Lorlatinib Achieves Success in Phase III Head-to-Head Study as First-Line Therapy

On November 19, 2020, Pfizer announced the positive results of the phase III head-to-head CROWN study, which evaluated Lorbrena (lorlatinib) versus Xalkori (crizotinib) as first-line treatments for patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).

The CROWN study is a global, randomized, open-label, parallel, two-arm, phase 3 trial that enrolled a total of 296 previously untreated (treatment-naive) patients with advanced ALK-positive NSCLC. In the study, these patients were randomly assigned in a 1:1 ratio to receive either Lorbrena (lorlatinib) monotherapy (n=149) or Xalkori (crizotinib) monotherapy (n=147). The primary endpoint was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), intracranial ORR, and safety.

The results showed that the study met its primary endpoint at the pre-specified interim analysis:

As assessed by BICR, treatment with Lorbrena (lorlatinib) demonstrated a statistically significant and clinically meaningful improvement in PFS compared with Xalkori (crizotinib) (hazard ratio [HR]=0.28; 95% confidence interval [CI]: 0.19–0.41; p<0.001), which translates to a 72% reduction in the risk of disease progression or death.

For the secondary endpoint, OS data were immature at the time of the interim analysis.

In terms of ORR, the rate was 76% (95% CI: 68–83) in the Lorbrena (lorlatinib) group versus 58% (95% CI: 49–66) in the Xalkori (crizotinib) group.

In addition, Lorbrena (lorlatinib) exhibited enhanced intracranial activity compared with Xalkori (crizotinib): at 12 months, 96% (95% CI: 91–98) of patients in the Lorbrena (lorlatinib) group had no central nervous system (CNS) progression, versus 60% (95% CI: 49–69) in the Xalkori (crizotinib) group.

Among patients with brain metastases (n=30), the intracranial ORR was 82% (95% CI: 57–96; n=14) in the Lorbrena (lorlatinib) group versus 23% (95% CI: 5–54; n=3) in the Xalkori (crizotinib) group, with intracranial complete response rates (CRR) of 71% and 8%, respectively.

In the study, adverse events (AEs) occurring in more than 20% of patients in the Lorbrena (lorlatinib) group included hypercholesterolemia (70%), hypertriglyceridemia (64%), edema (55%), weight gain (38%), peripheral neuropathy (34%), cognitive effects (21%), and diarrhea (21%).

Grade 3 or 4 AEs were reported in 72% of patients in the Lorbrena (lorlatinib) group and 56% in the Xalkori (crizotinib) group. The most common grade 3 or 4 AEs in the Lorbrena group were hypertriglyceridemia (20%), weight gain (17%), hypercholesterolemia (16%), and hypertension (10%).

AEs leading to permanent treatment discontinuation occurred in 7% of patients in the Lorbrena (lorlatinib) group and 9% in the Xalkori (crizotinib) group.

Data related to the CROWN study results have been published in The New England Journal of Medicine (NEJM), a top international medical journal.