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Lorlatinib (Lorbrena) topped an older first-line standard for patients with non-small cell lung cancer (NSCLC) and ALK rearrangements, an interim analysis of the international, randomized CROWN trial showed.

Compared with crizotinib (Xalkori), treatment with lorlatinib reduced the risk of disease progression or death by 72% for patients with untreated advanced ALK-positive NSCLC (HR 0.28, 95% CI 0.19-0.41, P<0.001), according to Alice Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, and colleagues.

Reported in the , 78% of patients treated with lorlatinib were alive without disease progression at 1 year compared with 39% treated with crizotinib, the standard of care when the trial was designed.

Median progression-free survival was not yet reached with lorlatinib versus 9.3 months with crizotinib. Overall survival data were not mature.

The confirmed objective response rate favored lorlatinib, with 76% of patients achieving a response compared with 58% of patients treated with crizotinib. The higher response rate was largely attributed to partial responses (PRs), as 73% of patients treated with lorlatinib achieved a PR and 3% a complete response (CR). All responses in the crizotinib arm were PRs.

John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, told 番茄社区app that alectinib (Alecensa) and brigatinib (Alunbrig) have also shown superiority over crizotinib in similar studies and both are approved as first-line treatments for patients with ALK-positive disease.

"Currently, alectinib is the most widely used drug in the space," said Heymach, who was not involved in the trial. Lorlatinib was granted an accelerated approval in 2018 for previously treated patients with ALK-positive metastatic NSCLC.

"While this study does not compare directly lorlatinib to these two current standard first-line therapies, the efficacy observed in this study appears to be at comparable to, if not greater than, these other two drugs," Heymach said.

Lorlatinib also showed intracranial activity in the intention-to-treat population of 149 patients and subgroup of patients with measurable brain metastases at baseline.

At 1 year, 96% of patients treated with lorlatinib were alive without progression in the central nervous system (CNS) compared with 60% of patients treated with crizotinib (HR 0.07, 95% CI 0.03-0.17).

Among 17 patients treated with lorlatinib who had measurable brain metastases at baseline, 14 (82%) achieved a CNS response, 12 (71%) of which had an intracranial CR. By comparison, only three of 13 patients (23%) with brain metastases achieved a CNS response with crizotinib, which included one intracranial CR (8%).

"While all the ALK inhibitors demonstrated some activity of CNS activity, the CNS activity of lorlatinib was particularly striking, with the majority of patients having major CNS responses," Heymach said. He noted that brain metastases are a "particularly important" problem for patients with ALK-positive disease.

The lorlatinib arm had more frequent grade 3/4 events compared with the crizotinib arm (72% vs 56%) and more serious adverse events (34% vs 27%). Five percent of patients in each arm died due to toxicity.

Common adverse events among patients who received lorlatinib were elevated cholesterol levels (70% any grade; 16% grade 3/4) and elevated triglyceride levels (64% any grade; 20% grade 3/4). Also, 21% of patients who received lorlatinib had cognitive effects, such as memory impairment, disturbance in attention, and confusion, and 16% had mood effects, such as anxiety, depression, and irritability.

Heymach described these side effects as "notable" and differing from other drugs in the class. He said it is "possible" that many patients with ALK-positive disease will continue to receive alectinib or brigatinib first and then lorlatinib as second-line treatment because of these side effects.

Although the safety profiles differed, the dose interruption rate due to adverse events was similar between the lorlatinib arm and crizotinib arm (49% vs 47%), as was the dose reduction rate (21% vs 15%). Overall, 7% of patients in the lorlatinib arm and 9% in the crizotinib arm discontinued treatment due to adverse events.

"The use of lorlatinib in the first-line setting will depend, in part, on the final efficacy results," Heymach said. "But when they are available, if they are significantly better than first-line alectinib or brigatinib, that would likely encourage many physicians to prescribe it as the first-line choice."

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