A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC

Abstract

Background: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%.

Methods: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab.

Results: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern.

Conclusions: Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

Keywords: EGFR; NSCLC; pembrolizumab; programmed death 1 (PD-1); programmed death ligand 1; tumor immunology.

Conflict of interest statement

Conflicts of Interest:

Dr. Lisberg reports compensated AstraZeneca advisory board attendance.

Dr. Garon reports funds to his institution from AstraZenca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech, Mirati, Merck, and Novartis.

Dr. Goldman reports grants from BMS and Medimmune/AstraZeneca during the conduct of the study.

Dr. Mendenhall reports compensation for Merck speaker’s bureau.

The remaining authors have no conflicts of interest to report.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Best Response for Target Lesions by Patient While on Trial

Waterfall plot for patients on trial with evaluable radiographic images. PD - progressive disease, SD - stable disease, EGFR-WT - epidermal growth factor receptor wild type. *Subject deemed to have progression based on dural thickening on brain MRI. †Subject with complete response of target lesion but non-target progression on first scan

Figure 2. Time on Trial and Subsequent Therapies

Swimmer plot of time on treatment with reason(s) for treatment discontinuation. *Adverse event leading to treatment discontinuation. †Completed treatment and now on surveillance, still alive at time point of data collection. ‡Death while on erlotinib. §Subject without EGFR mutation.