Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression

Abstract

Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that has improved survival and central nervous system (CNS) outcomes in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. However, little is known about the efficacy and safety of combining osimertinib with chemotherapy.

Methods: This was a retrospective study performed at 3 institutions. Patients with advanced EGFR-mutated NSCLC who received concurrent osimertinib with chemotherapy in the third-line or beyond were identified by chart review. Efficacy outcomes including duration on treatment (DOT), overall survival (OS), and CNS outcomes were assessed. Safety outcomes were also evaluated.

Results: A total of 44 patients met inclusion criteria. Median DOT with osimertinib plus platinum doublet (n = 28) was 6.1 months (95% CI 4.1 months-not reached), and with osimertinib plus single-agent chemotherapy (n = 29) was 2.6 months (95% CI 1.8-4.8 months). Median OS from the start of osimertinib plus chemotherapy was 10.4 months (95% CI 7.0-13.2 months). At initiation of osimertinib plus chemotherapy, 37 patients (84%) had CNS metastases; 9 of these (24%) had CNS disease progression on osimertinib plus chemotherapy. Chemotherapy was delayed or dose reduced due to toxicity in 8 patients (18%); osimertinib was discontinued in 1 patient (2%) for reduced cardiac ejection fraction, and dose reduced in 2 patients (5%).

Conclusions: The combination of osimertinib plus chemotherapy appeared safe and showed favorable control of CNS disease in this cohort of patients who had progressed systemically with multiple prior lines of therapy, with DOT and survival outcomes similar to historical chemotherapy controls.

Trial registration: ClinicalTrials.gov NCT04035486.

Keywords: Brain metastases; Chemotherapy; Combination therapy; EGFR; EGFR tyrosine kinase inhibitor; Osimertinib; Targeted therapy.

Conflict of interest statement

Disclosure Dr. White has nothing to disclose. Dr. Piotrowska reports research support from Novartis, AstraZeneca, Takeda, Spectrum, Tesaro and Cullinan Oncology, and consulting fees from Blueprint Medicines, Eli Lilly, C4 Therapeutics, InCyte, Medtronic, AstraZeneca and Genentech. Dr. Stirling has nothing to disclose. Dr. Liu reports grants from Alkermes, grants, personal fees and non-financial support from AstraZeneca, grants from Bayer, grants and personal fees from Blueprint, nonfinancial support from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb, personal fees from Catalyst, personal fees from Celgene, grants from Clovis, grants from Corvus, personal fees from G1 Therapeutics, grants, personal fees and non-financial support from Genentech/Roche, personal fees from Guardant Health, personal fees from Inivata, grants and personal fees from Janssen, grants and personal fees from Lilly, grants from Lycera, personal fees from LOXO, grants, personal fees and nonfinancial support from Merck/MSD, grants from Merus, grants from Molecular Partners, grants and personal fees from Pfizer, personal fees from PharmaMar, grants from Rain Therapeutics, personal fees from Regeneron, grants from RAPT, personal fees from Spectrum, grants from Takeda, grants from Turning Point Therapeutics, outside the submitted work. Ms. Banwait has nothing to disclose. Dr. Cunanan has nothing to disclose. Dr. Sequist reports research support from Novartis, AstraZeneca, and Genentech, LOXO and Blueprint Medicines, and consulting fees from AstraZeneca, Janssen and Genentech. Dr. Wakelee reports research support from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Xcovery; served an advisory role for AstraZeneca, Xcovery, Janssen, Mirati, Daiichi Sankyo, Helsinn, and Blueprint; and reports honoraria from Clinical Care Options Oncology LLC, Fishawack Facilitate LTD, Medscape, Onclive/Intellisphere LLC, Physicians Education Resource LLC, Prime Oncology LLC, Research to Practice, UpToDate, and WebMD Health. Dr. Hausrath has nothing to disclose. Dr. Neal reports research support from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, and GSK; serves an advisory role for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lily and Company, Calithera Biosciences, Amgen, and Iovance Biotherapeutics; and reports honoraria from Research to Practice, MLI Peerview, Medscape, Biomedical Learning Institute, Prime Oncology, Rockpointe, CME Matters, and MJH CME; and reports royalties from UpToDate.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Kaplan-Meier estimates of duration on treatment for (A) osimertinib plus first chemotherapy (n=44), (B) osimertinib plus platinum doublet (n=28), (C) osimertinib plus single agent chemotherapy (n=29). Median duration on treatment (mDOT) shown in months (95% confidence interval). NR, not reached.

Figure 2.

Kaplan-Meier estimates of overall survival for full cohort (n=44 patients) (A) from diagnosis of metastatic disease, (B) from start of osimertinib therapy, (C) from start of osimertinib plus chemotherapy. Median overall survival (mOS) shown in months (95% confidence interval). NR, not reached.