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Tiny Ignyta's Lung Cancer Drug Bested Pfizer's. Probably. Will We Ever Know For Sure?

This article is more than 6 years old.

There should have been a drug to prolong Stuart Brown’s life. But when his first option failed him, it seemed there was nothing else to try.

Then came a drug made by Ignyta Pharmaceuticals, a San Diego-based drugmaker, that shrank his tumors and has kept them in check for more than a year. Results of a 32-patient study of the drug, presented today at the World Conference on Lung Cancer in Yokohama, Japan, show a best case scenario: the medicine shrank tumors in 79% of patients and kept working for a median 28.6 months, about 10 months longer than the current drug, Pfizer’s Xalkori, did in separate clinical trials. Lung cancer doctors are impressed, and the results best what financial analysts say could be a best-case scenario for Ignyta’s stock, which has already increased 200% year-to-date.

But the study – and the race to develop new drugs for cancers like Brown’s that are driven by a a mutation called ROS1 that affects only 1% of non-small cell lung cancer patients – raises questions about whether it’s possible to compare similar cancer medicines, and whether it’s possible to keep innovating after a few gene-targeted drugs have been invented.

Brown’s non-small cell lung cancer showed up first as blood clots in his feet, which his doctors blamed on the three miles he jogged daily. Then the engineer, now 53, heard a gurgling in his lungs and insisted on a chest X-ray, which revealed spots of cancer. He was lucky, because the cancer was caused by a mutation in a gene called ROS1, which meant there was a good chance that Xalkori, the Pfizer drug, could keep it in check. Unfortunately, Xalkori raised his liver enzymes, and he could never get on an effective dose.

Stuart Brown

But Brown pushed his way into a clinical trial for entrectinib, the drug made by Ignyta. Brown’s liver levels stayed stable. And after just a month, his tumors had shrunk 30%. They kept shrinking. “It’s getting difficult to find them,” he says. He’s now been on entrectinib for 13 28-day cycles. The most significant side effect? He’s gained 30 pounds on his six-foot frame.

Oncologists say entrectinib’s duration of response stands out, as does its ability to shrink and perhaps prevent the spread of tumors to the brain, something Xalkori may not do as well. “I felt it was a pretty impressive result,” says Roy Herbst, Ensign Professor of Medicine at Yale Medical School. Alice Shaw, an attending physician at the Center for Thoracic Cancers at Massachusetts General Hospital, cautioned that the study didn’t directly compare entrectinib to Xalkori. But her previous work has shown that Xalkori keeps working for a median 19 months. “There is a suggestion the durability is quite a bit longer,” she says. One big reason appears to be that fewer new tumors are showing up in patients’ brains.

That’s likely to thrill investors, who were already expecting positive results. On October 12, J.P. Morgan analyst Anupam Rama predicted a win, and said that increasing the duration of response by four to five months compared to crizotinib would mean peak sales of $300 million a year and would push Ignyta shares up another 13% to 18%. The drug is likely to have a retail price of well over $100,000 a year, as Xalkori already does.

Cancer doctors have more mixed feelings, because they would like to see a direct comparison between entrectinib and Xalkori. Just putting each drug into a study with no control group is enough to show that tumors are shrinking. But tumor shrinkage rates are about the same (for Ignyta, 69% to 78%, depending on how they were assessed) for both medicines. Both drugs work. Which is really better?

“If they don’t do a trial, that’s a tough one,” says Herbst. Certainly, he says, people who fail Xalkori could benefit. And doctors would consider it in people with brain metastases that are not responding to Xalkori. “Whether to substitute it? It’s hard to say without a phase III trial.”

Jonathan Lim, Ignyta’s chairman and chief executive who in-licensed entrectinib and planned its development, says that such a trial isn’t planned and may be impossible. But he does see entrectinib as a first-line option for ROS1 patients, something Shaw, the MGH researcher who helped pioneer the use of ROS1 drugs, also foresees happening.

“It’s hard to really compare them like this,” says Shaw, who ran the big trial of Xalkori and a Roche drug, Alecensa, in patients with another mutation called ALK. But she says there may be no other choice. “I think it may be nearly impossible to conduct a randomized clinical trial in a reasonable time frame,” she says. “I think we go with single-arm data and cross-trial comparisons.”

The problem is that ALK+ patients represent about 5% of those with lung cancer. (About 200,000 Americans a year.) ROS1 is just 1%. Finding the patients and doing the study is incredibly difficult. And there are other ROS1 drugs in development. Pfizer is developing one called lorlatinib. A small San Diego company, TP Therapeutics, has a ROS1-targeted drug called TPX-005. These medicines may work against a mutation that causes resistance to Xalkori in as much as 40% of patients. Laboratory work indicates that Ignyta’s drug may not. Will that make the new drugs better? How will we know?

It would be possible to run a study with all of these experimental drugs in similar patients, at the same time. But that’s not the way the current system works. Each company designs its own studies, and sometimes they compete as much on designing the best study as on making the best drug. Unless there’s a way of improving that system, the next drug for patients like Stuart Brown could have trouble getting off the ground.