The FDA Approved It Immediately
Derek Laurie was working as a tow truck driver, living in a suburb outside Rochester, New York, and supporting two small children. It was tough work. He climbed under wrecked vehicles, or swam into ponds. So he thought the pains were pulled muscles. Maybe he was drinking too much beer. He stayed in denial until the tumor was pressing against his spine and he couldn’t walk. When he finally went to an emergency room in Rochester, he was told he had stage IV cancer and a year or two to live.
“They still don’t know where it came from or why it came,” says Laurie, 28. “Nobody knows why it is. They just know it’s an ugly gene in your body that makes you die.”
His fiancée wouldn’t accept that there was no hope. They went to two other hospitals before she found a rare tumor clinic in Greenville, South Carolina. They sold their house, his snowmobiles and most of their possessions and moved into a trailer near the clinic. There, the DNA of his tumor was sequenced, and he was entered into a clinical trial for an experimental drug called larotrectinib. He felt better within a day. Within 72 hours, he no longer needed a cane. Within two weeks, he was walking around Manhattan on his monthly clinical trial visits, playing with his kids and eating like a champ.
Laurie’s experience isn’t unique. Results in the first 50 patients treated with larotrectinib are being presented today at the annual meeting of the American Society of Clinical Oncology, the biggest gathering of cancer doctors. Of those 50 people, 38, or 76%, had clear shrinkage of their tumors. Of those, 30, or 79%, hadn’t had their tumors start growing or had new ones appear after 12 months of treatment, and are still on the drug. (Data on another five patients is also being presented, although Loxo is waiting for confirmatory scans. All five seem to have responded.)
A Different Way To Think About Cancer
“It looks great,” says Brian Druker, director of the Knight Cancer Institute at Oregon Health & Science University and a pioneer of gene-targeted cancer drugs. The big question, as with all these drugs, is how long the tumors will continue to respond to the medicine. But the new study represents a big change from when Druker helped develop the first major gene-targeted cancer pill, Gleevec, two decades ago. The 50 patients who’ve taken larotrectinib so far had 17 different kinds of tumors. These patients weren’t selected for where their tumor was, but whether it had a particular mutation in a gene called the tropomyosin receptor kinase gene, or (TRK).
In the words of the study’s lead author David Hyman, chief of early drug development at New York’s Memorial Sloan-Kettering Cancer Center, this embodies “the original promise of precision medicine”: That every cancerous tumor will someday be treated based on its genetics, not where a tumor is found in the body. That this has happened at all, Druker says, tells us how far the twin fields of genetics and oncology have come in two decades.
But the results are also a testament to larotrectinib’s maker, a small Stamford, Connecticut-based company called Loxo Oncology that has broken the rules of drug development. Loxo was willing to focus on TRK mutations when they are involved in as few as 0.5% of cancers. It has moved mountains to find these patients and get them its medicine, so that it can prove the treatment works. And it has, in another first, already started development of a second drug that may help people whose cancer outsmarts larotrectinib survive longer, and tested it on two patients in its original clinical trial. Still, stalking behind this success is the inescapable specter of a disease that has haunted humanity from its beginning, with its ability to disrupt lives, steal hope and kill.
Focusing On What’s Rare
Loxo Oncology was founded in 2013, the brainchild of an oncologist named Joshua Bilenker, who was then working as an investor at Aisling Capital, a private equity firm. Between 2004 and 2006, Bilenker had served as a reviewer in the oncology division of the Food and Drug Administration, working on applications for new uses of cancer drugs like Rituxan and Herceptin. But he was finding the role of an investor too passive. The companies that you want to put money in, he says, are by definition not those that need you to take a hands-on approach.
Bilenker’s idea for a company was simple: focus on cancer drugs that could “kill it” early with amazingly clear results, even if they only addressed rare diseases. One key area: tumors caused by genetic changes in which a gene that’s usually not in use gets turned on because it’s gotten permanently connected–scientists say “fused”–to another gene that’s not supposed to turn off. This is what happens with cancers driven by TRK. Loxo contracted with another company, Array BioPharma, to design its medicines and moved quickly toward clinical trials.
But TRK fusion cancers were so rare that a lot of the moves companies do make their studies more likely to succeed–for instance, excluding very sick patients–just wouldn’t fly. George Demetri, an oncologist at the Dana Farber, says he screened more than 200 patients just to find two with TRK mutations. One went in Loxo’s trial, one to another TRK drug being developed by a rival, Ignyta.
“A lot of big companies would say there is only downside. Why don’t I cherry pick my first cases?” Bilenker says. “That’s the perverse logic that dominates our industry. We’re proud of this, so I’m bragging about it a little bit. We’ll run through a cinderblock wall to get to a patient.”
Derek Laurie had moved to another state to get care. Yet to receive Loxo’s drug, he travels to Manhattan–four hours from where he grew up–every month on Loxo’s dime. “You get an email or a phone call: such-and-such patient was identified in Alabama, in Brazil, in wherever,” says Memorial’s Hyman. “Every one of those cases was an adventure. Every one presented another challenge to getting a patient on the study. We had people coming in the dead of winter in New York from climates where they didn’t own coats.”
Smart Drugs, Smarter Tumors
One of the sad realities of gene-targeted cancer drugs has been that their effects don’t last. This was least evident with Gleevec, the drug Druker developed, in chronic myelogenous leukemia. It stayed effective for years. But when Gleevec was tried in another disease, a type of gastrointestinal tumor, patients often relapsed in just a few years. Other drugs seemed even more capricious. Zelboraf, for melanoma, makes tumors vanish only to have them almost always come back in exactly the same place.
The solution? Usually developing another similar drug, or a second medicine that can be added to the first. But even though the need for such a medicine is a foregone conclusion, companies traditionally don’t start on the second drug until they have finished with the first. Druker remembers that with Gleevec in gastrointestinal tumors, it took three years to even figure out why the tumors were becoming resistant, and another three years to get medicines. Pfizer’s Xalkori was approved for certain lung cancer patients in 2011; second-line drugs, from multiple companies, are emerging now. This was another rule Bilenker wanted to break. He started on a second-line drug that could be used on the patients in the first clinical trial.
Too Often, Cancer Still Wins
Loxo hasn’t gotten to test this second medicine, Loxo-195, much yet, because larotrectinibis working so well. Of the 50 or so patients treated so far, six have relapsed. Two of those had new tumors that could be removed, and have stayed on larotrectinib. Two were in places where they could not be reached before they died. The other two received the new drug, and saw their tumors shrink again.
That sounds like a happy story. But it still involves an element of tragedy. I wrote about Loxo’s drug last April, and about one of the first patients to receive larotrectinib: a Florida toddler named Carina. Her parents, Christy and Joe, asked that I not use their last name, but I spoke to them again for this story.
Carina had large mass on her face and neck. Surgery to remove it involved removing much of her jaw. But with larotrectinib, Carina was doing great. She was receiving speech and feeding therapy, and a swallow study was going to be done so her tracheostomy tube could be removed. In July, Joe and Christy threw a party for Carina’s second birthday, and Christy announced her second pregnancy. Two days later, Christy was cleaning out Carina’s mouth and noticed something growing where the tumor had been before. A scan confirmed the cancer was back.
Carina got chemotherapy to slow the tumor’s growth while Loxo asked the FDA to let it try Loxo-195 in this little girl. In October, Carina got the drug, and her tumor shrank away again. Christy had her second baby, a boy, in mid-January. “I knew from the past that was it,” Christy says. “This was the last resort.”
Radiation was the only option if the tumor came back, and most doctors had cautioned Christy and Joe that it would be too harsh in a child so young. They held onto hope because at first the tumor was too small to be seen on imaging scans. The whole time, Carina was happy, a playful two-year-old. Then, one morning, she woke up and wasn’t herself. A chest X-ray revealed her lung was full of fluid. In the fluid were cancer cells. The tumor had spread. Carina passed away on March 8.
Hope, Tragedy And Hope
Despite what they’ve been through, Joe and Christy still see the Loxo drugs as a gift. “The recurring side effect we saw was happiness,” Joe says. “It made her just excited to see the world, and playful.” They were able to bring her in the water to play in the pool. When they had entered their baby in a clinical trial, it had seemed a frightening thing. Now, Christy says, she hears talk about clinical trials and things that even for people who die, a new medicine could offer better quality of life than chemo ever offered. “Those drugs doubled her lifespan,” Joe says. “That time that they gave her was the best she ever had.”
They both feel a personal connection to Loxo now, noting that two company representatives even came to Carina’s memorial service. “She wasn’t just another patient to them,” Christy says. “They really did care about her.”
Derek Laurie expresses similar feelings, saying he hates the bad reputation pharmaceutical companies have. “I have so much faith in this system,” he says. “It saves lives. And I’m really tired of the misconceptions that are out there. If there was more funding for more clinical trials to target more mutations for more cancers, then more lives would be saved.”
But while the efforts to create larotrectinib were driven by a desire to help patients, they were fueled by the fact of high drug prices and the possibility of profit. Josh Bilenker could not have developed this drug if he had stayed at the FDA instead of going to an investing firm. Nor would he have been able to fund this effort working at the National Cancer Institute. Memorial Sloan Kettering would not have invented the drug on its own. As of its last financial report, Loxo had $240 million in the bank. That kind of money comes from investors who expect to be paid back, and then some.
Who Should Pay To Speed Drugs To Market?
Although there will first have to be re-reviews of patient scans, it’s very likely that the data presented today will result in larotectinib being approved in the U.S. It will be a historic first. The FDA recently approved Merck’s Keytruda for use in any patients whose cancer shows a particular mutation, but Keytruda is already widely used. This would be the first time that a drug was approved just for a mutation, not for cancer in a particular location of the body.
But in some ways that’s more a change in how we think about studying drugs than the drugs themselves. Druker points out that you could have done the same thing with Gleevec 20 years ago, having one effort that found patients with leukemia, intestinal tumors and skin cancer. Gleevec made tumors shrink in all of them. The exception is with Zelboraf, which shrank tumors in melanoma but not in colon cancer. The reason that it could not be done before was that finding patients was so hard.
What really enables this kind of work is the ability to do genetic testing of patients, something that centers like Memorial do routinely. But our system right now is so absurd that a patient like Derek Laurie has to move to another region of the country and then travel back close to where he was before in order to be in the study.
The obvious solution is for patients to have their genes tested routinely, and for clinical trials to be available at far more places. But that is infrastructure we don’t have. So it falls to companies like Loxo and researchers like Memorial’s Hyman to push the boundaries of what we can do, to figure out how to develop medicines faster.
In some ways, this makes sense. No one is more motivated to get things done than someone who believes they can save lives by lining their own pocket. Right now, this is a wonderful thing to behold. But things change when drugs go from being experimental to marketed, and companies not only want to make sure that patients get them, but also that someone–usually insurance companies and governments–pays. Remember, the starting price of a new cancer drug is $100,000 per year and up. (Another issue for investors in Loxo, which is publicly traded: potential competition from Ignyta, the other company with a TRK drug.)
The need to pay for things can make life uncomfortable. No one talked more passionately about the bounds between a patient and a drugmaker than Leonard Bell, the founder of rare disease firm Alexion Pharmaceuticals, which charges as much as $700,000 a year for its rare-disease drug Soliris. These days, Alexion is in hot water over concerns its marketing went too far.
Loxo will have to deal with more of the system’s inefficiencies when its drug launches. The types of genetic tests used to identify TRK mutations in its study are not widely used enough; it is developing other tests that can be more quickly adopted.
But right now, we are paying for the disorganization of our healthcare system, and leaving the adoption of new technologies mostly to the profit motive. High drug prices are a powerful way to encourage people to solve these problems. But they are, by definition, not cheap.