The phase 3 CROWN study has revealed remarkable long-term efficacy for lorlatinib in patients with ALK-positive advanced non-small cell lung cancer (NSCLC), with 60% of treated patients achieving progression-free survival (PFS) at the 5-year mark.
These results, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrate lorlatinib's significant superiority over crizotinib, reducing the risk of disease progression or death by 81% (HR, 0.19; 95% CI, 0.13-0.27).
"These are fantastic results," said Misako Nagasaka, MD, PhD, in a conversation with CancerNetwork®, referring to the 5-year PFS analysis from the CROWN trial (NCT03052608).
Clinical Impact and Disease Context
ALK-positive NSCLC represents approximately 3-5% of all NSCLC cases, primarily affecting younger patients and non-smokers. Before targeted therapies, patients with this molecular subtype faced poor prognoses with conventional chemotherapy, with median survival typically under one year.
The introduction of ALK inhibitors has dramatically transformed the treatment landscape. Crizotinib was the first approved ALK inhibitor, but newer-generation agents like lorlatinib have shown improved efficacy, particularly against brain metastases, which affect up to 60% of ALK-positive NSCLC patients.
Study Design and Patient Population
The CROWN trial enrolled patients with previously untreated advanced ALK-positive NSCLC. Participants were randomized to receive either lorlatinib (Lorbrena) or crizotinib (Xalkori) as first-line therapy. The primary endpoint was progression-free survival, with secondary endpoints including overall survival, objective response rate, intracranial efficacy, and safety.
Notably, the trial included patients with brain metastases, a common and challenging complication in ALK-positive disease. This inclusion provides valuable data on lorlatinib's efficacy in this difficult-to-treat patient subset.
Detailed Efficacy Results
Beyond the impressive 5-year PFS rate of 60% with lorlatinib, the study demonstrated several other important findings:
- Median PFS was not reached in the lorlatinib arm, compared to a median PFS of 9.3 months with crizotinib
- The objective response rate was significantly higher with lorlatinib
- Intracranial efficacy was particularly notable, with lorlatinib showing superior control of brain metastases
These results represent some of the most durable responses ever reported for any therapy in advanced NSCLC, positioning lorlatinib as a potential new standard of care for first-line treatment of ALK-positive disease.
Safety and Tolerability Profile
While the CROWN study focused primarily on efficacy outcomes, the safety profile of lorlatinib remains an important consideration. Common adverse events associated with lorlatinib include hypercholesterolemia, hypertriglyceridemia, edema, and cognitive effects.
Treatment-related adverse events led to dose reductions in approximately 20% of patients receiving lorlatinib. However, the rate of permanent discontinuation due to adverse events was relatively low, suggesting that most side effects could be managed with appropriate supportive care and dose modifications.
Expert Perspectives
"The durability of response we're seeing with lorlatinib is unprecedented in ALK-positive lung cancer," noted Dr. Nagasaka. "These results suggest that we may be able to provide long-term disease control for a significant proportion of patients with this targeted approach."
Oncologists specializing in thoracic malignancies have emphasized that these results could change clinical practice, potentially establishing lorlatinib as the preferred first-line option for patients with ALK-positive advanced NSCLC.
Implications for Treatment Sequencing
The impressive efficacy of lorlatinib in the first-line setting raises important questions about optimal treatment sequencing for patients with ALK-positive NSCLC. Previously, treatment typically followed a sequential approach, starting with earlier-generation ALK inhibitors before moving to newer agents upon progression.
The CROWN data suggests that using the most potent ALK inhibitor upfront may provide the greatest clinical benefit. However, questions remain about subsequent treatment options for patients who eventually progress on lorlatinib.
Future Directions
While the 5-year PFS results from CROWN are encouraging, several important questions remain. Overall survival data continue to mature and will provide critical information about the long-term impact of first-line lorlatinib.
Additionally, research is ongoing to identify mechanisms of resistance to lorlatinib and develop strategies to overcome them. Combination approaches, including ALK inhibitors with immunotherapy or other targeted agents, are being explored in clinical trials.
The identification of biomarkers beyond ALK fusion status that might predict exceptional responders to lorlatinib could further refine patient selection and treatment strategies.
Conclusion
The 5-year PFS results from the CROWN study represent a significant advancement in the treatment of ALK-positive NSCLC. With 60% of patients remaining progression-free at 5 years, lorlatinib demonstrates unprecedented durability of response in this molecular subtype of lung cancer.
These findings reinforce the importance of molecular testing for all patients with advanced NSCLC to identify those who may benefit from targeted therapies like lorlatinib. For patients with ALK-positive disease, these results offer new hope for long-term disease control and improved outcomes.
