From preclinical efficacy to 2022 updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC

by Selleckchem | Jun 14 2023

Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5%. The median PFS of lorlatinib still has not been reached. Post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.

Comments:

The information suggests that among six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib), lorlatinib demonstrated the lowest IC50 in Ba/F3 cells against EML4-ALK variant 1 or 3, indicating its potent activity against this specific mutation.

In 2022, seven abstracts reported updated efficacy and safety data from the CROWN trial. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5%. It's worth noting that the median PFS for lorlatinib has not been reached, indicating a sustained and durable response.

The post-lorlatinib treatment median PFS2, which refers to the time from the start of lorlatinib treatment to disease progression after subsequent therapy, was reported at 74.0% at 3 years. This suggests that even after lorlatinib treatment, patients experienced a significant period without disease progression.

Asian patients treated with lorlatinib achieved a similar 3-year PFS rate as the overall lorlatinib-treated patient population. This implies that lorlatinib's efficacy is consistent across different ethnic backgrounds.

Among lorlatinib-treated patients with EML4-ALK variant 3, the median PFS was reported as 33.3 months. This suggests that even in patients with this specific mutation, lorlatinib demonstrated favorable efficacy.

The occurrence of central nervous system (CNS) adverse events (AE) was reported to be fewer than one per patient over the median follow-up time of 36.7 months. Importantly, most CNS AEs resolved without the need for intervention, indicating manageable toxicity associated with lorlatinib.

Based on the provided data, it can be inferred that lorlatinib has demonstrated potent activity against EML4-ALK variants, favorable long-term efficacy with sustained responses, and manageable side effects, particularly in the CNS. These findings support the notion that lorlatinib should be considered the treatment of choice for advanced ALK+ NSCLC. However, it's important to consult with healthcare professionals to make treatment decisions based on individual patient factors and available treatment options.