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FDA Approves Genentech's Antibody-Drug Conjugate, Marking Third Rx for HER2-Targeted Breast Cancer

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The US Food and Drug Administration last week approved Roche/Genentech's latest HER2-targeting breast cancer drug, trastuzumab emtansine (T-DM1).

The drug was granted priority review by the FDA last year with a decision due by Feb. 26. The agency approved the drug, brand named Kadcyla, a few days early on Feb. 22. Kadcyla is indicated as a treatment for patients with HER2-positive, late stage, metastatic breast cancer, who were previously treated with the HER2-targeting drug Herceptin and taxane chemotherapy.

The drug is an antibody-drug conjugate in that it combines Herceptin (trastuzumab), also developed by Genentech, 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.

Roche developed Kadcyla with ImmunoGen, garnering an exclusive license from the Waltham, Mass.-based firm to use its maytansinoid Targeted Antibody Payload Technology, or TAP Technology, to develop HER2-targeting cancer treatments. ImmunoGen said it is slated to receive $10.5 million in milestone payments from Roche as a result of the US drug approval.

Kadcyla is the first antibody-drug conjugate approved by the FDA for the treatment of a solid tumor. Two years ago, the FDA approved Seattle Genetics' lymphoma drug Adcetris, which is also an antibody-drug conjugate.

Kadcyla is the fourth drug approved by the FDA that targets HER2 overexpression in tumors. Other than Herceptin, the first HER2-targeting breast cancer treatment, the agency greenlighted GlaxoSmithKline's Tykerb (lapatinib) in 2010 and Genentech's Perjeta (pertuzumab) last June. Three out of the four currently approved HER2-targeting breast cancer drugs are marketed by Genentech.

In order to garner approval for Kadcyla, Genentech submitted data from a randomized, Phase III trial called EMILIA, in which researchers studied more than 900 women with HER2-overexpressing, locally advanced or metastatic breast cancer who had previously received Hercpetin and a taxane chemotherapy. The study participants were randomized to receive either Kadcyla or Tykerb plus capecitabine, and they received treatment until their cancer progressed or until they couldn't tolerate the side effects anymore.

Last year, at the Congress of the European Society for Medical Oncology in Vienna, EMILIA researchers reported that the risk of death in the trial was reduced by 32 percent for women receiving Kadcyla compared to those treated with the Tykerb/capecitabine regimen. Patients receiving Kadcyla experienced median overall survival of 30.9 months compared to 25.1 months for those in the comparator arm (PGx Reporter 10/3/2012).

Progression-free survival was a median of 9.6 months for women in the T-DM1 arm and 6.4 months for those on Tykerb/capecitabine. EMILIA data on progression-free survival was reported at the American Society for Clinical Oncology's annual meeting last summer (PGx Reporter 6/6/2012). Some common side effects reported in Kadcyla-treated patients were nausea, fatigue, muscle or joint pain, low blood platelet levels, increased liver enzymes, headache, and constipation.

The FDA approved Kadcyla with a boxed warning informing patients and doctors that the drug can cause liver toxicity, heart toxicity, and death in patients who take it. The drug should not be given to pregnant women, as it can cause "severe life-threatening birth defects," the agency said.

Kadcyla's approval has been anticipated for some time. Genentech tried to garner approval for the drug back in 2010, but the FDA refused to accept the company's filing of data from a single-arm, Phase II trial in third-line HER2-positive breast cancer patients. The agency wrote in its response to the company that "all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population."

Over the course of Kadcyla's development program, some experts have raised concerns about the antibody-drug conjugate hypothesis, particularly about the design of the linker holding the antibody and cytotoxic agent together.

However, with the approval of Kadcyla, Roche will have more confidence to advance other antibody-drug conjugate agents through its pipeline. Genentech is investigating Kadcyla in additional HER2-positive breast cancer indications and for HER2-positive gastric cancer. The company said in a statement that it has been studying antibody-drug conjugates "for more than a decade" and has eight such agents in Phase I or Phase II studies for different cancer indications.

In the case of Perjeta's approval in 2012, the FDA simultaneously approved two companion tests, developed by Dako, for gauging HER2 overexpression in patients (PGx Reporter 6/13/2012). It's unclear if the FDA is planning to review and approve companion HER2 tests specifically for Kadcyla.

Breast cancer is the second leading cause of cancer-related death among women. According to the National Cancer Institute, this year approximately 232,340 women will be diagnosed with breast cancer and 39,620 will die from the illness. Around 20 percent of breast cancer patients have tumors that overexpress the HER2 protein.

According to several reports, Genentech has priced Kadcyla at $94,000 for a typical course. At nearly $10,000 per month of treatment, the new drug is approximately double the cost of Herceptin.

According to Genentech, Kadcyla will be available to US patients in the next two weeks. The company will provide the drug through patient assistance programs to help get this treatment to those who may not be able to afford it.

Genentech also offers co-pay assistance programs to help those with insurance. With a co-pay card, for those who qualify based on income, Genentech may cover 80 percent of insured patients' out-of-pocket costs, giving them between $9,000 and $24,000 in assistance.

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