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Phase 2 study of intermittent pulse dacomitinib in patients with advanced non-small cell lung cancers
Helena A Yu1, Myung-Ju Ahn2, Byoung Chul Cho3
1Memorial Sloan Kettering Cancer Center, 300 East 66th, Street, New York, NY 10065, USA.
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.
Insights
Intermittent pulsatile dacomitinib dosing is safe but ineffective for non-small cell lung cancer patients with or without EGFR T790M mutations. Further research into novel EGFR TKI strategies is warranted.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).
- Pre-clinical studies indicated potential for intermittent pulsatile dacomitinib to inhibit EGFR T790M.
- EGFR mutations are key drivers in non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and efficacy of intermittent pulsatile dacomitinib.
- To assess outcomes in both molecularly unselected NSCLC patients and those with EGFR T790M mutations.
Main Methods:
- A clinical trial (NCT01858389) involving 38 patients treated with intermittent pulsatile dacomitinib.
- Two cohorts: Cohort A (16 patients with EGFR T790M) and Cohort B (22 unselected patients).
- Safety, pharmacokinetics, and efficacy endpoints were assessed.
Main Results:
- One partial response (6.3%) was observed in Cohort A (EGFR T790M positive).
- Median progression-free survival was 2.3 months in Cohort A and 1.6 months in Cohort B.
- Adverse events were similar to daily dosing, including diarrhea, rash, and stomatitis.
Conclusions:
- Intermittent pulsatile dacomitinib is safe and well-tolerated in NSCLC patients.
- This dosing strategy demonstrated lack of efficacy in patients with EGFR T790M mutations.
- The regimen was also ineffective in unselected non-small cell lung cancer patients.
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