For patients with previously untreated, advanced non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) mutation, treatment with the ALK tyrosine kinase inhibitor (TKI) lorlatinib led to longer progression-free survival (PFS) and better control and prevention of brain metastases compared to those treated with the ALK TKI crizotinib.

The research was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

“Despite significant advancements with newer generation ALK TKIs, the majority of patients treated with second generation ALK TKIs will have progression of their disease within three years. Lorlatinib is the only ALK TKI that has reported five-year progression free survival, and even after this time, the majority of patients continue to have their disease controlled, including control of disease in the brain. To our knowledge these results are unprecedented for any TKI in patients with metastatic NSCLC,” said lead study author Benjamin Solomon, MBBS, PhD, Head of Lung Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia.

In the phase 3 CROWN clinical trial, 296 people with advanced, previously untreated ALK+ NSCLC were randomly assigned to receive either lorlatinib (149 patients) or crizotinib (147 patients, of which 142 ultimately received treatment).

Approximately 25% of the participants had brain metastases when the study began. Study participants were 59.1% female, 43.9% Asian, and a median age of 59 years.

ALK tyrosine kinase inhibitors are a type of targeted therapy that binds to the ALK protein found in ALK+ NSCLC.

This helps stop the growth of tumour cells.

Key Findings

• As of October 31, 2023, 50% of the patients in the lorlatinib group were still receiving treatment (74 of 149 patients), while 5% of the patients in the crizotinib group were still receiving treatment (7 of 142 patients).
• Median PFS for the lorlatinib group has not yet been statistically reached, but more than half of the patients who received lorlatinib have not had any disease progression so far. Median PFS was 9.1 months in the crizotinib group.
• The 5-year PFS was 60% in the lorlatinib group and 8% in the crizotinib group.
• The median time to disease progression in the brain has not yet been reached with lorlatinib and was 16.4 months with crizotinib. In patients who did not have brain metastases at the start of the study, only 4 out of 114 developed brain metastases in the lorlatinib group and those 4 developed brain metastases within the first 16 months of treatment. 

Treatment-related adverse events occurred in 77% of patients who took lorlatinib and in 57% of patients who took crizotinib. Five percent of patients taking lorlatinib and 6% of patients taking crizotinib discontinued treatment due to adverse events.

The most common adverse events were oedema, which is swelling due to fluid trapped in tissues, high cholesterol, and elevated levels of lipids, or hyperlipidaemia.

The adverse events that caused patients to stop treatment included cognitive effects, hyperlipidaemia, and heart problems.

“These long-term data results are off the chart and this study confirms the outstanding durable efficacy of lorlatinib as a first-line choice for patients with ALK-positive non-small-cell lung cancer. However, it will be important to compare this treatment option to more commonly used ALK TKIs than crizotinib. Still, these findings report some of the best outcomes ever observed for an ALK TKI.” - David R. Spigel, MD, Chief Scientific Officer, Sarah Cannon Research Institute

Researchers will continue to follow the study participants to evaluate if patients who receive lorlatinib live longer than patients who receive crizotinib. They will also follow the patients receiving lorlatinib until the median PFS is reached.

Source: ASCO