Background
Phase I/II single-arm study; N=69 ROS1-positive advanced NSCLC; ~58% had received a prior ROS1 TKI; subset analysis from a larger lorlatinib program.
Interventions and follow up
Treatment: Lorlatinib 100mg PO daily
Primary endpoints: Overall and intracranial response by independent central review
mFollow up: NR
Primary endpoints: Overall and intracranial response by independent central review
mFollow up: NR
Results
ORR (overall): 62%
mDOR (overall): 21.1mo
mDOR (TKI-naïve vs prior crizotinib): 13mo vs 14mo
Intracranial ORR (TKI-naïve vs prior crizotinib): 64% vs 50%
mDOR (overall): 21.1mo
mDOR (TKI-naïve vs prior crizotinib): 13mo vs 14mo
Intracranial ORR (TKI-naïve vs prior crizotinib): 64% vs 50%
Adverse events
Metabolic (grade 3-4): Hypertriglyceridaemia 19%, hypercholesterolaemia 14%
Serious TRAEs: 7%
Class effects: Neurocognitive/mood changes, weight gain, edema (per lorlatinib labeling)
Serious TRAEs: 7%
Class effects: Neurocognitive/mood changes, weight gain, edema (per lorlatinib labeling)
Conclusions
Lorlatinib showed meaningful systemic and intracranial activity in ROS1-positive NSCLC, including in patients who progressed on prior crizotinib, supporting its use in later lines.
Key Limitations
Small single-arm cohort without comparator; mixed TKI-naïve and pretreated populations; activity reduced against the crizotinib-resistant G2032R solvent-front mutation; follow-up not reported.
Clinical Context
Lorlatinib is FDA/EMA approved for ALK-positive NSCLC; ROS1 use is supported by guidelines (ESMO) as a later-line option after prior ROS1 TKI rather than a labeled ROS1 indication.