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FDA Approves Alectinib For Initial Treatment of ALK-Positive Lung Cancer

December 6, 2017, by NCI Staff

Under FDA's approval, the ALK mutation must be identified by an FDA-approved lab test.

Credit: National Cancer Institute

On November 6, the Food and Drug Administration (FDA) approved alectinib (Alecensa®) for some patients with advanced non-small cell lung cancer (NSCLC).

The approval covers patients with previously untreated metastatic lung cancer whose tumors have a cancer-causing alteration in the ALK gene (also called ALK positive). Under the approval, the ALK mutation must be identified by an FDA-approved test.

Alectinib is an ALK inhibitor—a targeted therapy that blocks the activity of mutated ALK proteins. About 5% of NSCLC tumors are ALK positive.

FDA previously approved alectinib as second-line therapy for patients with ALK-positive NSCLC whose tumors are resistant to crizotinib or who can no longer tolerate the treatment due to side effects.

The new FDA approval is based on results from a phase 3 clinical trial, called ALEX, of 303 patients with ALK-positive NSCLC who were randomly assigned to receive alectinib or crizotinib (Xalkori®), the first ALK inhibitor approved to treat ALK-positive NSCLC.

In the trial, patients treated with alectinib lived more than twice as long without their disease getting worse or coming back than patients treated with crizotinib. Alectinib was also better at preventing cancer from spreading to and growing in the brain and central nervous system.

Patients in the trial haven’t been followed long enough to determine whether alectinib also improves how long they live overall.

But from the data available, it appears that there is not a large difference in overall survival between the treatment groups, pointed out Heather Wakelee, M.D., a lung cancer specialist at Stanford University, who was not involved in the ALEX trial.

“This is likely [because] some patients treated with crizotinib were treated with alectinib after their cancer grew back,” Dr. Wakelee said.

Results of the ALEX Trial

Although crizotinib can be an effective treatment, nearly all patients’ tumors eventually become resistant to it. “Next-generation” ALK inhibitors like alectinib were developed to be safer and more effective than crizotinib.

The ALEX trial was the second international study to compare alectinib with crizotinib as an initial treatment for patients with advanced NSCLC. The first trial, J-ALEX, was conducted in Japan and reported earlier this year. Both trials were sponsored by Roche, the manufacturer of alectinib.

In the ALEX trial, the median progression-free survival was 26 months for patients treated with alectinib, compared with 10 months for patients treated with crizotinib. The overall response rate was 79% for alectinib and 72% for crizotinib.

Because lung cancer tends to spread to the brain, researchers developed next-generation ALK inhibitors that cross the blood-brain barrier more effectively than crizotinib, in the hopes of both preventing new brain metastases and shrinking existing metastases.

That appears to be the case for alectinib, as it prevented new cancer metastases in the brain and central nervous system better than crizotinib. And treatment with alectinib shrank existing brain metastases in 81% of patients, whereas crizotinib shrank them in just 50% of patients.

The most common side effects of alectinib treatment were fatigue, constipation, edema, muscle pain, and anemia. Serious side effects occurred in 41% of patients in the alectinib group and 50% in the crizotinib group. A similar percentage of patients in both groups discontinued, interrupted, or altered their treatment due to serious side effects.

A New Standard of Care?

People with lung cancer should get tested for ALK alterations, said Dr. Wakelee, because “if someone does have an ALK translocation in their tumor, ALK-focused therapy is definitively a better initial therapy than chemotherapy or immunotherapy.”

Based on the results from the ALEX trial, the National Comprehensive Cancer Network recommended alectinib as the preferred first-line treatment for ALK-positive patients over both crizotinib and ceritinib (Zykadia®). FDA approved ceritinib, another ALK inhibitor, as a first-line therapy for patients with metastatic ALK-positive NSCLC earlier this year.

However, “there’s a bit of room for discussion” about the preferred first-line therapy, said Dr. Wakelee. “Alectinib is absolutely a great first-line option for patients with ALK-positive NSCLC, but ceritinib and crizotinib are also approved in this setting and can be considered for some patients.”

The cost of alectinib may be an issue for some patients, depending on insurance coverage and treatment availability.

Another issue is the availability of second-line therapies. As with crizotinib, patients treated with alectinib usually develop resistance to the drug over time. If a patient receives crizotinib as first-line therapy and later becomes resistant to it, he or she can be treated with another ALK inhibitor such as alectinib, ceritinib, or brigatinib (Alunbrig®), said Dr. Wakelee.

“But if you start on alectinib and it stops working, then the only option is chemotherapy,” she explained. Other ALK inhibitors are not FDA-approved to treat patients who are resistant to alectinib, she added, though that may change with new medications showing promise in ongoing research studies.

Two other ALK inhibitors, brigatinib and ensartinib (also called X-396), are currently being tested against crizotinib in clinical trials as first-line treatments for ALK-positive NSCLC.

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