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Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.

ABSTRACT: Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was tolerable and prolonged progression-free survival and reduced the frequency of acquired resistance. Intermittent EGFR-targeted high-dose schedules induce more profound as well as sustained target inhibition and may afford enhanced therapeutic efficacy.

SUBMITTER: Schottle J

PROVIDER: S-EPMC4770714 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.

Schöttle Jakob J Chatterjee Sampurna S Volz Caroline C Siobal Maike M Florin Alexandra A Rokitta Dennis D Hinze Yvonne Y Dietlein Felix F Plenker Dennis D König Katharina K Albus Kerstin K Heuckmann Johannes M JM Rauh Daniel D Franz Thomas T Neumaier Bernd B Fuhr Uwe U Heukamp Lukas C LC Ullrich Roland T RT

Oncotarget 20151101 36

Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was t ...[more]

PMID: 26540572

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Project description:BACKGROUND:Erlotinib is a standard first-line therapy for patients who have metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150?mg daily is the maximum tolerated dose (MTD). Few clinical data are available regarding its efficacy at doses less than the MTD. METHODS:An institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had received treatment with erlotinib. The treatment course, including the erlotinib dose at initiation of treatment, at 4 months into therapy, and at disease progression, was retrospectively studied. Progression-free survival (PFS) was compared between patients who received the MTD (150?mg) and those who received reduced-dose erlotinib (?100?mg). RESULTS:In total, 198 eligible patients were identified. Thirty-one patients (16%) were initiated on reduced-dose erlotinib; they were older (P?=?.001) and had lower performance status (P?=?.01) compared with those who were initiated on erlotinib at the MTD. The response rate to reduced-dose erlotinib was 77%. The median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at the MTD, a difference that was not statistically significant (hazard ratio, 0.81; 95% confidence interval, 0.54-1.21; P?=?.30). There was a nonsignificant trend toward higher rates of progression within the central nervous system with reduced-dose erlotinib. CONCLUSIONS:At doses below the MTD, erlotinib treatment results in a high response rate and a prolonged median PFS. Review of the literature indicates that 15 of 30 small-molecule inhibitors that are approved or in late-stage development for cancer therapy have recommended doses below the MTD. When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted. Cancer 2016;122:3456-63. © 2016 American Cancer Society.

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Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.

Publications

Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.

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