"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer

Abstract

Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months) and median overall survival was 12 months (range, 2.5 months-not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

“…In the four patients who had not received prior brain radiotherapy, a complete response was achieved in two patients and one had a partial response. In this study, at the 600 mg twice daily dose of alectinib, the CSF trough concentration of alectinib was 2.69 nM/L, which is nearly the same as the unbound systemic trough of alectinib of 3.12 nM/L, and exceeds the IC 50 for ALK inhibition for alectinib in cell-free assays (1.9 nM/L) [149]. In the Japanese phase I/II alectinib study, 15 patients had known brain metastases, 12 of whom had previous brain radiation.…”

“…In a retrospective analysis of 9 patients with EGFR-mutated NSCLC and brain metastases, a median erlotinib dose of 1500 mg weekly was utilized. Partial CNS response was witnessed in 67 % of patients with a median time to CNS progression of 2.7 months and median OS of 12 months [50].…”

“…Unlike crizotinib, it does not inhibit c-MET [136,143]. Ceritinib more potently inhibits ALK than crizotinib, as ceritinib produces IC 50 values of 0.15 nM in enzymatic assays (crizotinib IC 50 3.6 nM) and IC 50 of 25nM in cell lines [136,144]. The recommended starting dose is 750 mg administered orally once daily.…”

Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…Previous studies have indicated that re-initiation of EGFR-TKI may be an option for patients who previously exhibited EGFR-TKI resistance (10,11), possibly due to repopulation of the tumor tissue by cancer cells responsive to EGFR-TKI. Small-sample clinical trials have also demonstrated that a number of patients exhibiting acquired resistance to EGFR-TKIs benefited from treatment with high-dose pulsatile TKIs (12,13), potentially due to a dependence of resistant tumor cells on the EGFR signaling pathway. However, conventional TKI doses are not sufficient at inhibiting EGFR overexpression if a resistant cell population arises (14).…”

ALK on my mind: alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements

“…Whether specific fusion partners and/or breakpoint variant biology hold up in CNS-specific analyses or investigating if alectinib can overcome the biologic variation remains to be determined. Dosing strategies to overcome poor CNS activity have met some success in EGFR mutant NSCLC, and were not formally examined in the analysis by Gadgeel and colleagues (19). While alectinib 600 mg twice daily by mouth yields respectable intracranial response and tolerability it is unclear if higher or "pulse" dose would achieve superior response rate.…”