Patients with ALK-positive non–small cell lung cancer may soon have a new first-line treatment option in ceritinib, which outperformed chemotherapy in a phase III study. However, toxicity issues remain a problem for ceritinib, and another next-generation ALK inhibitor, alectinib, is more likely to become the drug of choice for untreated patients.

The ALK inhibitor ceritinib (Zykadia; Novartis) outperformed platinum chemotherapy in a phase III trial, ASCEND-4, of patients with untreated metastatic non–small cell lung cancer (NSCLC). These data could pave the way for ceritinib's use as a first-line therapy for the 3% to 7% of patients with ALK-rearranged NSCLC. Currently, it is approved only for patients who have previously been treated with crizotinib (Xalkori; Pfizer), an earlier-generation ALK inhibitor.

ASCEND-4 randomly assigned 376 patients to receive ceritinib or chemotherapy. Ceritinib more than doubled the median progression-free survival (PFS): 16.6 months versus 8.1 months for those given chemotherapy. Its main side effects were frequent gastrointestinal toxicity and liver function abnormalities. Investigators had to lower dose levels or interrupt treatment for 80% of patients, and 5% dropped out of the study.

These days, however, crizotinib—not chemotherapy—is the standard of care for ALK-positive NSCLC. As such, if first-line ceritinib is greenlighted by the FDA, oncologists like Alice Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, will face a stark choice: Go with the drug that seems safer up front (crizotinib), or the one that seems more efficacious (ceritinib). The two inhibitors have not been compared head-to-head, but data from studies of crizotinib indicate that although it yields a lower median PFS of 10 to 12 months, it's better tolerated than ceritinib.

“A key question is whether the benefit of ceritinib offsets its increased toxicity,” says Shaw. “It's very difficult to answer, but based on [the ASCEND-4] data alone, I don't know that most people will automatically switch from crizotinib to ceritinib.”

Shaw's question may soon be moot, though, because a third ALK inhibitor, alectinib (Alecensa; Roche)—currently another approved second-line option—is widely anticipated to become the first-line therapy of choice. Last year, J-ALEX, a phase III trial in Japan that pitted alectinib against crizotinib, was halted early for efficacy.

Given the observation that alectinib penetrates the brain to treat metastases—which occur in up to 90% of patients—better than either crizotinib or ceritinib, Sai-Hong Ignatius Ou, MD, PhD, from the University of California, Irvine, expects that “alectinib will probably have the leg up.” The field is eagerly awaiting findings from the global ALEX trial involving patients from 31 countries. Roche is expected to announce top-line results in coming weeks and present full analyses at the American Society of Clinical Oncology's annual meeting in June.

Multiple other next-generation ALK inhibitors, including brigatinib (Ariad), lorlatinib (Pfizer), and ensartinib (Xcovery), are also in development and being evaluated against crizotinib in the clinic. If these get the FDA's nod too, Shaw expects that “using the most potent, brain-penetrable drug that can cover as many resistance mutations as possible will likely produce the greatest benefits”—at least on a population level.

For individual patients, Tony Mok, MD, from the Chinese University of Hong Kong, envisions a future in which oncologists tailor their drug selection to the particular genetic sequence of a person's ALK fusion variant. “Hopefully,” he says, “we'll able to find a smarter way to differentiate which patients will benefit from which drug.” –Elie Dolgin