Osimertinib Demonstrates Early Efficacy for Leptomeningeal Disease in NSCLC

James Chih-Hsin Yang, MD, PhD

Phase I findings of a study examining the efficacy of osimertinib (Tagrisso) in heavily pretreated patients with EGFR-mutated advanced non—small cell lung cancer (NSCLC) and leptomeningeal disease showed promising activity in the patient population.

Seven patients in the study have been on osimertinib treatment for >9 months. “Time on treatment suggests durable clinical benefit,” said Yang, director of the Cancer Research Center, National Taiwan University, Taipei, Taiwan.

About 9% of patients with NSCLC with an EGFR mutation develop leptomeningeal disease, and these patients deteriorate rapidly. Even with TKI treatment, the median overall survival is poor (<10 months).

Blood-brain barrier penetration is limited with first- and second-generation EGFR TKIs. “First-generation EGFR TKIs…have some activity in leptomeningeal metastases; however, the activity seems to be transient,” Yang said, noting that most studies with early-generation TKIs excluded patients with leptomeningeal metastases.

Osimertinib is a third-generation EGFR TKI that has shown activity in patients with NSCLC who have brain metastases and harbor EGFR or T790M mutations. A preclinical study of osimertinib also showed sustained tumor regression in an EGFR-mutated PC9 mouse brain metastasis model. The brain-to-blood ratio increased more than two-fold within 90 minutes of exposure to osimertinib in nonhuman primate and mouse models, but the increase was trivial with rociletinib and gefitinib.

BLOOM was originally designed to assess the safety and activity of AZD3759 in patients with EGFR-mutated advanced NSCLC, but an arm to assess osimertinib, 160 mg/day, in patients with leptomeningeal metastases was added when brain-penetrating activity was discovered in the preclinical models, explained Yang.

Twenty-one patients were enrolled on the study with advanced or metastatic NSCLC, including patients with an EGFR mutation (either L858R or exon 19 deletion), stable extracranial disease, a confirmed diagnosis of leptomeningeal disease by positive CSF cytology, and at least 1 leptomeningeal lesion visualized by MRI.

To be eligible, patients must have been treated previously with at least 1 EGFR TKI. The most common prior TKI was gefitinib (n = 16); 14 patients had a partial response to a prior EGFR TKI as their best response, 6 had stable disease, and 1 had progressive disease. Patients received a median of 3 lines of systemic treatment prior to enrollment. Eleven patients had prior whole brain radiotherapy.

All 21 patients were Asian. Two patients had T790M detected in CSF at study entry and 6 had T790M detected in plasma. Nine patients had exon 19 deletion and 13 patients had L858R mutation, yet one patient had both mutations.

Duration of treatment ranged from 1 to 49 weeks, with treatment ongoing in 15 patients. The other 6 patients withdrew from the study due to progressive disease. Of the 15 patients still receiving treatment, 7 have been on treatment for longer than 9 months. Grade 3/4 adverse events occurred in 9 patients (43%), with only 3 being drug-related. Two patients required dose reduction to 80 mg, 1 due to pruritus and 1 patient because of neutropenia.

Seven of the 21 patients (33%) had a confirmed radiological response as assessed by intracranial MRI. Nine patients had stable disease as their best response and 3 had an unconfirmed response or stable disease (subsequent MRI scans were not available in these 3 patients).

Of the 11 patients who entered the study with normal neurologic status, only 1 patient worsened. Of the 10 patients with abnormal neurologic assessment at baseline, 5 were considered improved with 2 consecutive neurologic examinations showing improvement; improvement was unconfirmed in 3 of the patients.

Data on EGFR-mutant DNA copy numbers in CSF were available in 9 patients. Six of the 9 had >50% decrease in EGFR-mutant DNA copies, and 5 of the 6 had a decrease that persisted up to cycle 9. Four of 6 patients had improved neurologic function, 4 had a response and 2 had stable disease on MRI, and 2 had CSF clearance of tumor cells.

A second osimertinib cohort has since been added to the BLOOM study; accrual of 20 patients with T790M-positive NSCLC and leptomeningeal metastases is ongoing.

Jänne noted that current treatment approaches—such as radiation, pulse erlotinib, or gefitinib—for disease progression in the central nervous system (CNS) are limited due to poor CNS penetration. In contrast, osimertinib is a brain-penetrant drug, with the ratio of the unbound brain tissue concentration to unbound plasma concentration being 0.39.

"Anything greater than 0.3 is a very brain-penetrant drug,” he said. “Just for reference, gefitinib, its value is .021.”

“I look forward to being able to use this information to prescribe osimertinib for patients who develop this devastating complication with their lung cancer,” said invited discussant Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute.

Yang J C-H, Kim D-W, Kim S-W, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study. Presented at: American Society of Clinical Oncology, June 3-7, 2016; Chicago, IL. Abstract 9002.

In the BLOOM study, which was presented during the 2016 ASCO Annual Meeting, treatment with the third-generation EGFR TKI osimertinib was associated with radiologic improvement of leptomeningeal disease in 33% and neurologic improvement in patients who presented with neurologic impairment at baseline. In addition, 2 of the 21 patients (9.5%) enrolled experienced clearing of cerebrospinal fluid (CSF) cytology, said James Chih-Hsin Yang, MD, PhD, who announced the results.