Can a Third-Generation ALK Inhibitor Improve Outcomes in NSCLC?

The third-generation ALK and ROS1 inhibitor lorlatinib yielded strong treatment activity in patients with ALK-positive non–small-cell lung cancer (NSCLC), according to a phase II study. Good response rates were seen in patients with varying treatment history, including those who were treatment-naive and those who had progressed on previous ALK-directed therapy.

ALK rearrangements occur in 3% to 5% of NSCLC cases, and are typically treated with crizotinib, alectinib, or ceritinib. “However, most patients treated with crizotinib relapse over time because of acquired resistance,” wrote study authors led by Benjamin J. Solomon, MBBS, of the Peter MacCallum Cancer Centre in Melbourne. Though the other ALK-targeted therapies were developed to overcome that resistance, “most patients will develop resistance to second-generation tyrosine kinase inhibitors or develop disease progression in the CNS.”

Lorlatinib is a novel third-generation inhibitor of ALK and ROS1, and it showed promising results in a phase I trial. In this phase II trial, researchers included six expansion cohorts based on ALK mutation status and prior treatment. The results were published in Lancet Oncology.

In total, the trial included 276 patients: 30 were ALK positive and treatment naive (EXP1); 27 were ALK positive and had received previous crizotinib and no prior chemotherapy (EXP2), while another 32 of those did receive prior chemotherapy (EXP3A); 28 patients were ALK positive and had received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 66 patients were ALK positive and had received two previous ALK-directed therapies regardless of chemotherapy receipt (EXP4), while 46 had received three such prior therapies (EXP5); and finally, 47 patients were ROS1-positive with any previous therapy (EXP6; these patients were included in the safety analysis but efficacy data are being reported separately). All patients received lorlatinib 100 mg orally once daily in 21-day cycles.

In the full study, the median age was 54.0 years, 57% of patients were female, 48% were white and 37% were Asian, and 60% of patients had brain metastases present at baseline.

Promising response rates were seen across the cohorts. The confirmed objective response rate (ORR) was 90.0% in EXP1, 69.5% in EXP2 and EXP3A, 32.1% in EXP3B, and 38.7% in EXP4 and EXP5. Across all of these cohorts, the ORR was 47.0%, and the median time to first tumor response was 1.4 months. The median duration of response was not yet reached in any of the cohorts.

Among patients with at least one measurable CNS metastasis at baseline, the pooled intracranial ORR was 63.0%, with the highest ORR seen in EXP2 and EXP3A (those who had received previous crizotinib; 87.0%).

The pooled median progression-free survival was 7.3 months; the median was not yet reached in EXP1 and the combined EXP2-3A group, and it was 5.5 months in EXP3B and 6.9 months in EXP4-5.

“The results of this trial indicate that lorlatinib has promising antitumor activity in treatment-naive patients with ALK-positive advanced NSCLC and provides an important new treatment option for those patients whose disease has progressed after treatment with crizotinib or second-generation ALK tyrosine kinase inhibitors,” the authors concluded.

In an accompanying editorial, Saiama N. Waqar, MD, MBBS, and Daniel Morgensztern, MD, of the Washington University School of Medicine in St. Louis, agreed that these results “establish lorlatinib as a valuable addition for the treatment of ALK-rearranged tumors.” They added that the important next step will be to define the agent’s place in the optimal treatment sequence, and that an ongoing trial comparing it with crizotinib in untreated patients may help shed light on the question.

The authors also noted that there are no currently established combination regimens involving ALK tyrosine kinase inhibitors, and that immune checkpoint blockade has had limited success in patients with ALK rearrangements. “Therefore, novel approaches, including rationally designed combinations, might be required to achieve further improvement of outcomes in patients with ALK-rearranged NSCLC.”