The CROWN study suggests that lorlatinib is effective in patients newly diagnosed with advanced ALK-positive non–small cell lung cancer. In the phase III trial, patients treated with lorlatinib were twice as likely to be alive without disease progression after 1 year than those who received crizotinib—with slower progression of brain metastases.

A recent study suggests that the ALK inhibitor lorlatinib (Lorbrena; Pfizer) is superior to crizotinib (Xalkori; Pfizer) in patients newly diagnosed with advanced ALK-positive non–small cell lung cancer (NSCLC): In the phase III CROWN trial, lorlatinib doubled progression-free survival at 1 year and curbed growth of brain metastases. Physicians must now figure out how to integrate the drug with other first-line agents that are already approved.

A first-generation ALK inhibitor, crizotinib was the standard first-line treatment for patients with ALK-positive NSCLC when the CROWN study began in 2017. Since then, the second-generation ALK inhibitors brigatinib (Alunbrig; Takeda), ceritinib (Zykadia; Novartis), and alectinib (Alecensa; Genentech) have displaced crizotinib as the standard of care due to their greater efficacy.

Researchers suspected that lorlatinib, a third-generation ALK inhibitor, would also beat out crizotinib because it can enter the brain and blocks all known resistance mutations. However, it has been approved only as a second- or third-line treatment, prompting testing in the first line.

The CROWN trial randomized 296 patients newly diagnosed with advanced ALK-positive NSCLC to receive lorlatinib or crizotinib. After 1 year, 78% of the patients treated with lorlatinib were alive without disease progression, compared with 39% in the crizotinib group. The overall survival data are not yet mature.

Lorlatinib was also effective against brain metastases. After 12 months of treatment, 96% of patients in the lorlatinib group were alive and did not have central nervous system progression—defined as development of new metastases or growth of existing ones—compared with 60% of patients in the crizotinib group. Among patients with brain metastases when the study began, 66% had an intracranial response to lorlatinib, compared with 20% in the crizotinib group.

Lorlatinib triggered more severe side effects than crizotinib: Grade 3 or 4 adverse effects occurred in 72% of patients in the lorlatinib group and 56% of those in the crizotinib group. High cholesterol, high triglycerides, cognitive changes, and mood alterations were among the side effects associated with lorlatinib.

Lead author Alice Shaw, MD, PhD, of Novartis says her team expected the study to be positive, but “what was surprising was the degree of positivity and particularly the degree of central nervous system efficacy.” She notes that side effects such as high cholesterol and triglycerides are easy to manage, and that cognitive and mood effects are reversible and improve with dose reduction.

“It was a well-designed trial; the results are unambiguous,” says Thomas Stinchcombe, MD, of Duke University School of Medicine in Durham, NC, who wasn't connected to the study. He and other researchers unaffiliated with the trial predict that the drug will receive FDA approval. What remains unclear, they say, is the optimal way to use lorlatinib and the other current first-line ALK inhibitors such as alectinib.

“In the absence of a randomized trial, clinicians will need to make a decision on the relative magnitude of benefit compared to crizotinib,” as well as tolerability, says Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.

Lorlatinib is less familiar than its rivals, and physicians will have to gain experience with it, says Jose Pacheco, MD, of the University of Colorado Cancer Center in Aurora. “It's going to take some time before lorlatinib is widely adopted in the first line.”

In the end, Stinchcombe says, “doctors will likely choose among the available next-generation ALK TKIs [tyrosine kinase inhibitors] on a patient-by-patient basis depending on factors such as side effects and patient preference.” –Mitch Leslie