A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC
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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.
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The efficacy of α-PD-1/PD-L1 is modest in EGFR-mutated patients.
“Generally believed, the efficacy of α-PD-1/PD-L1 is modest in EGFR-mutated patients [184, 185]”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [185]
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- Authors
- Lisberg, A., Cummings, A., Goldman, J. W., Bornazyan, K., Reese, N., Wang, T., Coluzzi, P., Ledezma, B., Mendenhall, M., Hunt, J., Wolf, B., Jones, B., Madrigal, J., Horton, J., Spiegel, M., Carroll, J., Gukasyan, J., Williams, T., Sauer, L., Wells, C., Hardy, A., Linares, P., Lim, C., Ma, L., Adame, C., & Garon, E. B.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Garon, Edward B.
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 13
- Issue
- 8
- Pages
- 1138-1145
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC6063769
- OpenAlex
- W2889653218
- Cited by
- 580
- References
- 27
- Citations by year
- 2026: 29 · 2025: 63 · 2024: 78 · 2023: 74 · 2022: 81 · 2021: 87 · 2020: 78 · 2019: 71 · 2018: 19
- FWCI
- 48.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- pembrolizumab, EGFR-mutant non-small cell lung cancer, PD-L1 expression, immune checkpoint inhibitors, objective response rate, treatment-related adverse events, pneumonitis, EGFR tyrosine kinase inhibitors
- MeSH terms
- Adult, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Protein Kinase Inhibitors, B7-H1 Antigen, Antibodies, Monoclonal, Humanized, ErbB Receptors
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