Disease	Lung cancer – NSCLC
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	None
Type of Study	Phase II, single arm
Primary Endpoint	1‐year progression‐free survival rate
Secondary Endpoints
Progression‐free survival, overall response rate, toxicity, incidence of grade ≥ 3 adverse events
Additional Details of Endpoints or Study Design
Study design: This study was a single‐arm, phase II trial conducted at nine institutions in Japan.
Inclusion criteria: Eligible patients were aged 20 years or older, with cytologically or histologically confirmed NSCLC that was classified as clinical stage IIIB–IV, or a postoperative recurrence harboring sensitive EGFR mutations except exon 20 insertion or T790M. The patients had not previously been treated with an EGFR‐TKI, nor had they received more than two cycles of cytotoxic anticancer therapy except adjuvant chemotherapy after operation or immune checkpoint inhibitor, and they had at least one measurable lesion according to RECIST, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and an estimated life expectancy of ≥3 months. For radiation therapy, there was no history of radiation to the target lesion, ≥12 weeks had passed since the final dose of radiation had been administered to the chest, and ≥ 2 weeks had passed since the final dose of radiation had been administered to a body part other than the chest. Regarding surgery, ≥4 weeks had passed since the most recent day of operation. For patients with chest drainage or pleurodesis, ≥2 weeks had passed since the final treatment had been administered. Regarding anticancer agents, ≥3 weeks had passed since the last treatment had been administered. Laboratory criteria included a neutrophil count ≥1,500/mm3, a platelet count ≥100,000/mm3, a hemoglobin concentration ≥ 9 g/dL, total bilirubin level ≤ 1.5 mg/dL, aspartate transaminase and alanine transaminase levels ≤100 U/L, serum creatinine ≤1.5 mg/dL, and a partial pressure of arterial oxygen (PaO2) ≥60 mmHg. All enrolled patients provided written informed consent prior to enrolment in the present study.
Exclusion criteria: We excluded patients who had pulmonary disorders such as idiopathic pulmonary fibrosis or interstitial pneumonia; symptomatic brain metastasis; pleural effusion, ascites, or pericardial fluid requiring drainage; active infectious disorders; active double cancer; unstable cardiac disorders such as angina pectoris, acute myocardial infarction within 3 months or cardiac failure; uncontrollable diabetes mellitus or hypertension; gastrointestinal disorders with serious diarrhea requiring glucocorticoid therapy or immunosuppressive agents; and those regarded as unsuitable for this study by the investigators.
Treatment plan: The present study was conducted to evaluate the efficacy and tolerability of maintenance therapy with low‐dose afatinib among patients with NSCLC harboring an EGFR mutation not previously treated with an EGFR‐TKI. Patients initially received afatinib 40 mg orally once a day. The treatment was continued until disease progression, intolerable severe toxicity, or withdrawal of consent. Patients who experienced AEs of grade ≥ 2, rash of grade ≥ 3, or any grade of unacceptable toxicity could suspend treatment for up to 4 weeks. After suspension, treatment could be restarted based on the judgment of the investigators, and the dose of afatinib was decreased by 10 mg, initially to 30 mg/day and if needed down to 20 mg/day. After failure of afatinib, patients could receive any subsequent treatment, including continuation of afatinib, based on the judgment of the investigators.
Endpoints: The primary endpoint was the 1‐year PFS rate. The secondary endpoints were PFS, ORR, toxicity profiles, and the incidence of AEs of grade ≥ 3. The follow‐up period was 12 months after the last patient enrolment.
Statistical methods: For the primary endpoint, the minimum number of patients enrolled was 26, assuming a threshold 1‐year PFS rate of 42% and an expected 1‐year PFS rate of 63% with 90% power at a two‐sided alpha of .05. Considering that 10% of patients could be ineligible, the sample size was set at 30 patients. The 1‐year PFS rate and PFS were estimated using the Kaplan‐Meier method. Safety analyses were used to summarize AEs by maximum Common Terminology Criteria for Adverse Events grade at each dose of afatinib during the entire treatment period.
Investigator's Analysis	Active and should be pursued further