CROWN Trial: Lorlatinib in ALK-Positive Lung Cancer

Some non-small cell lung cancers are driven by a rearranged ALK gene. For these ALK-positive cancers, targeted pills can block the faulty growth signal. Lorlatinib (Lorbrena) is one of them. In 2024, the CROWN trial reported unusually strong 5-year results. Of the people who started on lorlatinib, 60% were alive at 5 years without their cancer having worsened.

What the trial tested

CROWN randomized 296 people in 23 countries. All had advanced ALK-positive non-small cell lung cancer that had not yet been treated with a systemic therapy. Half received lorlatinib. Half received crizotinib (Xalkori), another ALK-targeted drug. Both are daily pills. Pfizer, which makes both drugs, funded the trial, which began in 2017. The 5-year results were published in the Journal of Clinical Oncology and presented on May 31, 2024.

FDA's approved use for lorlatinib covers adults with metastatic non-small cell lung cancer. The tumor must be ALK-positive, as detected by an FDA-approved test. The result only speaks to cancers with this alteration. Testing comes first.

What the trial showed

The headline number is progression-free survival, or PFS: the time people live without the cancer growing or the person dying. After 5 years, 60% of the lorlatinib group were alive without the disease having worsened. In the crizotinib group, 8% were. Median PFS was 9 months with crizotinib. In the lorlatinib group, it still had not been reached, because most cancers had not progressed.

The brain results stand out. ALK-positive lung cancer often spreads to the brain, and about a quarter of participants had brain metastases at the start. Among them, disease progression at 5 years had occurred in 8% of those on lorlatinib versus 79% on crizotinib. Of 114 lorlatinib-treated people who started without brain metastases, only 4 later developed them.

What the trial did not show

Progression-free survival is not the same as living longer. NCI's report on the 5-year results does not include overall survival data. So the trial has not yet shown that starting on lorlatinib helps people live longer. Starting on a different ALK drug and switching later might turn out just as good, or might not.

The comparison arm also matters. Lorlatinib beat crizotinib. Other ALK inhibitors were not in this trial. As NCI's report notes, whether to use lorlatinib or another ALK inhibitor is a real question for patients and providers. Future studies comparing ALK inhibitors could help inform that decision.

Side effects, in numbers

Lorlatinib was harder on the body than crizotinib in this trial: treatment-related side effects occurred in 77% versus 57%. The most common problems included swelling from fluid buildup (edema), high cholesterol, and raised blood fat levels. Even so, only 5% of the lorlatinib group stopped treatment because of side effects. Reducing the dose during the first 16 weeks did not appear to reduce the drug's effectiveness.

The FDA label fills in the picture from lorlatinib studies overall. Common reactions include edema in 56% and peripheral neuropathy in 44%. Neuropathy means nerve symptoms such as numbness or tingling. Weight gain occurs in 31%, and effects on thinking in 28%. Central nervous system effects occurred in 52%. These include changes in thinking, mood, or sleep, and rarely seizures. In the trial, problems with attention and thinking were among the reasons some people stopped. Most people, 83%, needed cholesterol-lowering medicine. Rarer but serious risks include lung inflammation (1.9%) and heart-rhythm block that occasionally requires a pacemaker (0.2%). The recommended dose in the label is 100 mg once daily. That figure describes the label, not you — the dose any one person takes is set by their team, so follow the prescription your own team gave you.

What to raise with the team

• Has my tumor been tested, and does the report show an ALK rearrangement?
• If lorlatinib is an option, why this ALK inhibitor rather than another, given that they have not been compared head to head?
• What is the plan for monitoring cholesterol, mood, memory, and thinking while I am on it?
• If side effects appear, is lowering the dose an option before stopping?
• Do I need brain imaging now, and how often will it be repeated?

What this does not mean

• It does not mean lorlatinib helps lung cancers without an ALK alteration, which are the large majority.
• It does not mean lorlatinib has been proven to extend life compared with starting on another ALK inhibitor. The 5-year data are about progression, not overall survival.
• It does not mean lorlatinib is the best choice for every ALK-positive cancer. Side-effect profiles differ, and priorities differ.
• It does not mean the people whose cancer did progress did anything wrong or ran out of options.

Sources

• NCI Cancer Currents: Lorlatinib Slows Growth of ALK-Positive Lung Cancers, May Prevent Brain Metastases
• FDA prescribing information: LORBRENA (lorlatinib) tablets
• NCI drug information: Lorlatinib