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No Glee Over Gleevec

In late December 2002, the Food and Drug Administration (FDA) approved the drug Gleevec (also called imatinib mesylate or STI571) as a first-line treatment for patients with chronic myeloid leukemia (CML). CML afflicts about 40,000 people in the US. It is an unusual form of cancer in that its genetic origin is well defined. The genetic fault occurs when fragments of two different chromosomes break off and trade places, reattaching on the opposite chromosome. This results in the formation of a characteristically shortened chromosome -- the so-called "Philadelphia chromosome" -- which is unique to CML. This translocation of chromosomes leads to a certain blood cell enzyme, tyrosine kinase, being "turned on" all the time. As a result, white blood cells proliferate rapidly in the blood and bone marrow, eventually becoming life threatening. Gleevec was designed to turn off white cell tyrosine kinase.

In May 2001, the FDA rapidly approved Gleevec as a treatment for the advanced stages of CML. It was later approved as a second-line treatment for patients in the earliest stage of CML (called the chronic phase) after they no longer responded to standard interferon-alpha therapy. It has now been approved for virtually all CML patients. (It has also been approved as a treatment for a rare form of stomach cancer, gastrointestinal stromal tumor, or GIST.)

Back in 2001, the FDA said that further studies were needed to evaluate whether the drug provided a clinical benefit in CML, since there was no direct proof that Gleevec actually helps patients by alleviating their symptoms or extending their lives. As the manufacturer, Novartis Pharmaceutical Corporation, readily admitted:

"Accelerated approval of Gleevec was based on time to progression as the primary surrogate endpoint. Approval under these regulations requires further adequate and well-controlled studies to verify and describe clinical benefit. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival."

In his December 2002 announcement, FDA Commissioner Mark B. McClellan, MD, PhD, said, "Today's approval represents continued efforts by government and industry to provide patients suffering from CML with additional therapies that have proven safe and effective through ongoing research and clinical trials. With this new use even more patients will have access to this product earlier on in their fight against cancer."

Commissioner McClellan's statement certainly sounds like good news for patients with CML. But how accurate is it? Has Gleevec in fact been proven "safe and effective," as the FDA commissioner claims? If so, how safe? And effective to do what?

Improved Markers Versus Patient Benefit

In assessing the safety and effectiveness of cancer treatments, it seems self-evident that one should use a yardstick that measures patient benefit. Patients don't necessarily care whether a certain blood marker goes up or down. They want to be cured, or at the very least to obtain a meaningful extension of their life. And they almost always want to preserve or enhance their quality of life.

Yet the FDA's recent approval of Gleevec was based entirely on a clinical trial that measured improvement in "surrogate markers." These are not direct measures of patient benefit but simply test results that are supposed to correlate with patient benefit. The full data on this trial were disclosed on May 20, 2002, at the annual American Society of Clinical Oncology (ASCO) meeting in Orlando, Florida. It thus represents non-peer-reviewed data since, to my knowledge, it has not yet been published in a medical journal.

In this clinical trial of 1,106 patients with newly diagnosed CML, half of the patients were treated with Gleevec and the other half with what has been the standard CML therapy, a combination of the older drugs interferon and cytarabine. Those treated with Gleevec after one year had significantly fewer cancerous cells in their blood and bone marrow. The rate of disease progression was also decreased.

"The remarkable results from this trial show that Gleevec is ten times more effective than standard interferon therapy," enthused Brian Druker, MD, of the Oregon Health Science University, Portland, Oregon, and lead author of the study. The patients on Gleevec had a major (75 percent) or complete (54 percent) cytogenetic response (i.e., a reduction in the number of cancer cells in the bone marrow), while the patients on the standard two-drug combination showed only a 15 percent major response and a 3 percent complete response.

Does this mean that Gleevec was shown to increase survival in patients with CML? The answer is no. Although you might think that a decrease in cancer cells would necessarily lead to a meaningful increase in overall survival, this is not necessarily true. In cancer, all too often surrogate markers fail to correlate with any actual increase in survival.

So, why not just measure life prolongation? According to the FDA, since patients with CML often live for up to 10 years with their disease, the 14-month follow-up was simply "too short to measure long-term clinical benefits such as improved survival." While it may be true for those in the early, chronic phase of CML, there are more advanced phases of CML that could readily show whether or not the drug is effective at prolonging life.

To explain: CML occurs in three different phases: chronic, accelerated and blastic. In the chronic phase, there are less than 5 percent immature "blasts" in the peripheral blood and bone marrow. As the FDA correctly states, the severe form of the disease takes a long time to develop and survival in such cases would be difficult to measure. However, in the accelerated phase, there are between 5 and 30 percent immature blasts in both the peripheral blood and bone marrow, and in the blastic phase there are greater than 30 percent blasts in the peripheral blood and bone marrow. The "blastic phase" is a rapidly progressing form of the disease, and would be very amenable to tests of survival. Patients in a "blast crisis" generally do not live an average of 10 years. When the patient has entered a blast crisis, says the National Cancer Institute (NCI), survival is on the order of only a few months. Thus, the blastic phase of CML would be well suited to demonstrate the survival advantage of any new treatment, such as Gleevec.

In fact, according to the NCI, this question was addressed in an earlier phase I trial of Gleevec. In that study, just four out of 38 patients in a blast crisis had a complete hematologic remission while 17 had a decrease in blasts in the marrow to 15 percent or less. "Unfortunately," the NCI summarizes, "these responses have not been durable." In other words, cancer cells often develop resistance to this drug, as they commonly do to chemotherapy. Given its lack of durability, Gleevec cannot be deemed "effective" in the advanced phase of the disease, and there is no reason at this moment to conclude that Gleevec increases survival in CML.

A Safe Drug?

FDA Commissioner Mark McClellan implied that Gleevec has been proven safe. But safe is a relative term. Interferon has punishing side effects and so Gleevec might appear mild in comparison. However, it is not without serious adverse reactions. As the manufacturer's website states: "The majority of patients who received Gleevec in clinical studies did experience side effects." The most common were nausea (up to 71 percent of patients treated for CML), fluid retention (73 percent), muscle cramps (55 percent), diarrhea (55 percent), hemorrhage (52 percent), skin rash (44 percent), joint pain (36 percent), headache (34 percent), and indigestion (24 percent). Other side effects included fatigue, muscle and bone pain, vomiting and shortness of breath.

Serious and severe side effects were also reported with Gleevec, including liver problems and low levels of certain blood cells. According to a company document, 64 percent of those in the blast crisis experienced neutropenia, a serious or severe deficiency in white blood cells called neutrophils; 63 percent had another kind of white blood cell destruction, thrombocytopenia; and 52 percent developed anemia of the red blood cells. Gleevec was discontinued due to side effects in 5 percent of those in blast crisis. The company also states that "there are no long-term safety data for Gleevec available."

FDA approval was a generous Christmas present for Novartis. Online pharmacies have "discounted" each 100-milligram capsule to around $17. At a dose of 600 mg per day, this works out to $100 per day, or around $36,500 per year. If every CML patient in the US were to take the drug, this would represent around $1.46 billion in Gleevec sales for Novartis. Not bad for a drug whose effects on survival remain unproven.

Double Standard

Some readers have written to me with enthusiastic anecdotes about their responses to Gleevec. The drug has given a lot of hope and perhaps will eventually be shown to be life extending. I certainly would not want to deny even a glimmer of hope to any cancer patient. What irks me is not so much the hype surrounding Gleevec, but what its swift approval reveals about the double standard in the appraisal of new cancer treatments.

Drugs that are sponsored by big pharmaceutical companies are given first consideration and accelerated approval, then are praised to the skies by an alliance of company publicists, enthusiastic scientists, government officials and compliant media. (Gleevec has been featured on the cover of Time.) But when it comes to treatments that originate from individual entrepreneurs or small companies, suspicion reigns. Innovators are often ignored or harassed, and this is especially so if they happen to come from the field of complementary and alternative medicine (CAM).

Novartis's website for Gleevec contains patient anecdotes, but no data showing that the drug extends life. Yet the standard comeback to therapeutic claims coming from entrepreneurs is, "All you are presenting are anecdotes. Where are your randomized controlled trials proving the safety and efficacy of your alleged treatment?"

Unlike "Big Pharma," the entrepreneur is expected to perform to impossibly high standards. If these innovators have the temerity to submit their cases to the government, and they are accepted for review, they will be gone over with a fine-toothed comb. The slightest imperfection suffices to nullify the validity of the claim.

It is no wonder that neither the NCI nor the FDA has ever validated or approved an alternative, or nontoxic, method of treating cancer. Yet, at the same time, we have the bizarre spectacle of huge companies being allowed to market toxic drugs in the complete absence of any proof of life extension!

The cost of developing a new drug has escalated in recent years, which further keeps entrepreneurs from competing with "Big Pharma." To develop a new drug cost $54 million in 1979 and $231 million in 1991. Today, according to the Tufts Center for the Study of Drug Development, the average cost has skyrocketed to $802 million per drug. Those who cannot ante up this kind of money are relegated to the sphere of nutritional supplements and alternative medicine.

Our civilization is supposed to be based on equal justice under the law. But where is the equality, when independent inventors are held to impossible standards, while "Big Pharma" gets by with a wink and a nod? This situation makes a mockery of equality. Or, as Anatole France said many years ago, "The law, in its majestic equality, forbids the rich, as well as the poor, to sleep under the bridges, to beg in the streets, and to steal bread."

Best wishes to you and yours for a Happy New Year!

--Ralph W. Moss, Ph.D.

References:

Gleevec pilot study: Druker BJ et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med, 2001;344:1038-42.

Gleevec randomized trial: Druker BJ. STI571 (Gleevec/Glivec, imatinib) versus interferon (IFN) + cytarabine as initial therapy for patients with CML: results of a randomized study. Abstract #1 presented at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 20, 2002.
http://www.asco.org/ac/1,1003,_12-002324-00_29-00A-00_18-002002-00_19-001,00.asp

Gleevec approved for first line treatment of chronic myeloid leukemia (CML). Food and Drug Administration press release, December 20, 2002.
http://www.fda.gov/bbs/topics/NEWS/2002/NEW00860.html

Gleevec confirmed as superior over conventional treatment for CML. National Cancer Institute, May 20, 2002. http://www.nci.nih.gov/clinicaltrials/results/gleevec-superior-for-cml0502

Chronic myelogenous leukemia stage information. National Cancer Institute. http://www.nci.nih.gov/cancerinfo/pdq/treatment/CML/healthprofessional/#Section2.1

Tufts Center for the Study of Drug Development pegs cost of a new prescription medicine at $802 million. Tufts Center for the Study of Drug Development, November 30, 2001. http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6

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The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.