`
`ASCO: Unique Combination of Targeted Antibody Linked to
`Chemotherapy Shows Positive Results in HER2-Positive Breast
`Cancer Patients
`News [1] | June 03, 2012 | Breast Cancer [2], ASCO 2012 [3], ASCO 2012 Breast Cancer [4],
`HER2-Positive Breast Cancer [5]
`By Anna Azvolinsky, PhD [6]
`
` Results of a large phase III trial shows that a new oncology therapy, trastuzumab emtansine
`(T-DM1), significantly delays progression of disease in women with HER2-positive advanced breast
`cancer previously treated with a taxane chemotherapy and trastuzumab (Herceptin).
`Source:
`
`Results of a large, nearly 1,000-patient trial shows that a new oncology therapy, trastuzumab
`emtansine (T-DM1), significantly delays progression of disease in women with HER2-positive
`advanced breast cancer previously treated with a taxane chemotherapy and trastuzumab
`(Herceptin). The phase III trial compared the investigational T-DM1 against standard therapy of
`capecitabine (Xeloda) in combination with lapatinib (Tykerb). Approximately 30% of all breast
`cancers are HER2-positive.
`
`“T-DM1 will become standard therapy for all patients, after first-line
`trastuzumab–Taxotere–pertuzumab, given the very strong overall survival signal and excellent
`safety,” said Joyce O’Shaughnessy, co-director of Breast Cancer Research at the Baylor Charles A.
`Sammons Cancer Center Texas Oncology and US Oncology in Dallas, Texas. Dr. O'Shaughnessy was
`not involved with the trial. “All late-line patients will receive T-DM1 once it is available.”
`O’Shaughnessy added that she hopes there will be an expanded access program for the drug.
`Besides providing a potential new option for women with advanced-stage cancer who have few
`treatment options, the study also validates a novel approach—delivering chemotherapy directly to
`the tumor cells and thus avoiding off-target chemotherapy effects that cause many of the toxicities
`that plague patients.
`T-DM1 is an antibody-drug conjugate delivering a one-two punch—trastuzumab, an antibody against
`HER2 is attached to a chemotherapy agent, DM1, through a linker, delivering the cell-killing agent
`specifically to HER2-positive cancer cells. Trastuzumab binds to the cancer cells that express the
`HER2 receptor on their surface. The antibody, attached to the chemotherapy agent is internalized by
`the cell, allowing the cytotoxic agent to kill the cancer cell.
`The drug was developed by Genentech, a member of the Roche Group. The chemotherapy DM1 and
`the method of attaching the cytotoxic agent to the antibody via a linker were developed by
`Massachusetts-based ImmunoGen, Inc.
`Roche plans to file T-DM1 with both the Food and Drug Administration (FDA) and the European
`Medicines Agency by the end of 2012. The submission will also include data on companion
`diagnostics—The HercepTest and HER2 FISH pharmDx test, both from Dako, a Denmark-based
`diagnostics company. Roche and Dako have partnered to file an FDA submission for both tests that
`will identify patients who are HER2-positive and eligible for T-DM1 treatment. Earlier this year Roche
`announced that T-DM1 can control metastatic breast cancer better compared to the standard
`treatment arm.
`“[T-DM1] was significantly better than a very effective approved therapy for HER2 overexpressing
`metastatic breast cancer,” said Kimberly L. Blackwell, MD, professor of medicine and assistant
`professor of radiation oncology at Duke Cancer Institute at Duke University and lead author of the
`trial, in a press release. Blackwell also highlighted that T-DM1 has few dose-limiting toxicities.
`“Patients don’t lose their hair from this drug. For patients facing metastatic breast cancer, this is a
`breakthrough.”
`The phase III EMILIA trial was a 991 patient randomized, open-label trial. One half of the women
`received T-DM1 at a dose of 3.6 mg/kg every 3 weeks, the other half received the standard
`treatment. Both progression-free survival (PFS) and overall survival were primary endpoints.
`The phase II data, announced at the 32nd Annual San Antonio Breast Cancer Symposium in 2009
`showed that 33% of patients on T-DM1 had an objective response. These patients had previously
`
`Page 1 of 2
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`ASCO: Unique Combination of Targeted Antibody
`Linked to Chemotherapy Shows Positive Results in
`HER2-Positive Breast Cancer Patients
`Published on Cancer Network (http://www.cancernetwork.com)
`
`IMMUNOGEN 2303, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`received a staggering average of seven therapies, including chemotherapy, trastuzumab, and
`lapatinib. Roche had submitted an accelerated approval Biologics License Application based on these
`phase II data but the FDA rejected the application back in 2010, requesting data from the large-scale
`phase III EMILIA trial.
`The Trial Results
`Patients who received T-DM1 had a median 9.6 months before their disease progressed compared to
`6.4 months for those in the standard therapy arm—a difference of 3.2 months that was statistically
`significant (P < .0001).
`After 2 years, 65.4% of patients treated with T-DM1 were still alive compared to 47.5% on the
`capecitabine-plus-lapatinib treatment. This difference has not met the EMILIA trial’s predetermined
`survival threshold. A second analysis is planned for later this year. Patients who had a response were
`on therapy for a median of 12.6 months for T-DM1 and 6.5 months for the
`capecitabine-plus-lapatinib combination.
`T-DM1 was well tolerated and no unexpected toxicities were reported. Common high-grade toxicities
`for patients taking T-DM1 included thrombocytopenia (12.9% of T-DM1 patients compared to 0.2% of
`the standard therapy arm patients) and elevation in liver function test. Both toxicities were resolved
`when patients temporarily stopped taking the medication. Overall, dose reductions where higher for
`patients taking capecitabine and lapatinib compared to those taking T-DMI1 (53.4%, 27.3%, and
`16.3%, respectively).
`T-DM1 is also being studied in a treatment-nave HER2-positive breast cancer patient population. The
`three-arm trial is comparing T-DM1 in combination with pertuzumab, another HER-targeted antibody,
`T-DM1 alone, or trastuzumab with a taxane-based chemotherapy. The 1,000-patient trial is
`scheduled to read out in a few years. Pertuzumab is seen as a complimentary therapy to
`trastuzumab, which blocks the function of HER2. Pertuzumab is a HER2 dimerisation inhibitor that
`prevents intracellular HER2 signaling.
`“It will be of interest to combine T-DM1 with lapatinib or pertuzumab [in the neoadjuvant setting],”
`commented C. Kent Osborne, director of the breast center at the Baylor College of Medicine in
`Houston, Texas. “I favor lapatinib plus T-DM1 because [laboratory data] and early studies in the
`clinic suggest that [this combination] is better. Some patients, if they can be identified, may not
`need chemotherapy,” Osborne added. “However, this requires further study.”
`
`
`
`Source URL:
`http://www.cancernetwork.com/breast-cancer/asco-unique-combination-targeted-antibody-linked-che
`motherapy-shows-positive-results-her2-positive
`
`Links:
`[1] http://www.cancernetwork.com/news
`[2] http://www.cancernetwork.com/breast-cancer
`[3] http://www.cancernetwork.com/asco-2012
`[4] http://www.cancernetwork.com/asco-2012-breast-cancer
`[5] http://www.cancernetwork.com/her2-positive-breast-cancer
`[6] http://www.cancernetwork.com/authors/anna-azvolinsky-phd
`
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`Page 2 of 2
`
`ASCO: Unique Combination of Targeted Antibody
`Linked to Chemotherapy Shows Positive Results in
`HER2-Positive Breast Cancer Patients
`Published on Cancer Network (http://www.cancernetwork.com)
`
`IMMUNOGEN 2303, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`