Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers Journal Article
| Authors: | Yu, H. A.; Sima, C.; Feldman, D.; Liu, L. L.; Vaitheesvaran, B.; Cross, J.; Rudin, C. M.; Kris, M. G.; Pao, W.; Michor, F.; Riely, G. J. |
| Article Title: | Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers |
| Abstract: | Background: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. Methods: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib. Results: We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200mg days 1-2 and 50mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%). Conclusion: This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients. © The Author 2016. |
| Keywords: | acquired resistance; egfr-mutant lung cancer; egfr t790m; evolutionary modeling; pulse dose erlotinib |
| Journal Title: | Annals of Oncology |
| Volume: | 28 |
| Issue: | 2 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2017-02-01 |
| Start Page: | 278 |
| End Page: | 284 |
| Language: | English |
| DOI: | 10.1093/annonc/mdw556 |
| PROVIDER: | scopus |
| PUBMED: | 28073786 |
| PMCID: | PMC5834093 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 July 2017 -- Source: Scopus |
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