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Weiwei Tan
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.44 - Application of Longitudinal Exposure-Response Modelling to Support Dacomitinib Starting Dose in Patients with EGFR Mutation-Positive NSCLC (ID 2103)
00:00 - 00:00 | Presenting Author(s): Weiwei Tan
- Abstract
Introduction
Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) and EGFR-activating mutations. In a randomized, open-label, phase 3 trial (ARCHER 1050), both progression-free survival and overall survival were significantly increased with dacomitinib versus gefitinib. The recommended starting dose of dacomitinib is 45 mg QD with dose reductions of 30 mg QD and then 15 mg QD for adverse reactions. Due to a high rate of dose reduction or dosing interruption, we developed a longitudinal tumor growth inhibition model to evaluate the effectiveness of the dacomitinib dosing regimen.
Methods
The modelling analyses were based on pooled data from first-line patients with NSCLC and EGFR-activating mutations who were treated with starting doses of dacomitinib either at 30 mg QD or 45 mg QD in Study 1017 (n=45) and at 45 mg QD ARCHER 1050 (n=221). A longitudinal exposure-response (E-R) model for the time course of tumor size changes was developed using the time-varying exposure metrics at the time of tumor measurements. Simulations were performed to evaluate the effect of 3 dose reduction scenarios: 1) 45 mg QD starting dose with the first dose reduction to 30 mg at week 11 and the second dose reduction to 15 mg at week 20 (based on median time of the first and second dose reduction, respectively, in ARCHER 1050); 2) 45 mg QD starting dose with the first dose reduction to 30 mg at week 4 and the second dose reduction to 15 mg at week 11 (patients in ARCHER 1050 who quickly experienced dose reductions); and 3) 30 mg QD starting dose with no dose reductions.
Results
There was a positive and statistically significant E-R relationship, with higher dacomitinib exposure associated with greater tumor shrinkage. The simulations showed that the greatest reduction in tumor size occured in the first few weeks of treatment. Dosing scenarios 1 and 2, where patients receive the starting dose of 45 mg followed by dose reductions due to AEs, resulted in a greater average tumor shrinkage compared to a 30 mg QD starting dose without any dose reductions in Scenario 3 (see the figure).
Conclusion
A positive E-R relationship between dacomitinib exposure and tumor size reduction was demonstrated, supporting the higher starting dose (45 mg QD vs 30 mg QD) of dacomitinib associated with a greater tumor shrinkagein patients with EGFR mutation-positive NSCLC.
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P76.78 - Evaluation of the Development of Brain Metastases in Patients Treated with Dacomitinib or Gefitinib from ARCHER 1050 Study (ID 3461)
00:00 - 00:00 | Author(s): Weiwei Tan
- Abstract
Introduction
Dacomitinib (Vizimpro®) is a competitive, irreversible, small-molecule inhibitor of epidermal growth factor receptor (EGFR). ARCHER 1050 is a multicenter, Phase 3 study conducted in patients with metastatic or recurrent NSCLC harboring EGFR activating mutations (exon 19 deletion or exon 21 L858R substitution mutations) with no prior therapy for metastatic disease. Dacomitinib significantly improved progression-free survival (PFS) and overall survival (OS) against gefitinib with hazard ratios of 0.59 (p<0.001) and 0.75 (p=0.0155), respectively. The present analysis evaluated the risk factors of development of brain metastases from ARCHER 1050, including treatment, baseline characteristics, and dacomitinib exposure.
Methods
CNS imaging was performed in ARCHER 1050 at baseline for all patients and on treatment for patients with clinically suspected brain metastases at the discretion of investigators. Brain lesion data were recorded based on investigator (INV) and independent radiologic central (IRC) reviews. Patients, excluding any history or evidence of brain or leptomeningeal metastases as per the protocol exclusion criteria, were randomized to receive dacomitinib (starting dose of 45 mg QD with allowance of dose reduction to 30 mg or 15 mg) or gefitinib (250 mg QD). Dacomitinib exposure was measured by population PK model-based trough concentrations, average concentrations, or AUC at the end of Cycle 1. Other baseline characteristics were evaluated for its potential association with on treatment development of brain metastases using logistic regression (glm() function).
Results
Based on INV review, no patients in the dacomitinib arm (n=227) presented with baseline brain metastases and 1 patient presented with baseline brain metastases in the gefitinib arm (n=225). After median follow up of 22.1 months, total of 4 (1.8%) patients developed brain metastases in the dacomitinib arm comparing to 14 (6.2%) in the gefitinib arm [odds ratio (OR): 0.27 (95% CI: 0.08, 0.77; p=0.0229)]. Of the 4 patients with developed brain metastases in the dacomitinib arm, 1 patient had no dose reduction and the other 3 patients had dose reduced to 30 mg QD. Similarly, by IRC review, no patients presented with brain metastases at baseline in dacomitinib arm while 4 patients in gefitinib arm were retrospectively found to have baseline brain metastases. According to IRC, only 1 (0.4%) patient in dacomitinib arm and 9 (4.0%) patients in gefitinib arm developed new brain lesions [OR: 0.11 (95% CI: 0.01, 0.57; p=0.0341)]. No other covariates (eg., smoking status, race, sex, baseline ECOG performance status, EGFR mutation type, and baseline brain metastases) were associated with development of new brain lesions. Dacomitinib exposure was explored as a covariate for the INV reported new brain lesions and was not found to be associated with development of brain metastases.
Conclusion
Dacomitinib is associated with a lower incidence of symptomatic CNS progression in the ARCHER 1050 study.
