Gene Breakthroughs Spark a Revolution in Cancer Treatment
"Maybe three months," he told her in his office one sunny May morning in 2010, she recalls.
Yet she is still alive, a testament to the most extraordinary decade of progress ever in the long scientific struggle against lung cancer.
Tests found Ms. Carey's lung cancer to be of a rare type that researchers had found just three years earlier by deciphering its genetic code. The 45-year-old businesswoman in 2010 went on a drug Pfizer Inc. PFE +0.27% was testing for that type. By pinpointing her cancer, the drug probably helped give her years more to live than chemotherapy would have, her doctors say
That is remarkable because lung cancer for decades defied efforts to find drugs that could extend an average patient's life by even a few weeks.
But an explosion in knowledge about the genetic mutations that cause tumors is just now offering the first real promise of drugs that can control what is the most-common and most-deadly cancer.
Ms. Carey has one of at least 15 lung-cancer variations, almost all of which scientists didn't know existed 10 years ago. Researchers have identified those variations, most of them in just the past four years, by decoding DNA in tumors—akin to how crime labs analyze DNA to genetically fingerprint suspects.The drugs don't cure cancer and face significant hurdles. But doctors now talk of a "precision medicine" approach in which those pinpoint drugs can treat tumors far more effectively than catchall chemotherapy.The newfound variants have led major cancer centers to revamp their approach to treating cancer and have spurred a rush among drug companies to find medicines that narrowly target each one.
"What we're seeing is the beginning of a revolution in therapeutics," says Janet Woodcock, director of the Food and Drug Administration's Center for Drug Evaluation and Research. "We can only hope that this gets us to where cancer is managed or curable."
Among signs that revolution really is afoot: A June 2013 study found that lung-cancer patients who were treated with drugs targeted at their genetically identified varieties lived 1.4 years longer than patients on chemotherapy whose cancers weren't genetically identified.
In effect, lung cancer is no longer a few common diagnoses. Instead, it is a growing list of rare cancers, each a target for its own drug regimen.
"It's likely that more than half of tumors have some alteration we can target with a drug," says John V. Heymach, a lung-cancer specialist at MD Anderson Cancer Center, Houston. "They may not all have the same success, but we know that in many cases, a targeted agent will work very well."
The same goes for other malignancies: Scientists have decoded tumor DNA from breast, colon, kidney, skin and other cancers in recent years to discover scores of variations they didn't know existed before.
Research hospitals like MD Anderson, Vanderbilt University and Massachusetts General Hospital are among a growing number of cancer practices that routinely decode the tumor DNA of most patients with advanced cancer.
The lists of newfound variations have invigorated the drug industry, with companies like Pfizer, Roche Holding AG ROG.VX +0.38% and Merck MRK -0.08% & Co. racing to develop drugs that target each one.
Last year, nearly 1,000 cancer drugs were in clinical development, up 52% from 2006, says the Pharmaceutical Research and Manufacturers of America, a trade group. The "vast majority" of that growth is from drugs targeted at genetic mutations, says Bill Chin, the group's head of science and regulatory affairs.
Three drugs are on the market for newly discovered lung-cancer mutations. Dozens more are in clinical trials. Some approved for other cancers appear effective for specific lung cancers. And drug companies are targeting other mutations of all cancer types.
At least half the 27 medicines on Novartis AG's NOVN.VX +0.74% current list of oncology drugs in clinical development target cancer mutations. Precision medicine is "fundamentally changing the way we think about cancer drug development," says Hervé Hoppenot, president of the company's Novartis Oncology unit.
Just last year, the FDA established a "breakthrough therapy designation" to hasten approval of experimental drugs that show striking benefits in early trials, including those targeted at cancer mutations.
Ms. Carey's diagnosis in 2010 came just as that thinking was starting to change. Her roller-coaster ride of cancer remission and recurrence over the next three years shows the promise and shortcomings of precision medicine.
Ms. Carey, who worked for a business selling private jets, suffered an apparent seizure at her gym. Doctors discovered a nodule in her lung of cancer that had spread to her brain. Surgery and radiation treated the brain tumor.
But when the New York City resident's doctor said she probably had three months left, "I definitely felt like there were no options," she says.
It wasn't an unusual prognosis for lung cancer in 2010. Three decades of research starting in the 1970s into hundreds of potential lung-cancer drugs had produced dismal results, says MD Anderson's Dr. Heymach: Over that time, a lung-cancer patient's median survival improved by just one month, to eight months.
Ms. Carey found hope in news accounts of a drug Pfizer was testing against a cancer type researchers had identified in 2007. The type was caused by a mutation in the so-called ALK gene—it normally plays a role in brain development—and Ms. Carey wanted to know if that was her cancer.
In 2010, precision medicine was still so nascent that Ms. Carey had to show unusual persistence. Few doctors even considered testing tumors for mutations.
She says she had to demand the test. "Are you helping to save my life," she recalls asking her doctor at the time, "or just waiting for me to die?"
That ALK-gene mutation was only the second mutation researchers had identified using advanced DNA-sequencing technology on lung-cancer tumors. The first was in 2004, a mutation in the so-called EGFR gene that responded well to an existing drug, Tarceva, now sold by Roche. (Another mutation, KRAS was discovered previously, with earlier technology.)
The discovery of the role of the EGFR mutation in 2004 sparked the search for more cancer-causing mutations.
Before that, a pathologist would identify a patient's lung-cancer tumors through a microscope to see if they were of the "small-cell" or "non-small-cell" variety. The difference helped determine which regimen of chemotherapy to prescribe.
After finding the ALK-gene mutation, researchers in 2007 found another mutation. By 2010, for a few lucky patients whose tumors proved to be of the newly discovered varieties, there were a few drugs on the market or in trials.
Ms. Carey was among the fortunate: Her mutation proved to be of the ALK gene, which represents about 5% of lung-cancer cases.
The discovery of the ALK-gene mutation had prompted Pfizer to test a drug already in its portfolio, brand-named Xalkori and generically called crizotinib, to see if it worked on the mutation. Pfizer's study of the first patients showed dramatic results, which Ms. Carey read about.
Again, Ms. Carey needed persistence, this time to get the drug. She visited different sites participating in Pfizer's trials before finding a slot at the University of Chicago.
Within six weeks, two of three cancerous nodules in her lungs had disappeared, and the third had shrunk significantly.
The FDA approved the Pfizer drug in 2011 based on 250 patients, four years after the ALK-mutation link was discovered. That is lightning speed in an industry accustomed to spending a decade with thousands of test subjects to get drug approval.
Ms. Carey in 2011 began buying the Pfizer drug by prescription. It was expensive—today Pfizer charges $10,800 a month for it—but her insurance covered it.
Prices like that raise questions about the affordability of precision medicine. But those prices, and the speed at which genetically targeted drugs can come to market, had begun changing the economics of drug development.
The "precision medicine approach requires people to change the way they look at opportunities," says Mace Rothenberg, a senior vice president who heads cancer clinical development for Pfizer. Instead of trying to apply a drug to the largest number of patients possible, it is possible to "demonstrate very significant value of the drug to the patient, the physician, the payers and the company."
Discovery of new mutations accelerated. A 2011 report linked a mutation of a gene called RET to lung cancer, prompting researchers at Memorial Sloan-Kettering Cancer in New York to approach Exelixis Inc. EXEL -0.61% The South San Francisco biotechnology company was developing a drug called cabozantinib to treat a rare form of thyroid cancer linked to the RET mutation.
That mutation is found in only about 1% of lung-cancer patients, but Sloan-Kettering launched a drug trial. The first few patients tested had striking benefits. "These were patients who had nothing six months earlier," says Mark Kris, a lung-cancer specialist at Sloan-Kettering.
Discovery of still-more lung cancer mutations continued in rapid fire. The count is 15 today, accounting for about 60% of all lung cancers, according to some estimates, and researchers expect to find more.
Precision medicine is no cure. A tumor with a pinpointed mutation doesn't always respond to a drug targeted at it. The drug often shrinks tumors within weeks. But the tumors can develop resistance and come roaring back.
Ms. Carey's cancer found a way around the treatment, in early 2012. An analysis of her tumor found the ALK-gene mutation still active. She took to calling her mutation the "Darth Vader of cells."
Doctors think most patients will need a series of precision drugs, sometimes with chemotherapy. "The tumor will keep evading our best therapies," says Trever Bivona, a lung-cancer researcher at University of California San Francisco. "Ultimately we're going to have to get to combination approaches." exdiscovery of new
Ms. Carey in the spring of 2012 went off crizotinib for another regimen of brain radiation, then went back on the drug.
By that year, interest was surging among drug companies in targeted drugs. At least three "next-generation crizotinibs" against the ALK-gene mutation were now in trials. Ms. Carey entered a trial for one of them, being developed by Ariad Pharmaceuticals Inc. ARIA +0.27%
Not all patients can find a trial. Precision drugs are approved for only two lung-cancer mutations, the ALK and the EGFR-gene mutations. A patient with a different mutation must look for a drug in development and try to join its trial.
Dr. Bivona of University of California San Francisco says he treated a patient this year who died a month before the launch of a clinical trial for a drug that matched the patient's mutation. "We were in a black hole," he says. "Getting drugs to the patients who need them will take an entire remodeling of the drug-development system."
While there are drugs approved for other cancers that appear effective for some newfound lung cancers, insurers generally feel data don't yet justify coverage of such "off-label" drugs. And for several of the 15 known lung-cancer variants, an especially promising drug has yet to emerge.
Tests for mutations are less likely to be available in smaller doctors' offices. Even many large centers are just putting in place systems to act on the information. "A lot of places can tell you they do this now, but few really have the people in place who know what to do," says Roy Herbst, chief of medical oncology at Yale Cancer Center, New Haven, Conn., who is Ms. Carey's current oncologist.
But rapid diagnostic advances are making it easier for any doctor to test for the newfound cancers. Tests now can hunt for more than 200 mutations—of lung and other cancers—in one biopsy.
Evidence that precision medicine works will likely broaden its use quickly. A June 2013 report on 1,007 patients with advanced lung cancer whose tumors were sequenced by a group of researchers called the Lung Cancer Mutation Consortium found that 62% had alterations suspected of being driver mutations.
The researchers reported that the 265 patients on the study treated with a targeted drug had a median survival of 3.5 years from diagnosis, compared with 2.1 years for the 361 patients for whom a mutation wasn't identified.
"It opens up so many more doors for patients if you can find their target," says Alice Shaw, an oncologist at Mass General in Boston.
At Ms. Carey's checkup late this July, her doctor said her new drug regimen is keeping her lung tumor from progressing.
She is also considering a new class of drugs called PD-1 inhibitors that enlist the immune system. Such agents from Merck, Roche and Bristol-Myers Squibb Co.BMY +0.51% are creating a buzz among oncologists for use in parallel with the genomic strategy.
"Now when I look back, I'm astonished at the timing of everything," she says.
"My quality of life is extraordinary," she says. "The science in this and the positive response I've had—I wouldn't be alive without that."
Write to Ron Winslow at ron.winslow@wsj.com
A version of this article appeared August 12, 2013, on page A1 in the U.S. edition of The Wall Street Journal, with the headline: Gene Breakthroughs Spark A Revolution in Cancer Treatment.
Posted with Blogsy
No comments:
Post a Comment