A Rare EGFR R748T Mutation in A Squamous Cell Lung Carcinoma Patient with PD-L1 High Expression and Response to Immuno-Chemo Combination Therapy

Background: In present, patients with stage IV or recurrent/metastatic non-small cell lung cancer (NSCLC) whose tumors harbor programmed death ligand 1 (PD-L1) expression and active Epidermal Growth Factor Receptor (EGFR) mutations should receive initial EGFR tyrosine kinase inhibitors (TKIs) based on clinical guidelines and practice. However, high PD-L1 expression correlates with primary resistance to EGFR-TKIs in treatment advanced EGFR-mutant lung cancer patients, the optimal use of ICI therapy in patients with actionable EGFR mutations remains an important eld of ongoing research. Some studies also showed that patients with uncommon EGFR mutations have a good immunotherapy potential. Case prestation: Here, we report a 56-year old advanced squamous cell lung carcinoma (SCC) patient with a rare active mutation in EGFR gene (EGFR p.R748T) and PD-L1 expression who responded well to the immune-chemo combination therapy (pembrolizumab with nab-paclitaxel and nedaplatin). Conclusion: The EGFR R748T mutation is an uncommon active mutation and there is no report about immuno-chemo therapy on patient with EGFR R748T mutation and PD-L1 high expression. The result presented in this case provides a feasible therapy for some patients who harbor rare active EGFR mutations (except for G719X, L861Q, S768I, and Ex20 ins) with high PD-L1 expression.

with a rare active mutation in EGFR gene (EGFR p.R748T) and PD-L1 expression who responded well to the immune-chemo combination therapy (pembrolizumab with nab-paclitaxel and nedaplatin).
Conclusion: The EGFR R748T mutation is an uncommon active mutation and there is no report about immuno-chemo therapy on patient with EGFR R748T mutation and PD-L1 high expression. The result presented in this case provides a feasible therapy for some patients who harbor rare active EGFR mutations (except for G719X, L861Q, S768I, and Ex20 ins) with high PD-L1 expression.
Background Targeted therapies and more recently immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced NSCLC [1]. However, the activity of ICIs across NSCLC harboring oncogenic alterations is poorly characterized. On the one hand, patients with oncogene-driven NSCLC such as EGFR, ALK always have been left behind-either excluded from pivotal immunotherapy clinical trials or demonstrated lack of e cacy to immune checkpoint blockade [2,3]. On the other hand, targeted therapies are e cient in the context of oncogenic driver mutations [4]. But unfortunately, target therapies are associated not only with high response rate, but also with unavoidable development of resistance and tumor recurrence. Meanwhile, it has been reported that the high expression of PD-L1 was a factor of primary EGFR-TKI resistance [5,6]. In present, some studies have shown that different EGFR subtypes responded differently to immunotherapy, some rare EGFR mutations have immunotherapy potential [7][8][9]. Therefore, after exhaustion of targeted agents or naïve advanced EGFR-mutant with PD-L1 high expression, immunotherapy may be considered as a salvage treatment. In this case report, we presented a squamous cell lung carcinoma (SCC) patient with a rare active EGFR p.R748T mutation and PD-L1 high expression who bene ted from combination pembrolizumab with nab-paclitaxel and nedaplatin.

Case Presentation
A 56-year old men with history of smoking was admitted to our hospital with complaints of irregular coughing and fever. Nucleic acid test result was negative. The patient then had a thoracic computed tomography (CT) scan, which revealed a lesion in the lower lobe of the right lung and some pleural effusion. Transbronchoscopic needle aspiration biopsy indicated SCC and immunohistochemistry (IHC) revealed AE1/AE3 (+), Ki-67 (partial about 40%), P40 (+), P63 (+). With further imaging scan, the patient was diagnosed as SCC (IV stage), with multiple lymph node metastasis (including retroperitoneal, bilateral neck and supraclavicular fossa). Next-generation sequencing was conducted, and a rare mutation-EGFR R748T-was identi ed (Fig. 1a). Notably, it was only one reported in an ASCO abstract that an early stage patient with this mutation was treated with erlotinib as postoperative adjuvant therapy and had 54.4 months disease-free survival (DFS) [10]. At the same time, the EGFR R748T mutation located in the kinase domain of EGFR. Therefore, we believe that this mutation is an EGFR-activating oncogenic mutation. However, Simultaneously, The PD-L1 expression assessed by VENTANA PD-L1 (SP263) Assay showed more than 50% of tumor cells exhibit positive (Fig. 1b). Consideration of the possibility of primary resistance to EGFR-TKIs and multiple metastases of the patient, we decided to try the immuno-chemo combination therapy. The patient thus received 200 mg of pembrolizumab with nabpaclitaxel (220 mg/m 2 ) and nedaplatin (80 mg/m 2 ). Soon, CT scan revealed shrinkage of the tumor in inferior lobe of right lung and lung recruitment (Fig. 1c). During the period of rst administration, the patient appeared moderate gastrointestinal adverse reaction and III grade myelosuppression. After symptomatic treatment, patient's adverse reaction symptoms were relieved. Then we reduced the nabpaclitaxel dosage to 180 mg/m 2 . After treatment two cycles, imaging showed the neoplasm continuously reduced (Fig. 1c), and the patient was evaluated as partial response (PR). The treatment has lasted 2 months and the patient is still in follow-up.

Discussion And Conclusions
Review of some immunotherapy clinical trials that have included EGFR-mutant patients consistently demonstrates lack of improved clinical outcomes for this population [3,11,12]. In a phase II trial of untreated, EGFR-mutant, PD-L1 ≥ 1% NSCLC, none of the 11 patients responded to Pembrolizumab except for a patient whose EGFR-positive status was erroneous. Furthermore, this study included 73% of patients with PD-L1 ≥ 50%, thus illustrating the poor response in EGFR-mutated NSCLC even with high PD-L1 expression [3]. Several reasons to these poor outcomes have been identi ed, such as the association of EGFR mutation with low tumor mutation burden (TMB) and the lack of T cell in ltration while PD-L1 expression is variable [2,13,14]. Nevertheless, some studies showed that patients with uncommon EGFR (including G719X, L861Q, S768I, and Ex20 ins) mutations have a good immunotherapy potential [15][16][17]. Because these EGFR mutations showed higher rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment than the proportion in patients with classic sensitive mutations [7]. Therefore, immunotherapy for patients with rare EGFR mutations and its mechanism research are interesting direction.
To our best knowledge, there is no report about immuno-chemo therapy on patient with EGFR R748T mutation and PD-L1 high expression. The evidence presented in this case provides a feasible therapy for some patients who harbor a rare EGFR mutation (except for G719X, L861Q, S768I, and Ex20 ins) with high PD-L1 expression. However, the effect of immuno-chemo therapy to EGFR rare mutation, especially its side effect, should be further investigated in subsequent studies. In brief, more studies are needed for better understanding of immune checkpoint inhibitors in rare EGFR mutation NSCLC.

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Competing interests
None of the authors have con icts of interest to disclose.