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Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development.

ABSTRACT: 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.

SUBMITTER: Lampson BL

PROVIDER: S-EPMC5311035 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development.

Lampson Benjamin L BL Nishino Mizuki M Dahlberg Suzanne E SE Paul Danie D Santos Abigail A AA Jänne Pasi A PA Oxnard Geoffrey R GR

Cancer 20160815 22

<h4>Background</h4>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.<h4>Methods</h4>An institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had ...[more]

PMID: 27525836

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Project description:Background. Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent 'confirmatory' Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of 'the' maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as 'dose-finding', but as dose titration algorithm (DTA)-finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug's population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace 'the' MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents.

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Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development.

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Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development.

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