Drastic antitumor response following administration of afatinib immediately after atezolizumab in a patient with epidermal growth factor receptor tyrosine kinase inhibitor‐resistant lung cancer

Abstract

A 61-year-old Asian man with a smoking history underwent chemoradiotherapy for stage IIIB (cT4N2M0) left upper lobe pulmonary adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) gene. In December 2013, he received carboplatin (area under the curve, 2), paclitaxel (40 mg/m) on days 1, 8, and 15 for two 3-week-cycles, and radiotherapy (60 Gy distributed over 30 fractions, 5 days per week) as first-line therapy. He subsequently presented with primary tumor regrowth in July 2015. Treatment with cisplatin, pemetrexed, and bevacizumab was initiated; however, after 13 months, right pulmonary metastasis recurred. He responded well upon being switched to afatinib (40 mg/day) for approximately four years before experiencing multiple relapses. The results of pleural fluid biopsies showed an exon 19 deletion but no T790M mutation. Therefore, in November 2020, afatinib was discontinued and the immune checkpoint inhibitor (ICI) atezolizumab (1200 mg/bodyweight, every 3 weeks) was prescribed. Two months later, chest computed tomography (CT) revealed that the primary tumor had grown and formed a hilar mass (Figure 1(a)). In January 2021, samples from the left upper lobe were biopsied; there was an exon 19 deletion, no T790M nutation, and PD-L1 TPS 80%. A fifth strategy was initiated— rechallenge administration of afatinib (40 mg/day) immediately after atezolizumab. The hilar mass markedly diminished 10 days after commencing afatinib (Figure 1(b)). Response has been sustained for more than 12 weeks. Recently, researchers have demonstrated that EGFR inhibition improves responsiveness to programmed cell death 1 (PD-1) blockade in EGFR-mutated non-small cell lung cancer (NSCLC). EGFR signaling is important in driving high regulatory T cell (Treg) infiltration, despite low CD8 effector T cell infiltration in EGFR-mutated lung adenocarcinomas, via CCL22 upregulation through JNK/cJun and CXCL10 downregulation mediated by IRF1. EGFR–TKIs reduce the high levels of Treg infiltration associated with EGFR mutation-positive NSCLC. Animal studies indicated a greater antitumor effect with combination EGFR– TKI/anti-PD-1 antibody therapy than with either therapy alone. Further, Tregs express EGFR in inflamed tumor microenvironments, and the mast cell-derived epidermal growth factor-like amphiregulin enhances Treg immunosuppressive effects, a phenomenon inhibited by EGFR–TKIs. Immunohistochemical staining of the rebiopsied tissue before afatinib treatment showed that tumor cells expressed high levels of PDL1, and CD8-positive effector T cells infiltrated the tumor stroma but did not respond to antiPD-L1 antibody. This might be because of simultaneous FOXP3-positive T cell (Treg) infiltration (Figure 2(a)–(d)). Thus, although afatinib and atezolizumab were administered sequentially to our patient, EGFR inhibition by afatinib might have improved responsiveness to PD-1 blockade induced by atezolizumab in EGFR–TKI-resistant tumors. Declaration of Interest: The authors state that they have no conflict of interest. Received: 15 April 2021 Accepted: 18 May 2021