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FDA Approves Kadcyla (T-DM1 Anitbody conjugate) for Metastatic HER2 Breast Cancer

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    FDA Approves Kadcyla (T-DM1 Anitbody conjugate) for Metastatic HER2 Breast Cancer

    The FDA just approved the new treatment for about 20% of breast cancer patients who have a particular form of the disease that overproduces the protein HER-2.

    The drug now called Kadcyla, combines the Herceptin with a powerful chemotherapy toxin and a third chemical linking the medicines together. The chemical keeps the drugs intact until they bind to a cancer cell, where the medication is released.

    The cost of the drug is about $9,800 a month or $94,000 for a typical course of treatment. It is about twice the price of Herceptin itself and similar to the price of some other new cancer drugs.

    The label of Kadcyla has a warning saying the drug can cause liver toxicity, heart toxicity and death. It can also cause serious birth defects or fetal death for women of childbearing age.

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    The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.

    T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

    This product offers a new twist on an older product; it is an antibody–drug conjugate in which the HER2-targeted antibody trastuzumab is chemically linked to the cytotoxin mertansine (DM1). The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.

    T-DM1 "delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, in a press statement. "It is the fourth approved drug that targets the HER2 protein."

    In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months). Also, there were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy (43.1% vs. 59.2%), according to the company.

    The approval represents a "momentous" day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

    "Our HER2-positive patients with metastatic disease have another very powerful therapy that offers the real hope for prolonged disease control with less toxicity," she said.

    "This is the classic light-beer scenario; it's less filling and tastes great," she summarized, adding that T-DM1 was more effective in EMILIA than standard therapy on every outcome: overall response rate, disease-free survival, progression-free survival, and overall survival.

    However, another expert sees T-DM1 in a less dramatic light.

    Steve Vogl, MD, a private practitioner and former academic who practices in the Bronx, New York, called T-DM1 a "nice" drug when he discussed the product in an online essay last year.

    T-DM1 causes "no alopecia, little neutropenia, and only moderate thrombocytopenia. It requires only a short infusion every 3 weeks, lacks cumulative toxicity, and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab, with apparently longer remissions," he wrote.

    However, Dr. Vogl called the EMILIA control regimen (lapatinib and capecitabine) "distinctly suboptimal" and not a standard of care, even though it is an FDA-approved treatment option in this setting.

    "TDM-1 does not meet [the] goals of a major advance," wrote Dr. Vogl, who explained that such an advance must cure some patients, increase the rate of clinical complete remission, or produce a high rate of very long partial response.

    TDM-1 does not provide a "major change in prognosis" for women with metastatic disease who have progressed on trastuzumab treatment, he wrote, adding that it is likely to be "very expensive."

    Study Data and Boxed Warning

    The international open-label EMILIA study involved 991 patients with HER2-positive locally advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The study met the coprimary efficacy end points of overall survival and progression-free survival (assessed by an independent review committee).

    Median progression-free survival was longer with TDM-1 than with lapatinib plus capecitabine (9.6 vs 6.4 months). In addition, patients treated with TDM-1 lived significantly longer without their disease getting worse (hazard ratio [HR], 0.65; reduction in risk of disease worsening or death, 35%; P < .0001).

    The risk of dying was 32% lower with TDM-1 than with lapatinib and capecitabine (HR, 0.68; P = .0006).

    For patients receiving TDM-1, the most common adverse events (occurring in more than 2% of participants) of grade 3 or higher were low platelet count (14.5%), increased levels of enzymes released by the liver and other organs (8%), low red blood cell count (4.1%), low levels of potassium in the blood (2.7%), nerve problems (2.2%), and tiredness (2.5%).

    T-DM1 was reviewed under the FDA's priority review program, which provides for an expedited 6-month review of drugs that might provide safe and effective therapy when no satisfactory alternative exists, or that offer significant improvement over comparable products on the market.

    T-DM1 is being approved with a boxed warning that alerts patients and healthcare professionals that the drug can cause liver toxicity, heart toxicity, and death. The drug can also cause severe life-threatening birth defects, so pregnancy status should be verified prior to starting T-DM1 treatment.

    Dr. Vogl has disclosed no relevant financial relationships. Dr. Miller reports financial ties with Genentech, Bristol-Myers Squibb, AstraZeneca, Roche, and Clovis Oncology.

    Citation: FDA Approves New Treatment for Metastatic HER2 Breast Cancer. Medscape. Feb 22, 2013.
    Gregory D. Pawelski

    Response to anti-HER2 therapy after treatment with Kadcyla

    I've heard from breast cancer patients who were bumped from the T-DM1 clinical trial because of disease progression, which meant that their cancer was growing despite the drug. Bumped off the trial because of disease progression? Wonder how many more patients there were like this?

    Response rates (how much a tumor decreased in size) can be inflated when excluding patients during clinical trials (evaluable patients). Patients not considered "evaluable" are often those who do not get the benefit of an entire treatment plan. The response rate is calculated after removing patients, who die or have been excluded, from the calculation. This inflates the response rate.

    But clinical oncologists want to publish their papers. They need to report on the outcomes of their experiments, but if they had to wait for survival data, it could take years until all the data was aggregated. That wouldn't bode well for them to participate in pharma-sponsored trials in the future.

    Response rates give clinical oncologists the opportunity to take a more optimistic look at therapies that have limited success. They can describe results as being complete remission, partial remission or simply clinical improvement.

    If they treat all patients for three weeks, they can fairly evaluate the efficacy of a compound, which takes that lone (on average) before it can be regarded as effective. If they disregard all patients who die or were excluded after onset of therapy, and include only those treated three weeks or more, they can improve their data.

    To justify their existence, they have to publish papers. That's what they do.

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    Gregory D. Pawelski


      FDA Approves Two Companion Diagnostics For Kadcyla

      Dako, an Agilent Technologies Company and worldwide provider of cancer diagnostics, announced today it has received approval from the U.S. Food and Drug Administration for the addition of Kadcyla in the labeling of two Dako companion diagnostic assays.

      Kadcyla (ado-trastuzumab emtansine) is Genentech's new medicine for patients with HER2-positive metastatic breast cancer who have received prior treatment with Genentech's cancer medicine Herceptin (trastuzumab) and a taxane chemotherapy.

      The two assays are Dako's HercepTest and HER2 IQFISH pharmDx.

      Today's announcement is the result of a collaboration between Dako and Genentech, a member of the Roche Group. The collaboration was initiated in early 2012, and later the same year Dako submitted applications to the FDA requesting approval of the two Dako assays as companion diagnostics for Genentech's drug candidate for patients with HER2-positive metastatic breast cancer.

      Genentech's Kadcyla, an antibody-drug conjugate, and Dako's HercepTest and HER2 IQFISH pharmDx have received simultaneous approvals from the FDA.

      Dako's HercepTest and HER2 IQFISH pharmDx will serve as diagnostic tools to identify cancer patients with HER2-positive metastatic breast cancer who may be eligible for Kadcyla treatment.

      "At Dako, we focus on advancing cancer diagnostics, because patients' lives depend on it," said Lars Holmkvist, CEO of Dako and senior vice president, Agilent. "Partnering with companies who are also relentless in their commitment to fighting cancer is an important element in achieving this goal. Today's FDA approval is the result of excellent collaboration between Dako and Genentech."

      Dako's ongoing strategy is to combine its strength in developing companion diagnostics with its proven ability to partner with pharmaceutical companies to increase the number of companion diagnostic assays and ultimately improve personalized medicine.

      Citation: Agilent Technologies. "FDA Approves Two Dako Assays As Companion Diagnostics For Genentech's New Breast Cancer Medicine Kadcyla." Medical News Today. MediLexicon, Intl., 7 Mar. 2013
      Gregory D. Pawelski


        Companion Diagnostics for Kadcyla?

        The area of pharmacogenomics was ripe for proprietary tests invented alongside a drug and owned by the drug developer and/or a partner in the diagnostic field.

        HercepTest uses immunohistochemistry (IHC) analysis for the detection of HER2 protein over-expression in breast cancer. It measures the level of proteins in cancer cells providing clues about which therapies are "likely" to have clinical benefit.

        HER2 IQFISH pharmDX is a direct fluorescence in situ hybridization (FISH) assay, It uses breast carcinoma specimens (FFPE) stained with HER2 IQFISH pharmDX. FISH is used to examine gene copy number variation in the tumor.

        These tests serve as a companion diagnostic tool to identify cancer patients with HER2-positive metastatic breast cancer who "may" be eligible for Kadcyla treatment.

        Because the results of the IHC test can sometimes be ambiguous, many doctors suggest the FISH test for a second opinion. Tumors that are 3+ positive by IHC and those that test positive by FISH are most likely to benefit from HER2-inhibitors.

        Tumors that test 1+ by IHC are considered HER2/neu negative and those that test 2+ are considered equivical, in which case FISH testing is done to make the determination.

        Tumors that test negative for HER2/neu by FISH are "unlikely" to benefit from HER2-inhibitors.

        Either test examines "dead" tissue that is preserved in paraffin or formalin. According to a professor of translational genomics at the Scripps Research Institute, specimens obtained from biopsy or surgery are formalin-fixed, paraffin embedded (FFPE). FFPE ruins sequencing capabilities, denatures everything, and ruins the samples.

        How is that going to be predictive to the behavior of "living" cells in spontaneously formed colonies or microspheres? Can it describe the complex behavior of living cancer cells in response to the injury they receive from different forms of chemotherapy? There is a big difference between "living" and "dead" tissue.

        All the gene amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug inhibitor is better or wrose than another drug inhibitor which may target this.

        No gene-based test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs.

        The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems’ response to drug treatments, not just one target or pathway.
        Gregory D. Pawelski