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

Grommes, C.; Oxnard, G. R.; Kris, M. G.; Miller, V. A.; Pao, W.; Holodny, A. I.; Clarke, J. L.; Lassman, A. B.

doi:10.1093/neuonc/nor121

Cited by 349Lung Cancer Treatments and MutationsBrain Metastases and TreatmentHER2/EGFR in Cancer Research

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

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Grommes, C., Oxnard, G. R., Kris, M. G., Miller, V. A., Pao, W., Holodny, A. I., Clarke, J. L., Lassman, A. B.·2011·Neuro-Oncology

DOI 10.1093/neuonc/nor121PMC PMC3223088

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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.

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High-dose or pulsatile dosing of EGFR TKIs may produce a higher response rate in leptomeningeal disease.
“In particular, a high dose or pulsatile dosing may produce a higher response rate in this situation.[119][120][121]”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [121]

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Authors: Grommes, C., Oxnard, G. R., Kris, M. G., Miller, V. A., Pao, W., Holodny, A. I., Clarke, J. L., & Lassman, A. B.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Lassman, A. B.
ORCID: Grommes, C.
Oxnard, G. R.
Kris, M. G.
Pao, W.
Holodny, A. I.
Clarke, J. L.
Lassman, A. B.
Venue: Neuro-Oncology
Publisher: Oxford University Press (OUP)
Published: 2011-08-24
Volume: 13
Issue: 12
Pages: 1364-1369
ISSN: 1522-8517 (ISSN-L)
1523-5866
DOI: 10.1093/neuonc/nor121
PMC: PMC3223088
OpenAlex: W2128688922
Cited by: 349
References: 22
Citations by year: 2026: 7 · 2025: 9 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 10 · 2020: 22 · 2019: 22 · 2018: 39 · 2017: 57 · 2016: 40 · 2015: 33 · 2014: 32 · 2013: 24 · 2012: 14
FWCI: 19.63
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Neuro-Oncology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Doris Duke Charitable Foundation
Memorial Sloan-Kettering Cancer Center
Geoffrey Beene Cancer Research Center
National Institutes of Health
National Cancer Institute (R01CA121210)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: erlotinib, EGFR mutation, non-small cell lung cancer, brain metastases, leptomeningeal metastasis, cerebrospinal fluid drug concentration, CNS penetration, EGFR tyrosine kinase inhibitors, acquired resistance, T790M mutation, treatment response
MeSH terms: Erlotinib Hydrochloride, Adult, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, Retrospective Studies, Survival Rate, Central Nervous System Neoplasms, Treatment Outcome, ErbB Receptors

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

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