Helena A Yu1, Myung-Ju Ahn2, Byoung Chul Cho3, David E Gerber4, Ronald B Natale5, Mark A Socinski6, Nagdeep Giri7, Susan Quinn8, Eric Sbar9, Hui Zhang10, Giuseppe Giaccone11. 1. Memorial Sloan Kettering Cancer Center, 300 East 66th, Street, New York, NY 10065, USA. Electronic address: YuH@mskcc.org. 2. Samsung Medical Center, 50 Ilweon-Dong, Seoul 135-230, South Korea. Electronic address: silkahn@skku.edu. 3. Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: CBC1971@yuhs.ac. 4. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Mail Code 8852, Dallas, TX 75390-8852, USA. Electronic address: david.gerber@utsouthwestern.edu. 5. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd. Ste. AC1042 B Los Angeles, CA 90048-1804, USA. Electronic address: ronald.natale@cshs.org. 6. University of Pittsburgh Medical Center, UPMC Cancer Pavilion, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA. Electronic address: mark.socinski.md@flhosp.org. 7. Pfizer Global Product Development, 10646 Science Center Drive, San Diego, CA 92121, USA. Electronic address: nagdeep.giri@pfizer.com. 8. Pfizer Global Product Development Oncology, 300 Technology Square Suite 302, Cambridge, MA 02139, USA. Electronic address: susan.quinn@pfizer.com. 9. Pfizer Global Product Development Oncology, 500 Arcola Road, Collegeville, PA 19426, USA. Electronic address: eric.sbar@pfizer.com. 10. Pfizer(China) Research & Development Co., Ltd., 3/F, Building 3, Ascendas Lotus Business Park, Lane 60, Naxian Road, Pudong ZhangJiang Hi-tech. Park, Shanghai, 201203, China. Electronic address: Hui.Zhang2@pfizer.com. 11. Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road Washington DC 20007, USA. Electronic address: gg496@georgetown.edu.
Abstract
BACKGROUND: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of dacomitinib may result in inhibition of EGFR T790M. METHODS: We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389). RESULTS: Thirty-eight patients were treated on study with pulse dacomitinib; sixteen with EGFR T790M in Cohort A and 22 who were not molecularly selected in Cohort B. One patient out of 16 patients in Cohort A had a partial response to study therapy (ORR 6.3%, 95% CI 0.2-30.2%). The median progression-free survival (PFS) in Cohort A was 2.3 months and median PFS in Cohort B was 1.6 months. The adverse event profile was similar to standard daily dose dacomitinib with the most frequent treatment-related toxicities occurring in >20% of patients being diarrhea, rash, stomatitis, nausea, dry skin, paronychia, fatigue, and decreased appetite. CONCLUSION: Intermittent pulsatile dacomitinib is safe and relatively well tolerated but is not effective in patients that harbor EGFR T790M or in unselected patients with non-small cell lung cancer.
BACKGROUND: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of dacomitinib may result in inhibition of EGFR T790M. METHODS: We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389). RESULTS: Thirty-eight patients were treated on study with pulse dacomitinib; sixteen with EGFR T790M in Cohort A and 22 who were not molecularly selected in Cohort B. One patient out of 16 patients in Cohort A had a partial response to study therapy (ORR 6.3%, 95% CI 0.2-30.2%). The median progression-free survival (PFS) in Cohort A was 2.3 months and median PFS in Cohort B was 1.6 months. The adverse event profile was similar to standard daily dose dacomitinib with the most frequent treatment-related toxicities occurring in >20% of patients being diarrhea, rash, stomatitis, nausea, dry skin, paronychia, fatigue, and decreased appetite. CONCLUSION: Intermittent pulsatile dacomitinib is safe and relatively well tolerated but is not effective in patients that harbor EGFR T790M or in unselected patients with non-small cell lung cancer.
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