Lorlatinib Makes Its Mark at ASCO 2024 in ALK-Positive Lung Cancer

Key Points:

• At 5 years of follow-up, in previously untreated patients with advanced ALK-positive non-small cell lung cancer (NSCLC), lorlatinib continues to show a benefit over crizotinib in progression-free survival (PFS) , with no new safety signals.
• Median PFS has not been reached with lorlatinib, compared with 9.1 months with crizotinib.
• Most patients receiving lorlatinib (92%) remain protected from brain progression.

ASCO 2024 Congress opened its first day with the standout presentation of updated CROWN results.  

Median PFS has still not been reached in patients with advanced ALK-positive NSCLC receiving the ALK tyrosine kinase inhibitor lorlatinib. This represents the longest PFS reported to date in advanced NSCLC. Lorlatinib's striking systemic efficacy, combined with substantial intracranial activity, delivers unprecedented results for these patients and sets a new benchmark for targeted cancer treatments.

Finding a Target Can Change the Course of Cancer

Not every cancer type or lung cancer has a targetable genetic alteration. However, if genomic testing of a patient's tumor identifies an alteration such as ALK that can be targeted with newer cancer drugs, much better outcomes are now possible even in advanced disease.

These 5-year results have "raised the bar" not only for lung cancer but for what targeted treatments can achieve in general. The new data redefine their effectiveness and potential.

In the past, achieving 5-year overall survival in these patients was considered a major success. Today, we are discussing a 5-year progression-free survival rate of 60%. This represents substantial progress in targeted therapy, significantly improving quality of life and outcomes for patients with advanced ALK-positive NSCLC.

Median PFS with Lorlatinib Still Not Reached at 5 Years

Median progression-free survival (PFS) not being reached means that disease has not progressed in even half the patients. In other words, most treated patients have not experienced disease progression during treatment. This indicates highly effective treatment and continued disease control.

The phase 3 CROWN study randomized 296 patients with previously untreated advanced ALK-positive NSCLC to lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. Interim results showed a 72% reduction in progression or death risk with lorlatinib, forming the basis for US Food and Drug Administration (FDA) approval in March 2021 for metastatic ALK-positive NSCLC. An additional 3-year analysis also showed a sustained PFS benefit over crizotinib.

At the 2024 ASCO Annual Meeting, Dr. Benjamin J. Solomon presented a further analysis at a median follow-up of 60.2 months (LBA8503). At 60 months, 60% of patients receiving lorlatinib remained progression-free, compared with only 8% receiving crizotinib. Lorlatinib's PFS benefits were seen across all patient groups.

Comparison with Other ALK Inhibitors

Crizotinib is a first-generation ALK inhibitor and has consistently been the comparator in this field.

For comparison, in ALTA-1L and global ALEX, studies of the second-generation ALK inhibitors brigatinib and alectinib, 3-year progression-free survival rates ranged from 45.0% to 46.4%, respectively. Lorlatinib's 5-year progression-free survival rate was 60%, a striking result.

Lorlatinib Maintains Its Intracranial Activity

Among patients with brain metastases, median progression-free survival (PFS) has still not been reached with lorlatinib, compared with 6 months with crizotinib. Of patients with brain metastases at baseline, 53% remained progression-free at 60 months.

Lorlatinib also significantly improved PFS in patients without brain metastases at baseline. At 60 months, 63% of such patients receiving lorlatinib were progression-free, compared with only 10% receiving crizotinib.

Patients also appear protected against worsening disease in the brain. Those with existing brain metastases are protected from their worsening, while those without brain metastases are protected from developing them. Lorlatinib's intracranial activity is unique.

Time to intracranial progression was significantly longer with lorlatinib than crizotinib (median not reached versus 16.4 months). At approximately 60 months, 92% receiving lorlatinib were protected from intracranial progression, compared with 21% receiving crizotinib.

Use the Most Effective Treatment First

Each new generation of ALK inhibitors has shown greater potency against ALK and better central nervous system penetration. However, uptake of the third-generation ALK inhibitor lorlatinib initially varied after regulatory approval.

When lorlatinib was first developed, its accelerated FDA approval in 2018 was for patients who had already received an ALK inhibitor. The older oncology approach was to use available treatments before moving to newer agents. We now know that choosing much more effective drugs such as lorlatinib first-line—using the most effective treatment first—produces much better outcomes.

Another possible reason for variable uptake is lorlatinib's distinctive toxicity profile, which requires clinicians to address adverse effects and manage them optimally.

Nearly all patients in both study groups experienced adverse events of varying severity. Among those receiving lorlatinib, 77% had serious (grade 3/4) adverse events. Dose reduction occurred in 23%, temporary treatment interruption in 62% and permanent discontinuation in 11%.

Common adverse effects of lorlatinib include high cholesterol, high triglycerides, edema, peripheral neuropathy, weight gain and cognitive effects. Cognitive or mood effects can take several forms: mood swings, irritability, euphoria, insomnia, forgetfulness, difficulty multitasking or concentrating, slow speech or trouble finding words. Counseling patients, families and caregivers about these potential effects is important.

An analysis in CROWN showed that dose reduction during the first 16 weeks of treatment did not affect lorlatinib's efficacy.

Taken together, the 5-year CROWN results can be expected to lead to wider adoption of lorlatinib as a preferred first-line option for metastatic ALK-positive NSCLC.