CROWN: What the Lung Cancer Trial Found

The problem this trial was built for

A small share of non-small cell lung cancers carry a rearrangement of the ALK gene. ALK stands for anaplastic lymphoma kinase.

The rearrangement fuses ALK to another gene. The fusion protein signals cells to grow and does not switch off. Tumors with this feature respond to drugs that block ALK, which makes them one of the clearest examples of matching a drug to a molecular finding. Our page on biomarker testing and precision medicine covers how that test result is produced.

Crizotinib was the first ALK inhibitor in wide use. It had a known weakness: cancer that had spread to the brain. Drugs often fail to cross from blood into brain tissue in useful amounts, and brain metastases were the usual site of failure.

Lorlatinib is a third-generation ALK inhibitor designed with that problem in mind. CROWN asked whether it beat crizotinib as first treatment.

How CROWN was built

CROWN was a global phase 3 trial. Its ClinicalTrials.gov record, NCT03052608, lists 296 participants, randomized, parallel groups, no masking.

All had advanced ALK-positive non-small cell lung cancer and had received no previous systemic treatment for metastatic disease. They were split evenly: 149 to lorlatinib at 100 mg once daily, 147 to crizotinib at 250 mg twice daily.

Those were the assigned study amounts. If you are on either drug, your own thoracic oncology team sets your dose.

The primary endpoint was progression-free survival, assessed by blinded independent central review. That detail matters in an open-label trial. Nobody could hide which pill a person swallowed, but the people reading the scans did not know either.

An interim efficacy analysis was planned once about 133 of 177 expected progression or death events had occurred.

The interim result

At 12 months, 78% of the lorlatinib group were alive without their cancer progressing. In the crizotinib group it was 39%.

The hazard ratio for progression or death was 0.28, with a 95% confidence interval of 0.19 to 0.41 and a p-value below 0.001.

Tumors shrank in 76% of the lorlatinib group and 58% of the crizotinib group.

The brain results were the striking part. Among participants with measurable brain metastases, 82% responded on lorlatinib and 23% on crizotinib. Seventy-one percent of those on lorlatinib had all visible brain disease disappear.

What five more years showed

CROWN kept running. A 2024 analysis in the Journal of Clinical Oncology reported outcomes after five years.

Median progression-free survival was still not reached in the lorlatinib group, with a lower confidence bound of 64.3 months. In the crizotinib group it was 9.1 months. The hazard ratio was 0.19.

Five-year progression-free survival was 60% with lorlatinib and 8% with crizotinib.

Median time to progression inside the brain was also not reached with lorlatinib, against 16.4 months with crizotinib. That hazard ratio was 0.06.

The authors describe this as the longest progression-free survival reported for any single-agent targeted treatment in advanced non-small cell lung cancer.

What it costs

Lorlatinib has a distinctive side effect profile, and it is not a mild one.

The most common events were high blood lipids, swelling, weight gain, peripheral neuropathy — nerve damage causing numbness, tingling, or pain in the hands and feet — and cognitive effects.

Grade 3 or 4 events occurred in 72% of the lorlatinib group and 56% of the crizotinib group. The excess was mainly altered lipid levels rather than organ damage.

Discontinuation because of side effects was similar: 7% on lorlatinib, 9% on crizotinib. The five-year report found no new safety signals.

The cognitive and mood effects deserve naming plainly. They are not universal, they are often dose-related, and they are the reason dose reduction is a normal part of managing this drug rather than a failure.

When to get checked

For anyone on an ALK inhibitor, three things warrant contacting the team between visits: new confusion, memory trouble, slowed speech, or mood change; new numbness or burning in the hands or feet; and rapid swelling or weight gain. Blood lipids are checked on a schedule because high levels usually cause no symptoms at all.

For lung cancer itself, NCI says to check with a doctor about chest discomfort or pain, a cough that does not go away or worsens, trouble breathing, wheezing, blood in coughed-up mucus, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face or neck veins.

ALK-positive lung cancer skews younger and toward people who never smoked, so the usual mental shortcut — no smoking history, so not lung cancer — misleads here. NCI notes that some people with no known risk factors develop lung cancer. Our overview of lung cancer covers how diagnosis works.

Anyone diagnosed with advanced non-small cell lung cancer should ask directly whether their tumor has been tested for ALK and other targetable changes. Without that test, this entire class of drug is invisible.

The wider picture

About 229,410 new lung and bronchus cancer diagnoses and 124,990 deaths are projected in the United States for 2026 — an American Cancer Society figure that SEER reports. The median age at diagnosis is 71.

Only 24% is found while still confined to the lung. Fifty-one percent is found after spread to distant sites. Five-year relative survival is 65.5% for localized and 10.5% for distant disease, and 29.5% across all stages for people diagnosed from 2016 through 2022.

Those figures pool every subtype and every treatment era. ALK-positive disease is a small fraction of them, and CROWN's participants are not represented in that 29.5%.

What this trial cannot tell you

CROWN compared lorlatinib against crizotinib. By 2020 crizotinib was already being displaced by newer ALK inhibitors such as alectinib and brigatinib. The trial says nothing about how lorlatinib compares with those.

It also does not report overall survival as its answer. Progression-free survival was the primary endpoint, and living longer without the cancer growing is not the same thing as living longer.

The five-year analysis was described by its authors as post hoc, which means the comparison was made after the fact rather than planned in advance. That does not make it wrong; it makes it weaker evidence than a prespecified endpoint.

And eligibility was narrow. Everyone had ALK-positive disease and no prior systemic treatment for metastatic cancer. Nothing here applies to lung cancer without that gene rearrangement.

Sources

• Shaw AT et al., N Engl J Med 2020, CROWN (NCBI E-utilities)
• Solomon BJ et al., J Clin Oncol 2024, CROWN 5-year outcomes (NCBI E-utilities)
• ClinicalTrials.gov record for NCT03052608 (CROWN)
• NCI PDQ: Non-Small Cell Lung Cancer Treatment (Patient Version)
• NCI SEER Stat Facts: Lung and Bronchus Cancer

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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