A Phase I Trial of Afatinib (afa) and Bevacizumab (bev) in Chemo-Naïve Patients (pts) with Advanced Non-Small-cell Lung Cancer (NSCLC) Harboring EGFR-mutations: OLCSG1404

Background: In advanced EGFR-mutant NSCLC, Afa, a second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) has demonstrated a significant survival benefit over platinum-based chemotherapy (Lancet Oncol. 2015) and the combination therapies of gefitinib or erlotinib and Bev showed favorable PFS data (J Thorac Oncol. 2015 and Lancet Oncol. 2014). Also, our preclinical study revealed the synergistic effect of Afa and Bev (Mol Cancer Ther. 2013). We hypothesized Afa and Bev potentially yields further efficacy and conducted a phase I trial. Methods: Untreated pts with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was set as safety. First 6 pts received Afa at 40 mg/body daily and Bev intravenously at 15 mg/kg every 3 weeks until PD or unacceptable toxicity (level 0). If 2 or fewer pts experienced DLT defined as ≥ G3 non-hematological or G4 hematological toxicity, we repeated at the same dose to additional 6 pts. When 2 or fewer pts experienced DLT in the both sets, we concluded this dose schedule was feasible. Otherwise, we repeated the same method at the level -1 (Afa 30 mg/body, Bev 15 mg/kg). If the dose was feasible, the level was recommended. DLT was evaluated in the first month. Results: Nineteen pts were enrolled (level 0: 5 and level -1: 14). Three pts at level 0 experienced DLT, which concluded level 0 was unfeasible. At level -1, 3 pts developed DLT. All of the DLT were G3 non-hematological toxicities and soon recovered. Severe adverse events (AE) were shown in Table. Three pts at level 0 and 5 at level -1 required dose reduction for toxicity, respectively. Two pts at level 0 stopped protocol therapy for toxicity, whereas 2 at level -1 for wish of pts. Among 16 evaluable pts, the best response was CR/PR (81.3%) and SD (18.8%).Table: 426PLevel 0 (n = 5)Level -1 (n = 14)G4 AE00G3 AE54G3 (*: DLT)Diarrhea2*2*Skin rash11Hypoxia1*0Anorexia01*Paronychia10 Open table in a new tab Conclusions: Dose level -1 was well tolerated and had evidence of disease control. There was no refractory patient as well as other trials of EGFR-TKI and Bev. Clinical trial indentification: UMIN000015944. Legal entity responsible for the study: Okayama University Hospital Funding: None Disclosure: All authors have declared no conflicts of interest.