Mice engineered to express the fusion protein in their lungs quickly develop hundreds of cancer nodules. In fact, the protein generates cancer much more quickly than other genetic aberrations linked to the disease. “It is an early and principle event” in the development of cancer, says Mano.
Mano’s studies suggest that the fusion is responsible for about 4 to 5 percent of non-small-cell lung cancers (the most common type of lung cancer) in Asians. The frequency appears to be slightly lower in other groups. It is more common in cancer patients who are young, who have never smoked, and whose tumors lack the EGFR mutation, another mutation found in some lung cancers.
Pfizer already had a compound designed to block the activity of the ALK enzyme in clinical trials when scientists there learned of Mano’s discovery of the fusion protein. Researchers running clinical trials of the drug, including a group at Mass General Hospital, quickly opened their studies to patients with the EML4-ALK fusion. In the most recent study, which focused on 82 patients with the mutation, the treatment shrank tumor size in at least 47 and blocked tumor growth in 27 patients. Sixty-three patients, including Pihl, are still taking the drug, some for as long as two years. Unlike chemotherapy, patients take these drugs for the long-term, or until they stop working. A larger study of the drug is already underway.
“Most patients have tolerated the drug quite well,” says Eunice Kwak, an oncologist at the Mass General Hospital Cancer Center. Kwak led the study. “For those with side effects from their tumors, it allowed them to resume a normal life.”
The study is among the first to focus on a genetically defined group of cancer patients early on. Drugmakers say this approach makes it cheaper and faster to show that a particular drug works. In this case, about 80 percent of the patients in the study responded to the drug, a better rate than most tests of new cancer drugs, and much higher than would have been the case in an unselected population. “That makes a big difference; not treating patients who we don’t think will benefit from the drug,” says Keith Wilner, senior director of oncology clinical development at Pfizer. The company is collaborating with Abbott to develop a diagnostic that will be paired with the drug.
“There’s a good chance [the drug] will be approved by the FDA in the next few years, which is very fast,” says Jeffrey Engelman, director of the Center for Thoracic Cancers at MGH’s cancer center. “We’re well posed to see the clinical benefit of this drug, which will help thousands of patients over the next few years.”
It’s not yet clear why 20 percent of people with the mutation do not respond to the drug, but scientists speculate that their tumors have additional mutations that render them resistant. And as tests of other targeted cancer therapies have shown, most patients who initially respond to these drugs eventually evolve resistance. The time it takes to become resistant varies tremendously; some patients respond for years, others only for a few months.