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Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas.

Authors :
Elkrief A
Makhnin A
Moses KA
Ahn LS
Preeshagul IR
Iqbal AN
Hayes SA
Plodkowski AJ
Paik PK
Ladanyi M
Kris MG
Riely GJ
Michor F
Yu HA
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Apr 14; Vol. 29 (8), pp. 1423-1428.
Publication Year :
2023

Abstract

Purpose: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.<br />Patients and Methods: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.<br />Results: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%).<br />Conclusions: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.<br /> (©2023 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
29
Issue :
8
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
36729110
Full Text :
https://doi.org/10.1158/1078-0432.CCR-22-3484