After five years, 60% of patients remain alive without disease progression, compared to 8% on the crizotinib treatment arm.

RT’s Three Key Takeaways:

  1. After five years of median follow-up, the CROWN trial revealed that 60% of patients with ALK-positive advanced NSCLC treated with lorlatinib (Lorbrena) were alive without disease progression, compared to only 8% on the crizotinib (Xalkori) treatment arm, demonstrating an 81% reduction in the rate of disease progression or death.
  2. Lorlatinib showed a 94% reduction in the risk of developing intracranial progression, with the median time to intracranial progression not reached in the lorlatinib group, compared to 16.4 months for those on crizotinib. This indicates that lorlatinib provides significant protection against brain metastases in ALK-positive advanced NSCLC patients.
  3. At the time of analysis, 50% of patients in the CROWN trial were still receiving lorlatinib, compared to 5% on crizotinib, highlighting the long-term sustainability and effectiveness of lorlatinib as a treatment for ALK-positive advanced NSCLC.

Pfizer Inc announced longer-term follow-up results from the phase 3 CROWN trial evaluating lorlatinib (Lorbrena), a third-generation ALK inhibitor, versus crizotinib (Xalkori) in people with previously untreated, anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). 

After five years of median follow-up, median progression-free survival based on investigator assessment was not reached with lorlatinib, with an observed hazard ratio of 0.19 (95% confidence interval, 0.13-0.27), representing an 81% reduction in the rate of disease progression or death compared to crizotinib. 

Further, 60% of patients treated with lorlatinib were alive without disease progression after five years compared to 8% on the crizotinib treatment arm. 

These data were presented in an oral presentation at the 2024 American Society of Clinical Oncology annual meeting (Abstract LBA8503) and have been published in the Journal of Clinical Oncology.

‘Unprecedented’ Results in the CROWN Trial

“These results from the CROWN trial are unprecedented, as the majority of patients on Lorbrena are living beyond five years without disease progression,” says Roger Dansey, MD, chief development officer, oncology, Pfizer, in a release. “These results are an excellent example of Pfizer’s long-standing commitment to discovering and developing scientific breakthroughs for patients, and support Lorbrena as a standard of care for the first-line treatment of people with ALK-positive advanced NSCLC.”

NSCLC accounts for approximately 80-85% of lung cancers, with ALK-positive tumors occurring in about 3-5% of NSCLC cases. Approximately 25-40% of people with ALK-positive advanced NSCLC may develop brain metastases within two years from initial diagnosis.

Designed to Overcome Resistance

Lorlatinib was specifically designed and developed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood-brain barrier.

“ALK-positive advanced NSCLC is typically aggressive and often impacts younger people in the prime of their lives,” says Benjamin Solomon, MBBS, PhD, department of medical oncology, Peter MacCallum Cancer Centre, and principal Investigator of the CROWN trial, in a release. “This updated analysis shows that Lorbrena helped patients live longer without disease progression, with the majority of patients experiencing sustained benefit for over five years, including nearly all patients having protection from progression of disease in the brain. These improvements in outcomes for patients with ALK-positive NSCLC represent a remarkable advancement in lung cancer.”

Significant Reduction in Intracranial Progression

In this updated analysis, lorlatinib showed a 94% reduction in the risk of developing intracranial progression. The median time to intracranial progression progression was not reached with lorlatinib and was 16.4 months with crizotinib. In people without brain metastases at baseline receiving lorlatinib, four of 114 developed brain metastases within the first 16 months of treatment, compared to 39 of 109 patients who received crizotinib. 

At the time of analysis, 50% of patients in the CROWN trial were still receiving lorlatinib compared to 5% of patients receiving crizotinib.

Progress for ALK-Positive NSCLC

“Although ALK-positive advanced NSCLC accounts for only approximately 5% of all NSCLC cases, this translates to 72,000 people who are diagnosed worldwide each year,” says Kenneth Culver, MD, director of research and clinical affairs at the non-profit organization ALK Positive, in a release. “These new results of the CROWN trial symbolize significant progress in the first-line setting for the targeted treatment of ALK-positive lung cancer, which has led to notable improvements for the patient community.”

Lorlatinib is approved in the US for the treatment of adults with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test.

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