First-Line Lorlatinib Improves PFS in ALK-Positive NSCLC

Early treatment with lorlatinib led to improved progression-free survival in ALK-positive NSCLC patients compared with crizotinib treatment, a study published in the New England Journal of Medicine found.

Early treatment with lorlatinib (Pfizer’s Lorbrena), a third-generation anaplastic lymphoma kinase (ALK) inhibitor, led to improved progression-free survival (PFS) in ALK-positive non-small cell lung cancer (NSCLC) patients compared with crizotinib treatment, a study published in the New England Journal of Medicine found.1

About 1 in every 25 NSCLC patients is ALK-positive, and it most commonly occurs in patients who are younger, often less than 55 years of age, and have never smoked.2 “When ALK is turned on abnormally, it’s like stepping on the gas pedal—it drives uncontrolled proliferation and survival of cancer cells,” study lead Alice Shaw, MD, PhD, former director of the Center for Thoracic Cancers at Massachusetts General Hospital, said in a press release.3

Lorlatinib is currently approved for use in patients whose disease has advanced despite treatment with past generations of ALK inhibitors. While the first-generation, crizonitib, and second generations of ALK inhibitors can be very effective, patients typically relapse and are still at risk of metastasis to the brain.

The global, randomized, phase 3 CROWN trial (NCT03052608) aims to compare the efficacy of lorlatinib compared with crizotinib as a first-line treatment for ALK-positive NSCLC. The ongoing study includes 296 previously untreated patients with advanced ALK-positive NSCLC at 104 medical centers in 23 countries. Half were given standard-of-care crizotinib, and half received lorlatinib as first-line treatment.

The primary end point was PFS based on blinded independent central review. At 12 months, 78% (95% CI, 70-84) of patients in the lorlatinib cohort were alive without disease progression, compared with 39% (95% CI, 30-48) in the crizotinib group (HR for disease progression or death, 0.28; 95% CI, 0.19-0.41; P <.001).

Objective response was a secondary end point that was seen in 76% (95% CI, 68-83) of patients receiving lorlatinib versus 58% (95% CI, 49-66) of those in the crizotinib cohort. And in patients with measurable brain metastases, 82% (95% CI, 57-96) of the lorlatinib group had an intracranial response, compared with 23% (95% CI, 5-54) in the standard-of-care group. Moreover, 71% of patients in the lorlatinib group had an intracranial complete response.

The study noted that there were more grade 3 or 4 adverse events in the lorlatinib group than the crizotinib group (72% vs 56%, respectively), but that they were mainly related to altered lipid levels and could be managed with medication. Overall, 7% of the crizotinib and 9% of the lorlatinib patients stopped treatment due to adverse events.

Based on the interim analysis, study authors concluded that ALK-positive NSCLC patients who received lorlatinib experienced significantly longer PFS and had intracranial responses more often than patients in the crizotinib group. The trial is still ongoing but has shown promising results so far, and researchers will continue to follow patients to track longer-term outcomes like overall survival.

“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, Department of Medical Oncology, Peter MacCallum Cancer Centre in Australia, said in a press release.4 “The results from the CROWN trial demonstrate that Lorbrena 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.”


1. Shaw AT, Bauer TM, De Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. Published online November 19, 2020. Accessed November 20, 2020. doi: 10.1056/NEJMoa2027187

2. What is ALK positive lung cancer? And what are the options for treatment? Lung Cancer Foundation of America. Accessed November 20, 2020.

3. Early treatment with lorlatinib improves survival in some lung cancer patients. News release. Massachusetts General Hospital Cancer Center; November 19, 2020. Accessed November 20, 2020.

4. 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. Pfizer; November 19, 2020. Accessed November 20, 2020.