The Lucky Few

Rare ‘super responders’ keep patients hopeful in clinical research.

It was 2004 when a chest X-ray revealed an ominous shadow in Greg Vrettos’ lung. His doctors in Burlington, Vermont, couldn’t figure out what it was, so Vrettos, then 57, drove several hours to Massachusetts General Hospital for a second opinion. Doctors there told him he had advanced, inoperable lung cancer. They also told him about a new genetic test that could determine whether he had abnormalities in a gene called EGFR. If Vrettos had an EGFR mutation, then it was possible that instead of receiving chemo or radiation, he could benefit more from a new targeted treatment.

Vrettos had the mutation, and he was put on Iressa (gefitinib), which inhibits certain protein receptors on the surface of cells. EGFR proteins, encoded by the EGFR gene, are normally involved in biological processes that tell cells to grow and divide. In cancer patients with EGFR mutations, these receptors are overexpressed, constantly signaling to tumor cells to proliferate.

Back then, researchers were starting to figure out how EGFR markers could inform treatment decisions in lung cancer. Only about 10 percent of lung cancer patients responded to Iressa. Due to efficacy concerns, the FDA limited Iressa’s availability in 2005 for those patients already on it and benefiting. Meanwhile, there were rare individuals who experienced what some doctors described as having a “Lazarus response” to the drug. From the first dose, their tumors seemed to melt away.

We’re not guaranteed that we’re going to find what we’re looking for. But it’s
a great place to start, and it’s a great way to salvage drugs in trials that we think aren’t effective or good but that could have some real value for the right patients.

Vrettos joined a clinical trial, and on Thanksgiving morning he took the first dose of Iressa. “I almost immediately had a response … within a day,” he remembers. “My cough went away. I had shortness of breath, and that went away. The wheezing went away. It was really astonishing.”

Genomics researchers would eventually pinpoint that these remarkable responses to EGFR inhibitors were due to mutations in the gene that show up in approximately 10 percent of non-Asians with non-small cell lung cancer. Vrettos was one of those patients. “I was extremely lucky to find that this drug worked so well,” he says. Drugmaker AstraZeneca now only markets Iressa outside the U.S.; Vrettos receives it under the Iressa Access Program, which allows patients who are currently benefiting from the drug to continue receiving it. However, the FDA last year approved two new first-line treatment options — Tarceva (erlotinib) and Gilotrif (afatinib) — for advanced non-small cell lung cancer patients with EGFR mutated tumors. There are other drugs under development.

“The discovery of EGFR brought on this whole idea that you could select the right drugs for your patients upfront,” says Lecia Sequist, who is Vrettos’ doctor at Mass General and a professor at Harvard Medical School. By studying Vrettos and others like him, researchers kicked off a revolutionary paradigm in cancer treatment that we now call personalized medicine.

The National Cancer Institute even has a name for people like Vrettos: “exceptional responders.” They are outlier patients who took part in a failed drug trial where most participants didn’t respond well. For less than 10 percent of these so-called exceptional responders, however, their tumors completely disappeared or shrank for at least six months.

Exceptional responders are rare, but failure in drug development isn’t. About 90 percent of treatments in Phase 1 studies don’t make it through the FDA. So when these outliers show up in clinical trials, researchers jump at the chance to learn from them.

David Carbone, a lung cancer specialist and genetics expert at Ohio State University’s Comprehensive Cancer Center, led a team that performed in-depth genetic analysis of a 66-year-old woman who remained progression-free and asymptomatic for five years after treatment with the drug Nexavar (sorafenib). She had received the drug as part of a 300-patient trial where only nine lung cancer patients experienced a sustained response to Nexavar. At the end of 2011, she eventually relapsed and succumbed to her disease, but her outlier response inspired Carbone’s team to delve into the molecular characteristics of her disease.

Because they did, they discovered a rare mutation in the ARAF gene that may serve as a target for future drug development. Nexavar is approved in the U.S. for advanced forms of liver, kidney, and thyroid cancers, but not for lung cancer. Carbone says his group at OSU has identified another liver cancer patient with “a tremendous response” to Nexavar, and they’re investigating whether it is the result of the same ARAF mutation.

Vrettos is exceptional among exceptional responders. Less than 1 percent of lung cancer patients fare as well or for as long as Vrettos has on anti-EGFR therapy, Sequist says. And according to one of his doctors, without Iressa, Vrettos would have lived less than a year.

On average, these drugs stave off cancer for a year. Then there are some patients who don’t respond to EGFR inhibitors at all, even though they have the requisite mutations. “When EGFR [mutations] were first discovered, it was very exciting, but every discovery brings on a new round of questions,” Sequist says.

In order to discover why a super responder reacted so well to a drug, researchers have to go back and sort through the patient’s tumor DNA. OSU has developed a next-generation sequencing test that enables scientists to dig into the molecular characteristics of a patient’s disease and pinpoint what sets him or her apart from others with the same disease or given the same drug.

Even with the latest gene-sequencing techniques, researchers don’t always hit upon the reason for an extraordinary response. “We’re not guaranteed that we’re going to find what we’re looking for,” says Sameek Roychowdhury, who runs a lab at OSU where researchers perform genomic analysis on cancer patients. “But it’s a great place to start, and it’s a great way to salvage drugs in trials that we think aren’t effective … but that could have some real value for the right patients.”

Vrettos’ super response is part of a much bigger puzzle that researchers at Mass General are trying to figure out by molecularly testing cancer patients’ tumors at the time of diagnosis. “The majority of our research is focused on understanding at a basic level what makes people respond to treatment and what doesn’t,” Sequist says. “How can we predict [response] ahead of time? How can we modulate some of these [molecular] factors so people can respond? And how can we make exceptional responses the norm?”

Although genomics research is fueling treatment breakthroughs in cancer, advancing personalized therapy approaches, and helping extend lives, not all patients receive genetic testing to guide their care. A survey last year of nearly 400 medical oncologists showed that they tested for mutations in EGFR in less than 40 percent of advanced non-squamous, non-small cell lung cancer patients. Even when patients do get testing, they may not have the right mutation to receive the drug, or there may not be a therapy that targets their specific abnormality.

Still, Vrettos says, cancer patients feel uplifted hearing his story. “I think they see that the possibility is there,” he says. “All of us as patients hear the statistics that say [some] percent will live for so long. But that’s an average, and they realize there are outliers … and that gives them just a little bit of hope.”