Lorlatinib Therapy for Rapid and Dramatic Control of Brain and Spinal Leptomeningeal Metastases From ALK-Positive Lung Adenocarcinoma

Abstract

We report a patient with severe neurological deterioration due to leptomeningeal metastases involving brain and spinal cord from anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma, managed rapidly and successfully with lorlatinib therapy. A 48-year-old male patient presented with acute mental deterioration, severe headache, and weakness of both legs. The patient’s previous medical history included cerebral metastases from ALK-positive lung adenocarcinoma, which had been successfully managed via whole brain radiation therapy and gamma knife radiosurgery one year and three months before, respectively. Physical examination revealed neck stiffness and paraparesis with motor grade I. Gadolinium-enhanced brain MRI showed newly developed leptomeningeal enhancement along cerebellar folia, and whole spine MRI revealed similar leptomeningeal metastasis along the whole spinal axis. Lorlatinib was started orally with a dose of 100 mg/day. The patient showed rapid clinical improvement after one week. The patient was alert and the headache disappeared, while the paraparesis improved to normal ambulatory status. Two months of lorlatinib treatment resulted in almost complete disappearance of previous leptomeningeal enhancement of brain and spinal cord, and absence of newly developed metastatic lesions in the central nervous system, based on MRI results. The patient had been regularly followed with ongoing lorlatinib therapy for 5 months without any systemic complications or neurological abnormality. Conclusively, lorlatinib could be a rapid and effective treatment for patients with central nervous system leptomeningeal metastases arising from ALK-positive lung cancer.

Novel approaches to treatment of leptomeningeal metastases

“…(1) EGFRþ: Multiple studies assessing first-and second-generation EGFR-TKIs (gefitinib, erlotinib, afatinib) effect on leptomeningeal metastasis and OS was found to be nearly ]. Lorlatinib, a third-generation ALK-TKI and dual ALK/ ROS1i, has shown intracranial activity in patients with pretreated ALK-positive NSCLC [63] and dramatic responses in case series [64,65]. An international expanded access program of lorlatinib demonstrated that patients with leptomeningeal metastasis (nine ALKþ and two ROS1þ) achieved an intracranial ORR of 45% (95% CI 17-77), and a PFS of 9.3 (95% CI 1.0-NR), OS data were not included [66].…”

“…In the leptomeningeal metastasis arm ( n = 18), intracranial ORR was 12.5% (95% CI, 0.3–52.7), median PFS was 5.2 months (95% CI, 1.6–7.2) and median OS was 7.2 months (95% CI, 1.6–16.9) [62 ▪ ]. Lorlatinib, a third-generation ALK-TKI and dual ALK/ROS1i, has shown intracranial activity in patients with pretreated ALK-positive NSCLC [63] and dramatic responses in case series [64,65]. An international expanded access program of lorlatinib demonstrated that patients with leptomeningeal metastasis (nine ALK+ and two ROS1+) achieved an intracranial ORR of 45% (95% CI 17–77), and a PFS of 9.3 (95% CI 1.0–NR), OS data were not included [66].…”

Leptomeningeal Metastases: New Opportunities in the Modern Era

“…Investigation of a German early access program revealed a partial response rate of 77.8% among 9 patients with LM, but did not provide further details regarding duration of response [90]. While these expanded access datasets are limited due to their retrospective nature and lack of protocolized neuraxial assessments, they complement a number of case reports demonstrating improvement of both LM disease burden and neurologic symptoms following lorlatinib treatment [91][92][93].…”

Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases

“…CSF sampling of 10 total patients treated with lorlatinib 100 mg daily in phase I/II studies revealed a CSF-to-plasma ratio of 0.73 [92] and 0.77 [93], far higher than what had been previously demonstrated for crizotinib. Prospective studies of lorlatinib in patients with LM are lacking, however a phase II subgroup analysis and several case reports in patients with ALK+ LM have highlighted rapid symptom improvement and long-lasting intracranial responses, ranging 8-22 months [88,[94][95][96]. The largest cohort analysis of leptomeningeal activity of lorlatinib derives from an international early/expanded access program of 95 previously TKI-treated patients, in which 11 evaluable patients with LM (9 ALK+ and 2 ROS1+) achieved an intracranial ORR of 45% (95% CI 17-77) and DCR of 91% (95% CI 59-100) [97].…”