Trastuzumab Emtansine (T-DM1) Significantly Improves Breast Cancer Survival

[News]

The investigational drug, Trastuzumab Emtansine (T-DM1), improves survival of patients with HER2-Positive metastatic breast cancer "significantly", Genentech Inc. announced today as it published highlights of its Phase III EMILIA study results. T-DM1 was compared to lapatinib and Xeloda (capecitabine) combination therapy...

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[MJsHusband]

From the article:

"The EMILIA study has met both of its co-primary endpoints: progression-free survival and significant improvements in overall survival, the company added."

Does anyone know the details about what "significant" means for the results of this trial?

[gdpawel]

The concept of "statistical significance" is so difficult to understand that misunderstandings are forgivable, suggests Donald Berry, a biostatistician at the University of Texas M.D. Anderson Cancer Center. Carl Bialik of the WSJ asked several statisticians to offer definitions of "statistical significance."

Shane Reese had the briefest one, tailored for a clinical trial for a drug: “It is unlikely that chance alone could have produced the improvement shown in our clinical trial. Because it seems unlikely that chance produced the improvements, we logically conclude that the improvement is due to the drug.” Reese and other statisticians noted that this definition is backwards: It is based on assuming there is no link, then finding the probability that chance alone could have produced the experimental results seen.

Reese and Brad Carlin, who also offered a definition, suggest that Bayesian statistics are a better alternative, because they tackle the probability that the hypothesis is true head-on, and incorporate prior knowledge about the variables involved.

There are other problems with "statistical significance." It can be ill-suited to cases where it is unclear if all data is being collected, such as with the reporting of adverse events experienced by users of a drug that is past the clinical-trial stage, or never had to go through clinical trials, and is now on the market. In such a situation, “you have to make a lot of assumptions in order to do any statistical test, and all of those are questionable,” said Susan Ellenberg, a biostatistician at the University of Pennsylvania’s medical school.

“Every statistical test relies on half a dozen assumptions,” echoed Aris Spanos, an economist at Virginia Tech. “Before you use that test, you have to check your assumptions.”

Spanos wishes the Supreme Court had gone further in its recent ruling, in which it determined that a lack of statistical significance didn’t always provide drug companies with enough cover to avoid disclosing reports of adverse events from users of their drugs. Spanos would have liked to see more guidance for how to proceed without relying strictly on statistical significance. “It was a move in the right direction but then you open the system to different kinds of abuses,” Spanos said.

The U.S. FDA also doesn’t use such a black-and-white rule. In January the FDA warned women who have gotten breast implants or might get breast implants, because of an elevated risk of the rare cancer anaplastic large-cell lymphoma. The FDA did so even though the link wasn’t statistically significant, in part because the agency reasoned that perhaps not all such incidents were reported. “It underscores the importance of not solely relying on a statistical test to tell you there is a public-health issue,” said William Maisel, the chief scientist for the agency’s Center for Devices and Radiological Health.

There also are cases where seemingly statistically significant results aren’t, statisticians say. For example, a very large sample size reduces the effects of statistical noise, so it can yield very high levels of significance for fairly minor relationships, or roughly speaking, a large degree of confidence in the existence of a very small effect.

Checking for lots of potential effects can also lead to results that appear to be statistically significant, but aren’t. “In the early days of clinical trials, it wasn’t unusual for people to keep looking at data as they go along,” said Ellenberg. “It was a fishing expedition, completely subverting the whole notion of chance findings.”

Also, a "statistically significant" effect may not matter much in practice. “Statistics and value judgment belong to different domains,” Siu L. Chow, professor emeritus in psychology at the University of Regina in Saskatchewan, wrote in a written response. “It follows that statistical decision and assessment of substantive impact have their own respective metrics. Hence, it is incorrect to use "statistical significance" or any other statistical indices (e.g., effect size) to index real-life importance.”

Stephen Ziliak, an economist at Roosevelt University in Chicago, and co-author of the 2008 book “The Cult of Statistical Significance” with Deirdre McCloskey, an economist at the University of Illinois at Chicago, said he would like to see large effect sizes reported even when they are not statistically significant. Researchers “probably ought to go ahead and report what happened anyway,” Ziliak said. “There’s probably a lot of stuff out there that didn’t see the light of day.”

Stephen Stigler, a statistician at the University of Chicago, agrees with the general premise that “you can have a real effect which is nonetheless trivial in the practical sense.” He doesn’t think this is widely misunderstood, though: “I don’t think in science we generally sanction the unequivocal acceptance of significance tests.”

Ziliak disagrees, saying in his book: “It is passionate in the sense that we do reveal anger. We had collectively been working on this issue in a calm fashion for 45 years. We deserved to open up the conversation a little more widely in this way.”

http://blogs.wsj.com/numbersguy/a-st...-closeup-1050/

For an amusing take on statistical significance.

http://xkcd.com/882/

T-DM1 Anitbody-drug conjugates (ADCs)

http://cancerfocus.org/forum/showthread.php?t=3768

I heard women 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 patients there were?

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.

[gdpawel]

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.

http://www.fda.gov/NewsEvents/Newsro.../ucm340704.htm

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.

http://cancerfocus.org/forum/showthread.php?t=3768