein HER2 – also known as Human Epidermal growth factor Receptor 2 – is in high presence on tumor cells. [2]
In an educational session during the Annual Meeting of the American Society of Clinical Oncology, which was held May 29 – June 2, 2015, (ASCO) in Chicago, IL, Francisco J. Esteva, MD, PhD, of the NYU Langone Medical Center in New York, NY, presented data on ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche), an antibody drug conjugate or ADC that has shown promising results for patients with HER2-positive metastatic breast cancer or MBC, a disease that is, in most cases, incurable, requiring treatment designed to optimize health elated Quality of Life (hrQoL), manage symptoms, and prolong survival. To date, trastuzumab (Herceptin®; Genetech/Roche) + chemotherapy is regarded as standard first-line treatment of HER2-positive MBC.
Powerful anticancer agents
Ado-trastuzumab emtansine is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic, HER2-positive breast cancer that has grown despite other HER2-targeting treatments.
Antibody-drug Conjugates or ADCs combine tumor-specific antibodies with powerful anticancer agents, providing potent cancer treatment while minimizing damage to healthy cells. ADCs are able to recognize and enter cancer cells and release cytotoxic agents once inside the cell, making this kind of drug less harmful to healthy, non-cancerous cells. [3]
Numerous clinical studies have shown that one ADC in particular (ado-trastuzumab emtansine) is showing improvements for patients with advanced (metastatic) HER2-positive breast cancer or MBC when used as a second and third line treatment. This is good news for many patients, since these findings have now led to ado-trastuzumab emtansine being integrated into clinical practices. The results of these studies have also sparked an interest in testing the combination of the drug with other cancer therapies. Additionally, ado-trastuzumab emtansine is being assessed for its potential as a first line treatment for women with early stages of breast cancer.
High Expression of HER2
Patients with MBC where the expression of HER2 is high, and who have already had previous chemotherapy regimen, are suitable candidates for treatment with ado-trastuzumab emtansine. Ado-trastuzumab emtansine is composed of the monoclonal antibody trastuzumab connected to DM1-a derivative of the cytotoxin maytansine-via a chemical linker. The trastuzumab antibody is able to recognize and bind to HER2 proteins on the surface of tumor cells and then degrade once it has been taken up in the cell. After degradation, DM1 is released into the cell, where it will inhibit microtubule production. By combining a powerful cytotoxin like DM1 with the specific tumor recognition of trastuzumab, a more targeted and better tolerated form of therapy is now made possible. [4]
Clinical Trials
In the EMILIA trial, 991 patients with MBC who had received prior treatment with trastuzumab and a taxane based chemotherapy, were treated with either ado-trastuzumab emtansine or with a standard treatment combination of capecitabine (Xeloda®; Genetech/Roche) and lapatinib (Tykerb®; GlaxoSmithKline/GSK).
Patients who received ado-trastuzumab emtansine had a median progression free survival (PFS) of 9.6 months, while that of the standard treatment was only 6.4 months. The patients treated with ado-trastuzumab emtansine also saw a higher objective response rate (OR) (43.6%) compared to the patients treated with capecitabine plus lapatinib (30.8%). Additionally, treatment with ado-trastuzumab emtansine was generally better tolerated, showing fewer grade 3 or higher adverse effects (57% vs. 41%). [5][6]
Emilia and Th3resa
While EMILIA included patients with metastatic breast cancer who had not yet received any prior treatment with lapatinib, another trial (TH3RESA) included 600 patients that had already received both lapatinib and trastuzumab. These previously heavily treated patients were either given ado-trastuzumab emtansine or a treatment of the physician’s choice. The results of TH3RESA were also promising. PFS in the ado-trastuzumab emtansine group was higher (9.6 months) than that of the standard treatment receiving group (6.4 months). Overall survival (OS) was also higher (30.9 months vs. 25.1 months).
Additionally, response rates were improved by 31% in the ado-trastuzumab emtansine treated group, compared to 9% improvement that was seen in the group receiving standard treatment. There were also significantly fewer adverse events seen in the group treated with ado-trastuzumab emtansine compared to standard treatment (32% vs. 43%).[7][8] Lisa Carey, MD, medical director of the UNC Breast Center and associate director for clinical science at UNC Lineberger Comprehensive Cancer Center, in Chapel Hill, NC noted that the positive results seen from TH3RESA confirm those seen in EMILIA, and show that ado-trastuzumab emtansine is safer as well as more effective than the standard treatment for MBC in the advanced settings. [9]
Ado-trastuzumab as First Line Treatment
After the success of ado-trastuzumab emtansine as a second and third line treatment, the use of this drug as a first line treatment merited investigation. In the MARIANNE trial, over 1,000 patients, all of which had no prior treatment in the metastatic setting, received either ado-trastuzumab emtansine + placebo, ado-trastuzumab emtansine + the anti-HER2 targeted therapy pertuzumab (Perjeta® Genentech), or the standard treatment, trastuzumab plus chemotherapy. The researchers involved in this trial wanted to find out if ado-trastuzumab emtansine could be an option as a first treatment for metastatic disease. The research focused on progression-free survival (PFS).
However, data presented at this year’s ASCO meeting revealed that the study met the PFS non-inferiority end point, but not the superiority end point. OS was similar across all treatment arms. [10] [11] Paul Anthony Ellis, MD, at Guy’s Hospital and the Sarah Cannon Research Institute, in London, United Kingdom, found that in this trial, ado-trastuzumab emtansine worked as well as the standard treatment but it did not work significantly better.
PFS was 13.7 months in the standard treatment group, 14.1 in the ado-trastuzumab emtansine alone group, and 15.2 in the group treated with ado-trastuzumab emtansine + pertuzumab.
The ado-trastuzumab emtansine containing groups did see an overall lower percentage of grade 3-5 adverse events when compared to the standard treatment group. The percentage of these adverse events was lower in the ado-trastuzumab emtansine alone group and the ado-trastuzumab emtansine + pertuzumab group by 8.7% and 7.9%, respectively. Neutropenia, the most common adverse event in all groups, was 19.8% in the standard treatment group, 4.4% in the ado-trastuzumab emtansine alone group, and 2.7% in the ado-trastuzumab emtansine+ pertuzumab group. However, the researchers noted that some adverse events such as thrombocytopenia and anemia were higher in the ado-trastuzumab emtansine containing groups. [see Table 1.0]
Because neither of the study treatments worked better than the standard treatment, Ellis believes that the current standard therapy, trastuzumab + chemotherapy, should, at this time, remain the recommended first treatment for newly diagnosed metastatic HER2-positive breast cancer. [12]
Although MARIANNE did not indicate that ado-trastuzumab emtansine was significantly better than standard first line MBC therapy, the results seen when it is used as a second and third line treatment have created a great interest in testing it’s utility for early stage breast cancer. Additionally, ado-trastuzumab emtansine is being tested for its potential in treating other forms of cancer. Amanda Fallon, the Senior Manager for Corporate Relations at Genentech in South San Francisco, CA, stated that “[Genentech has] a number of ongoing trials evaluating Kadcyla [ado-trastuzumab emtansine] in various different treatment settings… [and] we continue to see ADCs as a very promising technology.”
| Outcome | HT | T-DM1 | T-DM1 + P |
|---|---|---|---|
| Median Follow up, mo | 34.8 | 34.9 | 34.7 |
| Median PFS, mo | 13.7 | 14.1 | 15.2 |
| HR [97.5% Cl] | .93 [.73-1.13], p = .31 vs HT | .87[.69-1.08], p = .14 vs HT .91 [.73-1.13], p = .31 vs T-DM1 | |
| ORR% | 67.9 | 59.7 | 64.2 |
| Median duration of response, mo | 12.5 | 20.7 | 21.2 |
| Grade 3-5 AEs, % | 54.1 | 45.4 | 46.2 |
| Most common grade 3-5 AEs, % | |||
| Neutropenia | 19.8 | 4.4 | 2.7 |
| Febrile neutropenia | 6.5 | 0 | 0 |
| Anemia | 2.8 | 4.7 | 6 |
| AST increased | 0.3 | 6.6 | 3 |
| Thrombocytopenia | 0 | 6.4 | 7.9 |
Table 1.0: Outcome and Most common Adverse Events. Adapted from Ellis PA, et al. J Clin Oncol 33, 2015 (suppl; abstr 507). Data presented during the 2015 annual meeting of the American Society of Clinical Oncology. (ASCO). [12]
Potential for Brain Metastasis MBC Treatment
Another significant result of the ado-trastuzumab emtansine trials is the effect seen on the overall survival of patients whose cancer has moved to the brain, a condition that currently holds a very low prognosis.
Although trastuzumab has revolutionized the treatment of HER2-positive breast cancer, by dramatically lowering the risk of recurrence in HER2-positive breast cancer patients, high rates of primary and treatment-emergent resistance are considered barriers to improving long-term outcomes [13][14]. One major shortcoming is the potential association with cardiotoxic effect and increased incidence of brain metastases when used in the adjuvant setting [15]. These brain metastases pose a major clinical challenge due to their associated (increased) morbidity and significant impact on the patients’ heath related Quality of Life (hrQoL). About half of these patients them will eventually die from CNS disease progression [16]. Depending on the size and number of lesions, treatment options for patents with brain metastases in breast cancer include steroids, neurosurgery, stereotactic radiosurgery and whole brain radiotherapy (WBRT).
While the correlation between trastuzumab and brain metastases has, so far, not been confirmed, it has been suggested that the Central Nervous System (CNS) is a sanctuary site for micrometastatic disease and that systemic disease control with trastuzumab along with its inability to penetrate the blood–brain barrier may result in a higher incidence of brain metastases.
Patients with brain metastasis that, have so far, have been treated with ado-trastuzumab emtansine had a median overall survival rate significantly higher than those treated with capecitabine and lapatinib (26.8 vs. 12.9). These results reveal a potential for combination of ado-trastuzumab emtansine with other standard (radiation) therapies for the treatment of this patient subgroup, limiting the effects of this potentially devastating complication.[17]
