As reported in The New England Journal of Medicine by Alice T. Shaw, MD, PhD, Global Head of Translational Clinical Oncology at Novartis Institutes for BioMedical Research,* and colleagues, an interim analysis of the phase III CROWN trial has shown that first-line lorlatinib significantly improved progression-free survival and intracranial response rate vs crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC).¹

Alice T. Shaw, MD, PhD

As stated by the investigators: “Lorlatinib, a third-generation inhibitor of … ALK, has antitumor activity in previously treated patients with ALK-positive … NSCLC. The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.”

In the open-label trial, 296 patients from sites in 23 countries who had received no prior systemic treatment for metastatic disease were randomly assigned between May 2017 and February 2019 to receive lorlatinib at 100 mg daily (n = 149) or crizotinib at 250 mg twice daily (n = 147) continuously in 28-day cycles. Randomization was stratified according to the presence of brain metastases and ethnic group (Asian vs non-Asian). Treatment continued until independently assessed disease progression or unacceptable toxicity. Crossover between groups was not permitted. The primary endpoint was progression-free survival on blinded independent central review.

Progression-Free Survival

The median follow-up for progression-free survival was 18.3 months in the lorlatinib group and 14.8 months in the crizotinib group. Progression-free survival at 12 months was 78% (95% confidence interval [CI] = 70%–84%) in the lorlatinib group vs 39% (95% CI = 30%–48%) in the crizotinib group (hazard ratio [HR] = 0.28, 95% CI = 0.19–0.41, P < .001). Median progression-free survival was not reached (95% CI = not reached to not reached) vs 9.3 months (95% CI = 7.6–11.1 months).

Hazard ratios favored lorlatinib across all prespecified patient subgroups. For stratification factors, hazard ratios were 0.20 (95% CI = 0.10–0.43) among patients with brain metastases and 0.32 (95% CI = 0.20–0.49) among those without brain metastases and 0.47 (95% CI = 0.27–0.82) among Asian patients and 0.19 (95% CI = 0.11–0.32) among non-Asian patients.

The 12-month cumulative incidence of central nervous system (CNS) disease progression as the first progression-free survival event was 2.8% in the lorlatinib group vs 33.2% in the crizotinib group (HR for CNS disease progression without previous non-CNS disease progression or death = 0.06, 95% CI = 0.02–0.18). The 12-month cumulative incidence of non-CNS disease progression as the first event was 15.4% vs 44.3% (HR for non-CNS disease progression without prior CNS disease progression or death = 0.30, 95% CI = 0.19–0.47).

Objective response was observed in 76% of patients in the lorlatinib group vs 58% in the crizotinib group (odds ratio [OR] = 2.25, 95% CI = 1.35–3.89), including complete response in four vs zero patients. Median duration of response was not reached vs 11 months.

Overall survival data were not mature at data cutoff. Death had occurred in 23 patients (15%) in the lorlatinib group and 28 patients (19%) in the crizotinib group (HR = 0.72, 95% CI = 0.41–1.25). 

Intracranial Response

Among 17 vs 13 patients with measurable brain metastases at baseline, confirmed intracranial response was observed in 14 (82%) vs 3 patients (23%; OR = 16.83, 95% CI = 1.95–163.23), with a complete response in 12 (71%) vs 1 (8%); median duration of response was not reached vs 10.2 months. Among the 38 vs 40 patients with measurable or nonmeasurable brain metastases, a confirmed intracranial response was observed in 25 (66%) vs 8 (20%; OR = 8.41, 95% CI = 2.59–27.23), with a complete response in 23 (61%) vs 6 (15%); median duration of response was not reached vs 9.4 months.

Adverse Events

The most common adverse events of any grade occurring with more than 10% greater incidence in either group were hypercholesterolemia (70%), hypertriglyceridemia (64%), and edema (55%) in the lorlatinib group and diarrhea (52%), nausea (52%), vision disorder (39%), and vomiting (39%) in the crizotinib group. Grade 3 or 4 adverse events occurred in 72% vs 56% of patients. The most common adverse events in the lorlatinib group were elevated triglycerides (20%), increased weight (17%), elevated cholesterol (16%), and hypertension (10%). The most common grade 3 or 4 adverse events in the crizotinib group were laboratory abnormalities including neutropenia (8%); decreased neutrophils (7%); and increased alanine transaminase (5%), creatine phosphokinase (5%), and lipase (5%).

Serious adverse events occurred in 34% vs 27% of patients; the most common side effects were pneumonia (5%), dyspnea (3%), and respiratory failure (3%) in the lorlatinib group and pneumonia (4%) and pyrexia (2%) in the crizotinib group. Adverse events led to discontinuation of treatment in 7% vs 9%, with causes in more than one patient consisting of cognitive effects (n = 2) in the lorlatinib group and pleural effusion (n = 3) and pneumonitis (n = 2) in the crizotinib group. Fatal adverse events occurred in seven patients in the lorlatinib group and seven patients in the crizotinib group, with no causes occurring in more than one patient. Two deaths in the lorlatinib group were considered possibly related to treatment, with causes consisting of acute cardiac failure in one approximately 2 months after discontinuation of lorlatinib, and respiratory failure due to pneumonia in the other.

The investigators concluded: “In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels.” 

DISCLOSURE: The study was funded by Pfizer. Dr. Shaw has received advisory board fees and lecture fees from Blueprint Medicines and Foundation Medicine; advisory board fees from KSQ Therapeutics; institutional research support and consulting fees from Loxo Oncology and Turning Point Therapeutics; consulting fees from Bayer, Natera, Takeda, EMD Serono, Syros Pharmaceuticals, Chugai Pharmaceutical, Achilles Therapeutics, and ArcherDX; institutional research support, consulting fees, and lecture fees from Ignyta; institutional research support and advisory board fees from Ariad Pharmaceuticals; lecture fees from Guardant Health; consulting fees, lecture fees, and advisory board fees from Servier; institutional research support, consulting fees, lecture fees, and advisory board fees from Genentech–Roche; and has received research support, is employed by, and owns stock in Novartis.

*At the time the study was published, Dr. Shaw was in the Center for Thoracic Cancers at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School.

REFERENCE

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 383:2018-2029, 2020.