Cancer Med Labels May Reflect Genetic Issues
5 CommentsBy Ed Silverman // December 12th, 2008 // 4:07 pm
Drugmakers may be forced to change prescribing info on cancer meds already being sold in the US to advise patients that some treatments won’t work in people who carry certain genes, Bloomberg News writes.
Prescribing drugs on the basis of genetic profiles can limit use of medicines to patients who will benefit most and increase their safe use, FDA staffers wrote in briefing materials for an advisory committee meeting on December 16. The change may also hinder sales of drugs that previously might have been given to more people, just on the chance they may work.
The meeting is being held to discuss whether to recommend that doctors screen patients for the so-called KRAS gene mutation before prescribing Erbitux, which is marketed by Lilly and Bristol-Myers Squibb, and Amgen’s Vectibix, which are used to treat colon cancer. The drugs, which cost $8,000 to $10,000 a month, don’t work in people with the mutation.
“We’re going to see this story played out over and over again,” Richard Schilsky, a University of Chicago cancer specialist who is president of the American Society of Clinical Oncology, tells Bloomberg. “This is the kind of change that’s about where cancer drugs should be moving. They shouldn’t be used in those with no chance of benefit.”
Researchers estimate 40 percent of colon cancer patients have the KRAS mutation, which would make them ineligible to get Erbitux or Vectibix. Prescribing according to the mutation may not necessarily reduce Erbitux sales, as more patients would be tested and the pool of individuals that would benefit from the drug may increase, Les Funtleyder, an analyst with Miller Tabak, tells Bloomberg.
Last year, Erbitux generated $1.3 billion in sales and Vectibix rang up $170 million. Almost 150,000 people in the US will be diagnosed with colorectal cancer this year, according to the American Cancer Society data cited by Bloomberg.
Testing for a genetic variant known as HER-2 is already required for Genentech’s Herceptin breast cancer med, which treats tumors that produce too much of the HER-2 protein. The KRAS discovery came after Erbitux and Vectibix were on the market - in the US, Erbitux was approved in 2004, and Vectibix in 2006.
“An ideal scenario is one in which the relationship of the biomarker to potential action of the drug is recognized very early - indeed, such a relationship might be the motivation for starting the drug’s development,” FDA reviewers wrote in briefing documents. “The ideal scenario is a rarity to date.”
In studies, Erbitux and Vectibix reduced by 30 percent the risk that colon cancer worsened. Subsequent analyses found patients with a normal KRAS gene did much better than those with mutations. “The consistency across studies makes this data really strong,” Fouad Namouni, executive director of oncology for Bristol-Myers Squibb, tells Bloomberg. Reducing by 40 percent the number of patients who spend on those drugs may benefit “society at large.”
“The whole concept of proper genetic markers is not to put people in the position of having to receive toxic medicines if they’re not going to do any good,” Ira Loss of Washington Analysis tells Bloomberg. “The FDA probably feels that’s an improvement over giving it to everybody and hoping for the best.”
The National Comprehensive Cancer Network recommended genetic screening last month because of the studies. Tests for the KRAS mutation involve analyzing a sample of tissue from a patient’s tumor. The effort is also part of an FDA drive to identify which genes interact with drugs. A few meds already require genetic testing before being prescribed, and the FDA created an initiative to discover more.
In July, Bloomberg points out, the FDA recommended testing patients for a gene, called HLA-B-5701 that causes a reaction in patients taking Glaxo’s Ziagen AIDS drug. Last month, the agency reported that people with a gene dubbed HLA-B-5702 have an increased risk of skin reactions from Pfizer’s seizure drugs Dilantin and Cerebyx.
Here are the documents filed by Amgen and Lilly’s Imclone.
Greg Pawelski
Mutations in the gene KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. The change of a single base in DNA that encodes the mutant EGFR protein has been shown to cause drug resistance.
Tumor cells from patients who develop secondary resistance to a drug like Erbitux after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells have new mutations in EGFR. Drug resistance evolves by multiple mechanisms. This further indicates that secondary resistance is very different from primary resistance.
However, all the EGFR mutation or amplification 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 is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.
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.
No genetic profile test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available it identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs.
former marketing exec
This is a good thing and I applaud it. These cancer drugs, from what I have learned, are very expensive and if specific molecular testing up front can save money and precious time to ensure that a patient is started on the right therapy up front - then I say let’s do it.
Lately I have heard of a few stories of patients eroding their insurance caps until it was discovered that they were on the wrong treatment. Very often the disease can become even more resistant to other therapy making the chances for other therapies to work, less likely.
Drugs aside, this shows how far technology has come. With a variety of drugs to choose from, maybe it is not so impossible that patients will be much better matched to their therapy and therefore improve the odds for all patients.
Refreshing news in such dire economic times.
Bravo!
Greg Pawelski
I wholeheartedly agree, patients should be much better matched to their therapy and therefore improve their odds. However, molecular testing doesn’t tell you if one drug is better or worse than some other drug which may target a mechanism/pathway. There are differences.
Functional profiling with cell-based testing measures the response of the tumor cells to drug exposure. Following this exposure, it measures both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome.
No matter which genes or proteins are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive ore dead. This kind of testing can save money and precious time to ensure that a patient is started on the right therapy up front.
Insider
Unfortunately I’m afraid this type of information may be of has been applied selectively. If companies can show efficacy without testing they will, then when the patent life is running out we may see new information with drug-device co-labeling. Companies have been collecting genetic information for more than a decade. In spite of the fact that they were required by law to submit all information related to safety. Which this does fall under. Companies in the interim arranged with FDA to have a safe harbor to submit this genetic information to develop standards for approval and safety testing without it being revealed to the review staff under the voluntary genomic submission guidance (VGSG). While I agree with this approach for the future I’m afraid of the likely probability that during the past several years there has been a delay in release of critical information like this until it’s financially convenient. Even if the tests themselves were not ready for commercial sale we don’t know that this type of knowledge might have lead to switching therapies in the absence of a response for this or other conditions.
Salmon
Gregory D. Pawelski
I would not want to be denied treatment with EGFR antibody therapy because of KRAS gene testing. KRAS gene testing for EGFR is not a clear predictor of a lack of benefit from EGFR antagonist antibodies in colon cancer.