Phase 3 CROWN Trial Shows Promise for Lorlatinib in Previously Untreated ALK-Positive NSCLC

November 23, 2020
Hannah Slater

An interim analysis of the trial revealed that among patients with previously untreated advanced ALK-positive non-small cell lung cancer, those who received lorlatinib (Lorbrena) had significantly longer PFS, a higher overall and intracranial response, and better quality of life.

An interim analysis of the global, randomized, phase 3 CROWN trial revealed that among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), those who received lorlatinib (Lorbrena) had significantly longer progression-free survival (PFS), a higher overall and intracranial response, and better quality of life than those who received crizotinib (Xalkori).1

Moreover, the study, published in the New England Journal of Medicine, indicated that though the incidence of grade 3 or 4 adverse events (AEs) was higher with lorlatinib than with crizotinib, this was due to the frequent occurrence of hyperlipidemia, a known side effect of lorlatinib.

“Biomarker-driven medicines have improved outcomes for people living with ALK-positive non-small cell lung cancer, but innovative therapies are still needed to delay disease progression,” Benjamin Solomon, MD, of the department of Medical Oncology at the Peter MacCallum Cancer Centre, said in a press release.2 “The results from the CROWN trial demonstrate that [lorlatinib] has the potential to be a practice-changing, first-line option, and we thank the many people and their families who participated in this trial.”

The study enrolled 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease and compared lorlatinib monotherapy (n = 149) with crizotinib monotherapy (n = 147). Of note, the interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.

The primary end point was PFS as assessed by blinded independent central review. Key secondary end points included independently assessed objective response and intracranial response.

At 12 months, the percentage of patients who were alive without disease progression at was 78% (95% CI, 70-84) in the lorlatinib group and 39% (95% CI, 30-48) in the crizotinib group (HR, 0.28; 95% CI, 0.19-0.41; P < .001). Moreover, an objective response was observed in 76% (95% CI, 68-83) of the patients in the lorlatinib group and 58% (95% CI, 49-66) of those in the crizotinib group. Of those with measurable brain metastases, 82% (95% CI, 57-96) and 23% (95% CI, 5-54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response.

Regarding safety, the safety profile of lorlatinib was similar to that reported in previous studies. The most common AEs reported with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was also associated with more grade 3 or 4 AEs than crizotinib (in 72% vs. 56%), consisting of mainly altered lipid levels. Discontinuation of treatment due to AEs occurred in 7% and 9% of the patients, respectively.

Importantly, the FDA approved lorlatinib in 2018 for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease. This indication was approved under accelerated approval based on tumor response rate and duration of response. The CROWN trial is the confirmatory trial for the conversion to full approval.

The positive interim analysis data observed in the CROWN trial will be reviewed under the FDA’s real time oncology review pilot program and will be shared with other health authorities to seek approval for an indication that includes previously untreated ALK-positive advanced NSCLC.

References:

1. Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. New England Journal of Medicine. doi: 10.1056/ENJMoa2027187

2. RESULTS FROM PHASE 3 CROWN TRIAL OF PFIZER’S LORBRENA® (LORLATINIB) IN PREVIOUSLY UNTREATED ALK-POSITIVE LUNG CANCER PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE [news release]. New York. Published November 19, 2020. Accessed November 20, 2020. https://www.pfizer.com/news/press-release/press-release-detail/results-phase-3-crown-trial-pfizers-lorbrenar-lorlatinib