Ten percent of non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations harbor uncommon variants. These mutations are mainly involved in lung adenocarcinomas but are rare in lung squamous cell carcinoma (LSCC). In 2018, the Food and Drug Administration-approved afatinib for this specific patient population. However, there is limited information regarding the effectiveness of afatinib for LSCC with EGFR mutations. This case report documented a unique case of a patient with LSCC, which had a rare compound EGFR mutation (G719C and S768I) and showed significant response to afatinib treatment, with 10 months of progression-free survival. New NTRK1 and RET gene mutations may play a potential role in the development of acquired resistance to afatinib following clinical progression. This case highlights the importance of genetic profiling in patients with LSCC. Although these patients have a low positive rate of EGFR mutations, searching for EGFR mutations in these patients might broaden their treatment options.

Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment.
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【中文题目：罕见CRISPLD2-NRG1融合突变晚期混合型非小细胞肺癌1例并文献复习】 【中文摘要：肺癌是中国发病率和死亡率最高的恶性肿瘤。非小细胞肺癌（non-small cell lung cancer, NSCLC）占全部肺癌的80%以上，NSCLC的基因突变概率高，并且种类繁多。随着基因检测技术的进步，越来越多的罕见融合基因变异被检测出来。神经调节蛋白1（neuregulin 1, NRG1）可促使人表皮生长因子受体3（human epidermal growth factor receptor 3, Her3/ErbB3）介导的通路激活，从而导致肿瘤形成。本文报道了1例罕见CRISPLD2-NRG1融合突变的晚期混合型NSCLC颅内转移的患者，接受阿法替尼治疗1个月后头部磁共振成像（magnetic resonance imaging, MRI）显示颅内病灶明显缩小，患者对阿法替尼治疗反应良好。同时，我们对以往报道的NRG1基因融合突变的NSCLC病例进行总结，以供临床借鉴。
】 【中文关键词：肺肿瘤；阿法替尼；CRISPLD2-NRG1融合突变】.

We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed afatinib-induced toxic epidermal necrolysis (TEN). We have also performed a PubMed/Medline literature review to detect other possible cases of TEN/Stevens-Johnson syndrome associated with afatinib treatment and found only 5 other cases reported. To our best knowledge, this is the first case of afatinib-induced TEN successfully treated with cyclosporine.

MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging.

Tumor lysis syndrome (TLS) is a potentially fatal oncological emergency that typically develops during the treatment of rapidly proliferating malignancies. It is infrequently reported in solid tumors, such as pulmonary adenocarcinoma. A 59-year-old male patient with shortness of breath presented with a 3.3 cm × 3.0 cm mass in the right upper lobe, along with massive right-sided pleural effusion. A percutaneous needle biopsy was performed, and a diagnosis of pulmonary adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation was made. The patient was treated with afatinib because of the malignant pleural effusion and multiple metastases to the intrathoracic lymph nodes, left scapula, and brain. After 4 days of afatinib treatment, he developed oliguric acute kidney injury and progressively worsening dyspnea. Based on the clinical and laboratory findings, the patient was diagnosed with afatinib-induced TLS. To the best of our knowledge, this is the first reported case of afatinib-induced TLS in pulmonary adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of non-small cell lung cancer (NSCLC), of which mutations in exons 18-21 are frequent, especially the loss of exon 19 and exon 21 L858R mutation are the most frequent. Other rare gene mutations are rare. Simultaneous occurrence of two or more rare EGFR mutations are extremely rare in lung cancer, and the incidence of EGFR L833V/H835L rare gene compound mutations is very low, and there is little clinical data and evidence of relevant treatment methods. Some EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective in treating lung cancer patients with rare gene mutations. In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment.
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【中文题目：罕见EGFR L833V/H835L复合突变的
肺腺癌患者1例及文献回顾】 【中文摘要：表皮生长因子受体（epidermal growth factor receptor, EGFR）突变是非小细胞肺癌（non-small cell lung cancer, NSCLC）发生发展过程中最常见的驱动基因，其中18-21号外显子的突变常见，尤其是19号外显子的缺失和21号外显子L858R点突变最为常见，但是EGFR L833V/H835L罕见基因复合突变的发生率非常低，患者数量很少，相关临床数据和治疗方法的证据也不足。部分EGFR-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitors, EGFR-TKIs）在治疗伴有罕见基因突变的肺癌患者方面同样具有良好疗效。本文报道了1例携带EGFR L833V/H835L罕见基因复合突变的NSCLC患者，在给予阿法替尼治疗5个月后，计算机断层扫描（computed tomography, CT）显示肺部病灶缩小，患者对阿法替尼联合安罗替尼治疗反应良好。同时，我们还对以往报道的EGFR L833V/H835L罕见基因复合突变的NSCLC患者进行了整理，总结了该类患者的特点及应用不同种类EGFR-TKIs治疗的效果。
】 【中文关键词：肺肿瘤；表皮生长因子受体；复合突变；L833V/H835L；阿法替尼】.

Afatinib, the world\'s first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.

UNASSIGNED: To report a case of afatinib-induced toxic epidermal necrosis (TEN), in a patient with metastatic non-small cell lung cancer (NSCLC) and compare these findings with that of evaluate similarities and differences to other cases reported in the literature.
UNASSIGNED: With use of the algorithm of drug causality for epidermal necrolysis (ALDEN), the effects of afatinib were evaluated in a NSCLC patient who developed TEN. In addition, previous case reports on this topic were included to provide a review of patients\' clinical characteristics, treatment regimens and therapy outcomes in response to afatinib treatment.
UNASSIGNED: In our case, toxic epidermal necrolysis was observed at five days after afatinib therapy, while other Stevens-Johnson syndrome/toxic epidermal necrolysis responses, as associated with afatinib, did not seem to be induced until a latency period of over thirty days post-afatinib. Treatment with corticosteroids resulted in significant improvements of these clinical symptoms, and eventually to a complete remission.
UNASSIGNED: Afatinib can result in grade four cutaneous adverse effects like SJS/TEN, with an uncertain latency period. The skin lesions which appear during this period of afatinib treatment should be closely monitored.

BACKGROUND: Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens.
METHODS: PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models.
RESULTS: This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups.
CONCLUSIONS: A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM.

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), targeting EGFR exon 19 deletions, L858R, and T790M, has shown robust clinical efficacy and promising survival advantages in a subset of non-small cell lung cancer (NSCLC) patients. However, osimertinib-treated patients ultimately develop secondary resistance. Besides EGFR C797S mutation and EGFR amplification, a rare EGFR mutation, L718V, has been reported to confer osimertinib resistance in the literature, which is developed in about 8.0% of osimertinib-resistant NSCLC patients. Although the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology NSCLC guidelines recommend radiotherapy, anti-angiogenesis therapy, chemotherapy and or immunotherapy for the treatment of NSCLC patients who acquire resistance to osimertinib, the feasible treatment options for patients harboring EGFR L718V remain elusive. There is an unmet need to develop effective strategies to treat EGFR L718X-positive NSCLC patients. Herein, we report that a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib derived durable response to the second-generation EGFR-TKI afatinib with a progression-free survival of 18 months and counting. Our work provides clinical evidence to administer afatinib in metastatic NSCLC patients who develop EGFR L718V at progression to osimertinib and paves the way for its potential clinical utilization.