Seven years after the first patients enrolled, a landmark lung cancer trial has delivered results that oncologists say could change treatment for a rare but aggressive form of the disease.
ALK-positive lung cancer: a shifting outlook
About 4% to 5% of non-small cell lung cancer cases involve a genetic rearrangement called ALK-positive. This small share still affects thousands of patients worldwide each year. The arrival of successive generations of ALK inhibitors has dramatically improved outcomes.
New generations of ALK inhibitors have steadily improved survival rates. The current standard of care has moved far beyond chemotherapy, with multiple drugs now approved as first-line treatments. However, the best choice among them remained unclear due to limited long-term data.
Alice Shaw, chair of the Department of Medical Oncology and chief of strategic partnerships at Dana-Farber Cancer Institute, explained that the terminology around ALK can confuse patients. Terms like “ALK rearranged,” “ALK fusion,” and “ALK mutation” are often used interchangeably, though they describe the same genetic change involving chromosome 2, where the ALK gene is located. For clarity, both Shaw and Christine Lovly, professor of medical oncology and division chief of thoracic medical oncology at City of Hope Cancer Center, agreed to use “ALK positive” consistently.
Testing before treatment: the role of molecular profiling
Molecular profiling is now recommended for all NSCLC patients. Blood tests that detect circulating tumor DNA offer a fast, noninvasive way to screen for ALK rearrangements. However, Shaw cautioned that liquid biopsies have sensitivity limitations, and a negative result does not rule out an ALK rearrangement. Tumor tissue testing — using next-generation sequencing of DNA or RNA, or ALK immunohistochemistry — remains necessary to confirm biomarker status.
“Effective ALK-targeted therapy cannot be delivered without reliable testing,” Lovly said. She emphasized that clinicians should collaborate with molecular pathologists to understand the limitations of any given assay.
Once a patient’s ALK-positive status is confirmed, the treatment approach is straightforward: systemic therapy that reaches cancer cells throughout the body. ALK inhibitors have long replaced chemotherapy as the preferred first-line option for advanced disease. “We know now, after many years, that ALK-targeted therapy is the most effective first-line therapy we should give,” Shaw said.
Seven-year results from the CROWN trial
The phase 3 CROWN study compared lorlatinib, a third-generation ALK inhibitor, with crizotinib, an earlier drug, in 296 treatment-naive patients with stage 4 ALK-positive NSCLC. After seven years, 44% of patients on lorlatinib remained on the drug, compared with just 3% on crizotinib. The median follow-up was 83 months for lorlatinib and 77.2 months for the older treatment.
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The median progression-free survival for lorlatinib has still not been reached, meaning more than half of patients remained free of cancer progression at seven years. In contrast, the median for crizotinib was 9.1 months. The hazard ratio of 0.19 shows an 81% reduction in the risk of progression or death with lorlatinib. The median time to intracranial progression—a major concern, since up to 30% of ALK-positive patients have brain metastases at diagnosis—has also not been reached with lorlatinib, versus 16.4 months with crizotinib.
Severe adverse events occurred in 77% of lorlatinib patients and 57% of those on crizotinib, though permanent discontinuation rates were similar between the groups.
For patients who reached the two-year mark without progression, the chance of remaining progression-free at seven years was about 79%. Lovly added that for those patients, it offers a rare moment of relief.
While overall survival data are not yet final, both oncologists believe the results will likely reflect the progression-free survival benefit. Shaw noted that lorlatinib’s advantage over second-generation inhibitors like alectinib, brigatinib, and ensartinib—none of which have reached a median progression-free survival beyond two to three years—is large enough to matter clinically, even without a direct comparison.
Managing side effects over time
Because lorlatinib is taken continuously for years, its side effects require careful attention. High cholesterol and triglycerides often appear within two weeks of starting treatment and usually need a statin. Other common effects include fluid retention, weight gain from increased appetite, and neurocognitive symptoms such as brain fog and mood changes.
All of these effects are reversible and depend on the dose. Shaw described her approach of starting many patients, especially older or frail ones, at a lower dose of 75 milligrams daily instead of the standard 100 milligrams. Prescribing lorlatinib as four 25-milligram tablets instead of one 100-milligram tablet makes dose adjustments easier without requiring a new prescription.
Weight gain and fluid retention tend to worsen gradually. Managing them requires a proactive approach: dietary counseling, an exercise plan combining aerobic activity and strength training, and nutritionist referrals when needed. While some have asked about glucagon-like peptide 1 drugs to counter weight gain, Shaw said more evidence is needed before recommending them routinely.
Early monitoring is essential. Shaw recommended lab tests and side effect checks every two weeks at first, then spacing them to every six months for long-term patients. Written materials and biweekly visits during the first few months help patients and families prepare for side effects.
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This is not the first cancer drug to show long-term benefits while requiring close attention to quality of life. The challenge lies in balancing effectiveness with tolerability, especially when treatment may last for years. For patients who respond well, the trade-offs can be worthwhile—but the decision is rarely easy.
Why some patients progress
Not all patients respond equally to lorlatinib. Shaw noted that most progressions in the CROWN trial happened within the first two years. Preliminary research she participated in suggests that patients who progress early often have more genetic alterations at baseline, a higher tumor mutation burden, and more frequent mutations in the tumor suppressor gene p53.
“This shows the difference between early progression and long-term response,” she said. While the analysis is still early and based on small samples, it hints at a future where biomarkers could identify high-risk patients who might need stronger treatment from the start.
Lovly emphasized that despite the positive results, not every patient will benefit. “We still need better therapies,” she said.
Changes in clinical practice
The seven-year CROWN data are likely to influence how oncologists choose first-line therapy for ALK-positive NSCLC. National Full Cancer Network guidelines currently list lorlatinib alongside second-generation inhibitors alectinib, brigatinib, and ensartinib as preferred options. But Shaw argued that the CROWN results set lorlatinib apart.
“You need a strong reason not to offer lorlatinib,” she said, citing exceptions like older, frail patients with significant health issues or those with baseline psychiatric conditions. Her key points were an unprecedented progression-free survival benefit, strong central nervous system activity (92% of patients remained free of intracranial progression at seven years), and a safety profile that requires ongoing counseling and monitoring.
Lovly stressed that these outcomes depend on universal biomarker testing. Without it, ALK-targeted therapies cannot be used. She pointed to ALK Positive, a patient advocacy group, as a resource for support and research funding.
Access to such treatments remains uneven. Lower drug costs could improve availability for more patients.
