Effect of pembrolizumab on patients harboring uncommon epidermal growth factor receptor mutations
Authors: Y. Taniguchi, A. Tamiya, S. Ishii, S. Atagi
Journal: Annals of Oncology (2018)

In patients with advanced non-small-cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression, pembrolizumab was associated with significantly longer progression-free and overall survival than was platinum-based chemotherapy [1.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6192) Google Scholar]. The efficacy of immune checkpoint inhibitors (ICIs) in advanced NSCLC patients with epidermal growth factor receptor (EGFR) mutations is limited [2.Haratani K. Hayashi H. Tanaka T. et al.Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.Ann Oncol. 2017; 28: 1532-1539Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 3.Lee C.K. Man J. Lord S. et al.Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis.J Thorac Oncol. 2017; 12: 403-407Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. Furthermore, the efficacy of ICIs in patients harboring uncommon EGFR mutations is unknown. Here we report four NSCLC cases with uncommon EGFR mutations and high PD-L1 expression (>50%) on tumor cells that were treated with the ICI pembrolizumab. Case 1 is a 59-year-old Japanese male smoker with T3N0M1c stage IVB NSCLC harboring EGFR G719A mutation and 80% PD-L1 expression, accompanied by right adrenal gland and brain metastasis, who underwent two cycles of pembrolizumab therapy. Although chemotherapy did not affect the primary lesion, the metastasis in the right adrenal gland was resolved. The therapy was continued as the patient was evaluated with stable disease (SD). Case 2 is a 78-year-old Japanese male ex-smoker with T4N3M1a stage IVA adenocarcinoma harboring EGFR G719C mutation and 65% PD-L1 expression, accompanied by malignant pleurisy, who underwent two cycles of pembrolizumab therapy. Although the primary lesion reduced after chemotherapy (patient had SD), ground glass opacity appeared in the right upper lobe, which possibly caused grade 1 pneumonitis post-treatment. Case 3 is a 45-year-old Japanese male ex-smoker with T4N3M1c stage IVB NSCLC harboring EGFR G719C mutation and 75% PD-L1 expression, accompanied by brain metastasis after radiologic treatment. The size of the primary lesion had increased rapidly after 1-month treatment with afatinib. The patient subsequently underwent two cycles of pembrolizumab treatment, which reduced the size of the primary lesion. The treatment is currently being continued as it elicited partial response (PR). Case 4 is a 70-year-old Japanese female non-smoker with T2aN1M0 stage IIA squamous-cell carcinoma harboring the EGFR E746-T751 del ins A/T790M mutation and 60% PD-L1 expression. Despite left upper lobe resection, the cancer metastasized to the brain, liver, and left adrenal gland. After stereotactic irradiation for brain metastasis, she underwent one cycle of pembrolizumab treatment. However, since liver metastasis increased, the patient was treated with gefitinib, albeit with no effect. Finally, osimertinib decreased the extent of liver metastasis. Pathologic analyses and computer tomography results of the four cases are shown in Figure 1. In summary, three patients with the G719X mutation were male former/current smokers and were effectively treated with pembrolizumab. However, one patient with both common mutation and de novo T790M did not respond to pembrolizumab. The efficacies of non-afatinib treatment strategies for patients harboring uncommon EGFR mutations are uncertain [4.Yang J.C. Sequist L.V. Geater S.L. et al.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Lancet Oncol. 2015; 16: 830-838Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar]. The characteristics of patients harboring uncommon mutations differ from those of patients with common mutations. For example, male smokers were more common among patients with uncommon mutations [5.Tu H.Y. Ke E.E. Yang J.J. et al.A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.Lung Cancer. 2017; 114: 96-102Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Therefore, ICI-based treatment of patients harboring uncommon EGFR mutations. Further investigations are warranted to optimize ICI treatment of patients with uncommon EGFR mutations. None declared.