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Genentech Planning Regulatory Filing This Year for New Personalized Rx for Advanced Breast Cancer

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Originally published June 4.

CHICAGO – Patients with HER2-positive advanced breast cancer lived longer without their disease progressing after treatment with trastuzumab emtansine -- a pharmacogenomically targeted drug being developed by Genentech -- than did patients treated with Tykerb (lapatinib) plus the chemotherapy agent Xeloda (capecitabine), researchers reported in a presentation here this week.

The so-called EMILIA study is still ongoing and final results are slated for early 2014, but the interim Phase III data show positive signs that in a few years trastuzumab emtansine – an antibody-drug conjugate that combines Genentech's Herceptin (trastuzumab) with the chemotherapy DM1 – will likely be a viable option for HER2-positive breast cancer patients who are progressing despite treatment with Herceptin or taxanes.

"The EMILIA trial provides convincing evidence that an immuno-conjugate targeted HER2 has potent anti-tumor activity in women with HER2 overexpression metastatic breast cancer," Louis Weiner, a medical oncologist at Georgetown University's Lombardi Cancer Center, said during a presentation reviewing the study data at the American Society of Clinical Oncology's annual meeting here this week.

Weiner disclosed that he was a consultant for a number of drug companies. The interim study results were presented at the meeting by study leader Kimberly Blackwell of Duke Cancer Institute.

"Clearly there is a need for women with metastatic breast cancer with progressive disease [despite] trastuzumab-based therapy," Weiner said. "T-DM1 was reasonably well tolerated and showed less toxicity than the [Tykerb/Xeloda] combination."

Based on findings from EMILIA, Genentech will submit marketing applications for T-DM1 in HER2-positive mBC this year with the US Food and Drug Association and the European Medicines Agency. "We are working with global regulatory authorities to submit these data as quickly as possible and hope that trastuzumab emtansine will soon be available to patients with this aggressive type of breast cancer," Hal Barron, Genentech chief medical officer, said in a statement.

Genentech licensed technology for T-DM1 from ImmunoGen.

HER2 overexpression is a prognostic marker for cancer and a predictive marker for drugs that target the receptor, such as Herceptin, a monoclonal antibody developed by Roche subsidiary Genentech that was approved by the FDA in 1998. It is considered one of the first examples of a molecularly targeted personalized medicine launched with a companion diagnostic to ensure that only patients who have a chance of responding to the treatment will receive it.

"At this same ASCO meeting in 1998, trastuzumab was introduced as an effective and innovative way of targeting cancer cells with a monoclonal antibody," reflected Blackwell. "Today, 14 years later, the same antibody has been improved in a way that can expect to benefit patients and lessen the toxicity of traditional chemotherapy with the use of an antibody drug conjugate.

"Targeted therapy for cancer has progressed another step forward with [the EMILIA] study," added Blackwell.

Trastuzumab emtansine, or T-DM1, joins Herceptin with the chemotherapy DM1 via a stable linker. The two bonded agents attach to HER2-positive cancer cells, block abnormal signaling pathways driving tumor growth, and induce the body's immune system to destroy malignant cells. "Once trastuzumab emtansine is absorbed into those cancer cells, it is designed to destroy them by releasing the DM1," Genentech described in a statement announcing the results from EMILIA.

In EMILIA, 980 first-, second-, and third-line metastatic breast cancer patients were confirmed to have tumors overexpressing the HER2 protein by central laboratory testing. All patients had to have been treated previously either by taxanes or Herceptin. These patients were then randomized to receive either T-DM1 or a combination regimen containing the HER2-targeted agent Tykerb plus the oral chemo agent Xeloda.

The primary endpoints of this study are progression-free survival (evaluated by a independent review body), overall survival, and safety. Secondary endpoints of the study are progression-free survival (as established by investigators), objective response rate, and patient-reported outcomes. The final overall survival analysis will be reached when 632 events occur. The data cutoff for the data presented at the ASCO meeting was Jan. 14.

Weiner noted that additional studies need to be done to better understand T-DM1's mechanism of action, its efficacy in other cancers; and whether only HER2-positive patients will benefit from the antibody conjugate. However, based on the interim data from EMILIA, Weiner is convinced that T-DM1 "really works in this population" of women with metastatic, HER2-overexpressing breast cancer.

Based on an independent review of the interim data, patients in the T-DM1 arm experienced a PFS of 9.6 months compared to 6.4 months for patients in the Tykerb/Xeloda arm. In T-DM1-treated patients, risk of cancer progression or death was reduced by 35 percent compared to patients in the control arm. When patient responses were broken down by clinical factors, all groups tended to benefit more from T-DM1 than from Tykerb/Xeloda, except women over the age of 65.

Although the interim data suggested that T-DM1-treated patients lived longer than patients in the comparator arm, this data has not yet matured, according to Genentech. At the meeting, Blackwell reported that the median overall survival was around 23 months for patients who received the Tykerb/Xeloda regimen, but the prespecified number of people who must be treated with T-DM1 in the trial hasn't yet been achieved.

"As the hazard ratio for OS did not cross the prespecified stopping boundary for the study, the OS analysis is not considered statistically significant at this time," Genentech said in a statement.

So far, approximately 85 percent of T-DM1-treated patients are still alive after one year of treatment, while 77 percent are alive in the control arm. After two years of treatment, 65 percent of patients are alive in the T-DM1 arm and 48 percent are alive on Tykerb/Xeloda.

Meanwhile, nearly 44 percent of patients in the T-DM1 arm experienced tumor shrinkage compared to 31 percent of patients in the control arm. A patient-reported outcome measure was time-to-symptom progression, which was 7.1 months for patients treated with T-DM1 compared to 4.6 months for patients receiving Tykerb/Xeloda.

In terms of safety, T-DM1 was better tolerated and patients had fewer toxicities compared to those treated with the Tykerb/Xeloda regimen. Researchers needed to reduce the dose of T-DM1 less frequently than patients treated with the Tykerb/Xeloda combination.

Approximately 41 percent treated with T-DM1 experienced severe toxicities versus 57 percent of patients in the control arm. T-DM1-treated patients experienced anemia at higher rates, lower platelet counts, and greater incidence of increased enzyme levels released by the liver and other organs. However, enzyme levels returned to normal as treatment with T-DM1 continued. The most common Grade 3 or higher toxicities that were higher in the Tykerb/Xeloda arm compared to T-DM1 were diarrhea, hand-foot syndrome, and vomiting.

EMILIA is the first Phase III trial for T-DM1. Genentech is conducting two additional Phase III studies for the drug. MARIANNE is comparing T-DM1 monotherapy with or without pertuzumab versus Herceptin plus taxane chemotherapy in patients with HER2-positive metastatic breast cancer patients who haven't previously been treated for their advanced-stage disease. In February, Genentech filed for marketing approval from the FDA for Herceptin plus the investigational agent, pertuzumab, as a treatment for metastatic HER2-positive breast cancer.

Another trial, THERESA, is comparing T-DM1 against the physician's treatment choice in HER2-positive metastatic breast cancer patients who have been treated with both Herceptin and Tykerb.

Besides T-DM1, Genentech is currently evaluating approximately 25 antibody drug conjugates in its pipeline.

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