Long-Term Response to Afatinib in Lung Adenocarcinoma Harboring Compound Uncommon EGFR Mutations: Case Report Long-Term to in

Lung cancer is the most common cause of cancer-related death worldwide and the prognosis in stage IV is poor with the overall survival not exceeding one year in patients treated with chemotherapy. Molecular disturbances in tumor cells such as EGFR gene mutations (exon 19 deletion or L858R substitution in exon 21 EGFR gene) are indication to use targeted therapies. We present a case of a 31-year-old female with metastatic adenocarcinoma of the lung with the presence of compound uncommon EGFR gene mutations, in which afatinib was used in first line treatment, with a partial response successfully obtained. The treatment was initiated fifteen months ago and is still continued despite acute skin side effects at the beginning of therapy.


Introduction
Lung cancer is the most common cause of cancer-related deaths in the world. The prognosis of patients with advanced or metastatic lung cancer is still poor. The median survival time in patients treated with classic chemotherapy does not exceed 12 months. The presence of specific molecular alterations is a positive predictor of the effectiveness of treatment with tyrosine kinase inhibitors (TKIs). In addition to better effectiveness in this specific population as compared to standard chemotherapy, they show an improvement in the quality of life and a different safety profile. At present, first-(erlotinib and gefitinib) [1,2] second-(afatinib and dacomitinib) [3,4] and third generation (osimertinib) [5] inhibitors can be used in the first-line systemic treatment. Activating epidermal growth factor receptor (EGFR) mutations are reported in approximately 10-15% of Caucasian patients with non-small cell lung cancer (NSCLC), mostly in female, younger patients, and in non-smokers or light smokers [6]. The most frequently found EGFR gene mutation is a deletion in exon 19, representing 45% of all mutations, followed by L858R substitution in exon 21 (40-45%) [7,8] So-called uncommon EGFR gene mutations are found in 7-23% of patients [9,10]. Compound mutations are identified in up to 25% of uncommon mutations [11]. The prognosis depends strictly on the type of mutation. Patients with the most common rare mutations ("major" uncommon), such as G719X, L861Q and S768I, or patients with compound mutations have a better prognosis, and patients with EGFR exon 20 insertion or T790M mutation have a far worse prognosis [12].

Case Report
In July 2019, a 32-year-old non-smoking female reported to her family doctor due to a dry cough lasting for a month. In May 2019, she had a miscarriage in the 10th week of pregnancy. Medical history revealed no comorbidities, and the family history was also not burdened. A chest X-ray showed bilateral shadows of 4 to 6 mm in Detailed results of patient's diagnostic tests are presented in Table 1. The patient was qualified for treatment with afatinib at daily dose of 40 mg and the therapy was initiated in October 2019.
After 2 weeks of using the drug, the patient returned for a followup visit. The presence of CTCAE G3 acne-like rash accompanied by skin redness and itching was found on the skin of the face and neckline (Picture 1-4, author's own archive). Afatinib treatment was stopped and the oral lymecycline (at a dose of 2 x 300 mg for 10 days) and topical clindamycin were administered. Antipruritic drugs were also introduced with desloratadine and dexamethasone in a dose of 4 mg for 5 days. After a week, the skin lesions began to resolve (to G2), and after 14 days the G1 acneiform rash on the face was present (Picture 5, author's own archive). After a two-week break, treatment with afatinib was resumed at a reduced dose of 30 mg/d. In the first follow-up imaging assessment after 3 months of therapy, a partial response was found according to the RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria which currently retains. The patient continues treatment, there were no other side effects or recurrence of the acne-like rash. The patient is professionally active [13].

The Test Result
Chest X-ray  of patients in the LUX-Lung 3 and LUX-Lung 6 trials, respectively.
Acneiform rash was a reason for discontinuing of afatinib therapy in 2.1% of patients in the LUX-Lung 6 study and no patients in the LUX-Lung 3 study. In the presented patient the grade 3 rash resolved after the temporary discontinuation of afatinib therapy, the use of topical and oral antibiotics, and thereafter was successfully resumed at a reduced dose (Figures 1-5).

Summary
Afatinib is an effective and safe therapeutic option in lung cancer patients with certain uncommon EGFR gene mutations.
The presented case is an example of a long-term response to afatinib. In addition, it emphasizes the need for close monitoring of patients in terms of possible side effects, including dermatological complications. Treatment with EGFR TKIs maintains a good quality of life, and possible side effects are usually transient and manageable.