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Lorlatinib surpasses crizotinib as first-line treatment for advanced ALK+ lung cancer

New England Journal of Medicine
Reuters Health - 18/11/2020 - A comparison of two Pfizer anticancer drugs has concluded that lorlatinib produces more progression-free survival and is more effective against brain tumors as a first-line treatment than crizotinib in people with advanced ALK-positive non-small-cell lung cancer (NSCLC).

Treatment with lorlatinib exactly doubled 12-month progression-free survival, at 78% versus 39% (P<0.001). Among patients whose lung tumors that had spread to the brain, 82% had an intracranial response compared with 23% with crizotinib.

The researchers behind the randomized CROWN trial, designed to test whether lorlatinib should be a first-line treatment for incurable disease, reported that "71% of the patients who received lorlatinib had an intracranial complete response."

The drug was specifically designed to cross the blood-brain barrier.

"If you use this most potent and brain-penetrant therapy you can have an enormous impact on how long the responses last and how durable they are," lead author Dr. Alice Shaw told Reuters Health by phone. "Also you're protecting the brain, and this type of lung cancer is incredibly prone to brain metastases."

Side effects caused discontinuation of lorlatinib therapy in only 7% of the patients, a rate two percentage points lower than the rate seen in crizotinib patients.

"The data suggest this drug has a greater impact compared to earlier-generation drugs," said Dr. Shaw, former director of the Center for Thoracic Cancers at Massachusetts General Hospital, in Boston, and now global head of translational clinical oncology at the Novartis Institutes for BioMedical Research.

Lorlatinib also seems to be resistant to tumor mutations that have limited the effectiveness of other treatments.

The data reflect the interim results from CROWN. The findings appear in the New England Journal of Medicine.

ALK-positive NSCLC is a particularly aggressive type of lung tumor responsible for about 4% of lung-cancer cases. It is not caused by smoking and often appears at an earlier age than typical lung cancer.

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, is sold under the brand name Lorbrena in the U.S. and Lorviqua in the European Union. It is currently considered standard treatment after first- or second-generation ALK inhibitors have failed.

Crizotinib (brand name Xalkori), approved four years earlier, is a first-generation ALK inhibitor and was the standard of care when the study began. It has since fallen out of favor to second-generation therapies.

The study on 296 patients was done at 104 medical centers in 23 countries.

At the data cutoff point, 28% of the lorlatinib patients had died or had disease progression versus 59% of crizotinib patients.

Progression-free survival at 12 months as judged by the investigators was also significantly longer with lorlatinib, at 80% versus 35%.

For the 30 patients who had a central-nervous-system metastasis at the start of the trial, 71% who received the third-generation drug experienced a complete intracranial response compared to just 8% in the control group.

Overall survival favored lorlatinib at 15% vs. 19%, but was not different enough in the two groups to be statistically significant in the interim analysis.

Some of the side effects most common with lorlatinib were hypercholesterolemia (seen in 70% of patients but only 4% of crizotinib recipients), edema (55% vs. 39%), weight gain (38% vs. 13%) peripheral neuropathy (34% vs. 15%) and cognitive effects (21% vs. 6%).

Asked about the cognitive effects, Dr. Shaw said patients "most typically would be feeling like they can't multitask. They feel like they're stumbling on words. They feel like they can't concentrate as well. You feel emotions more strongly."

"But all the neurocognitive side effects are reversible and dose dependent," she said.

Seven people in each group died from side effects of the drugs.

Pfizer paid for the study.

By Gene Emery

SOURCE: https://bit.ly/2UwjZcq The New England Journal of Medicine, online November 18, 2020.

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