Abstract
Background: In the majority of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations, first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are ineffective. The second-generation TKI, afatinib, is considered effective in patients with uncommon mutations, however, long-term survivors have been rare. Case Report: We report herein a patient with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations, who is free of disease 32 months after initiation of afatinib therapy. To our best knowledge, this patient has the longest response among other patients with double uncommon mutations. Conclusion: Patients with this type of NSCLC may obtain long-term survival with afatinib.
Clinically, non-small cell lung cancer (NSCLC) patients with rare epidermal growth factor receptor (EGFR) mutations are resistant to first-generation EGFR- tyrosine kinase inhibitors (TKIs). The second-generation EGFR-TKI, afatinib, has binding a stronger affinity to the EGFR receptor compared to first-generation TKI (1). Regarding EGFR-TKI therapy, two issues are currently being discussed. One is, in which order to give each TKI when treating cells with sequential TKIs in order to improve overall survival (2). The other is which TKI to select for patients with uncommon EGFR mutations (3). The efficacy of afatinib in NSCLC patients with uncommon EGFR mutations has been confirmed in clinical trials (3). As there are several types of uncommon EGFR mutations, it is necessary to evaluate the effect of afatinib for each mutation type. In order to assess the efficacy of afatinib treatment, information from case reports is important. This is one of the most important methods to evaluate treatment for orphan diseases. In fact, there have been case reports of patients who have responded to afatinib, and who have survived for a long period of time (4-14). We herein describe the case of a patient with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations, who is free of disease 32 months after initiation of afatinib therapy. To our best knowledge, this patient has the longest response known among patients carrying double uncommon mutations.
Case Report
A 65-year-old man was referred to our hospital with complaints of right chest pain and general fatigue. He was a 30 pack-year smoker. Chest CT scan revealed a tumor in the left lung with enlargement of bilateral mediastinal lymph nodes (Figure 1). Physical examination was normal except for enlargement of the right cervical lymph nodes. Biopsy specimens from the cervical lymph nodes were obtained, and the patient was diagnosed as having lung adenocarcinoma. Examination of the DNA sequence of the EGFR gene revealed the uncommon EGFR L861Q and G719X mutations. Chest and abdominal computed tomography (CT) scan, brain magnetic resonance imaging (MRI), and bone scan showed multiple rib metastases in both sides (Figure 2). Clinical stage was T1cN3M1c (LYM, OSS) stage IVB. The patient received afatinib (orally 80 mg/day). Chest CT scan taken one month after the initiation of afatinib revealed shrinkage of the primary lesion in the left lung and bilateral mediastinal lymph nodes (Figure 3). No severe adverse effects were observed, except for grade II skin toxicity. CT scans performed 30 months after the initiation of therapy revealed no recurrence. The patient is still well 32 months after the initiation of afatinib with no recurrence.
Chest radiograph revealed a tumor 3 cm in diameter in the left lung with enlargement of bilateral mediastinal lymph nodes.
Discussion
Herein, we report a 32-month responder with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations, who was treated with afatinib therapy. The clinical activity of afatinib in NSCLC patients with uncommon EGFR mutations has been confirmed in clinical trials (3). This study was a combined post-hoc analysis of three clinical trials, LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, in patients with advanced NSCLC harboring uncommon EGFR mutations (3). In the analysis, 75 (12%) of 600 patients, who were treated with afatinib, had uncommon EGFR mutations (3). Median progression-free survival of the three uncommon mutation groups: point mutations or duplications in exons 18-21, de novo Thr790Met mutations in exon 20 alone or in combination with other mutations, or exon 20 insertions, was 10.7, 2.9, and 2.7 months, respectively. Median overall survival was 19.4, 14.9, and 9.2 months, respectively (3). It is well known that there are many types of uncommon mutations (3-14). In addition, the existence of patients with multiple uncommon mutations has been clarified (3-14). Since the number of patients with each uncommon mutation type is small and there are many types of uncommon mutations at the gene level, it is difficult to clarify the PFS and OS of each type of patients with uncommon mutations. Given these backgrounds, case reports on the treatment of each type of uncommon mutation patient should be important. This is one of the important methods to evaluate treatment for orphan diseases. With regard to afatinib therapy in patients with lung adenocarcinoma harboring uncommon EGFR mutations, there were 11 case reports (4-14). In most case reports, afatinib was given as a first-line therapeutic drug (4-12, 14). Most cases had a PFS of less than one year (5-7, 9, 10, 14), but some patients had a PFS of more than one year (8, 11, 13). An et al. reported a case with a great efficacy of afatinib on a patient with lung adenocarcinoma harboring uncommon EGFR delE709_T710insD mutations. According to the Authors of this study, PFS of the patient was 11 months and the overall survival exceeded 21 months (5). Čoupková and Vyzula reported on a patient with EGFR (in exon 18-T179X) mutation persistent PFS for 19 months (8). Watanabe et al. showed good response without progression for 12 months in a patient with G719X and S768I mutations (12). Chan et al. presented a patient with a PFS of 37 months and of 54 months after a second-line afatinib therapy (11). This patient had EGFR exon 20 insertion mutation (11). In these case reports, as described above, EGFR mutation of the patients was heterogeneous (4-14). Among these case reports, interestingly, there was one report of a patient with the same double uncommon EGFR L861Q and G719X mutations as observed in our patient (14). In this report by Kimura et al., the effectiveness of afatinib for this patient with the double uncommon mutation, was confirmed by using a special visual assay (14). Also, this report showed that the PFS of the patient was ‘more than 10 months’ (14). To our best knowledge, therefore, this is a case report of the longest survival of an afatinib responder with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations. While there were reports of patients who had a therapeutic effect and those who had a long survival (5-14), there are possibly many patients who had no response and a short survival (15). This is a publication bias. Of course, clinical trials cannot clarify ‘the truth’ due to the small number of patients. Although the ‘evidence level’ is low, it is important to carefully examine the information obtained from case reports and to collect and analyze information from case reports. Our results suggest that patients with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations might have long-term survival, if the suitable treatment is provided.
Bone scan revealed multiple rib metastases in both sides.
Chest CT scan taken one month after the initiation of afatinib revealed shrinkage of the primary lesion in the left lung and of the bilateral mediastinal lymph nodes.
Footnotes
Authors' Contributions
GO and HS designed the study. GO, SO and YS, collected the data. TS, HY, KM and HS analyzed the data and prepared the article. All Authors approved the final version of the article.
This article is freely accessible online.
Ethics Statement
This study was approved by the institutional Ethics Committee of each Hospital (approval number: NO16-66). Written comprehensive informed consent for obtaining pathological specimens at the time of admission was obtained from the patient.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received March 9, 2020.
- Revision received March 23, 2020.
- Accepted March 24, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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