Many oncologists have already adopted ceritinib as a second-line treatment for ALK-positive non–small cell lung cancer in patients who have developed resistance to crizotinib. The results of a randomized trial, presented at the European Society for Medical Oncology 2016 Congress, confirm that ceritinib is an effective option because it increases progression-free survival by 4 months over chemotherapy.

The ALK inhibitor ceritinib (Zykadia; Novartis) can extend progression-free survival for patients with ALK-positive non–small cell lung cancer (NSCLC) who have developed resistance to crizotinib (Xalkori; Pfizer), according to results of the phase III ASCEND-5 trial. Data were presented at the European Society for Medical Oncology 2016 Congress in Copenhagen, Denmark, in October.

The first drug of its kind, crizotinib has been the treatment of choice for newly diagnosed patients with ALK-positive NSCLC, but patients inevitably develop resistance to it. Until recently, chemotherapy was considered the second-line treatment for these patients.

A newer ALK inhibitor that binds more potently to the protein than crizotinib does, ceritinib was approved in the United States and Europe based on compelling phase I data, says Alice Shaw, MD, PhD, director of the Center for Thoracic Cancers at Massachusetts General Hospital in Boston and principal investigator for ASCEND-5. Since then, she adds, many oncologists have been using it in lieu of chemotherapy as a second-line treatment.

“The field in many ways had already come to the conclusion that ceritinib was better than chemotherapy,” comments Gregory Riely, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the trial. “These data make it crystal clear.”

The open-label trial, conducted at 99 cancer centers around the world, enrolled 231 people with ALK-positive NSCLC previously treated with crizotinib and chemotherapy. Half were randomly assigned to receive chemotherapy (pemetrexed or docetaxel); the other half received ceritinib. Participants were followed for a median of 16.5 months, and those in the chemotherapy arm could switch to ceritinib if their disease progressed.

Not only did ceritinib result in improved median progression-free survival of 5.4 months, compared with 1.6 months for chemotherapy, it also had a better response rate—39.1% compared with 6.9%. Overall survival was unaffected by treatment arm, in part because it's too early to see any significant difference between the groups, and in part because 75 patients in the chemotherapy group eventually began taking ceritinib, diluting the new drug's magnitude of benefit over the control treatment arm.

The side effects of each treatment differed. Chemotherapy most often caused fatigue, nausea, alopecia, and neutropenia, whereas the most common side effects of ceritinib were diarrhea, nausea, and vomiting.

The next question is whether ceritinib or another ALK inhibitor, such as alectinib (Alecensa; Roche), which is also available in the United States, should be prescribed as first-line therapies. In addition, researchers want to know which ALK inhibitor should be given first. “These new, more potent second-generation inhibitors are all effective in single-arm trials,” said Shaw. “We are now waiting on the results of randomized trials comparing second-generation ALK inhibitors with crizotinib in the first-line setting.” –Amber Dance

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.