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Yazdi K. Pithavala
MA08 - Clinical Trials in Brain Metastases (ID 906)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study (ID 12760)
15:45 - 15:50 | Author(s): Yazdi K. Pithavala
The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.a9ded1e5ce5d75814730bb4caaf49419 Method
Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.4c3880bb027f159e801041b1021e88e8 Result
In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.
Months Cumulative Incidence Probability Patients with ≥1 prior ALK TKIa CNS Progression
Death All patients (n=198)
Patients with baseline CNS metastases (n=131)
6 mos12 mos
Patients with no baseline CNS metastases (n=67)
6 mos12 mos
aPatients in expansion cohorts EXP2–5 from the phase 2 studyNE, not evaluable
Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.
1. Collier, et al. Mol Imaging 2017;16:1–3.
2. Zou, et al. Cancer Cell 2015;28:70–81.6f8b794f3246b0c1e1780bb4d4d5dc53
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