Final progression-free survival analysis of phase II study with the combination therapy of DFP-14323, protease inhibitor, and low-dose afatinib as first-line therapy for common EGFR mutation–positive NSCLC.
Authors: Yoshioka Hiroshige , Mori Masahide , Katakami Nobuyuki , Yokoyama Toshihide , Kaneda Hiroyasu , Matsumoto Hirotaka , Kumagai Toru , Yamamoto Kouji , Huang Cheng-long 
Published: June 2022

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Background: DFP-14323(INN: ubenimex) was developed as a biological response modifier and has been approved for maintenance therapy of AML in Japan. Ubenimex is an inhibitor of aminopeptidase N (APN), originated from Streptomyces olivoreticuli. APN is well known as one of the prognostic factors for several cancer types, including non-small-cell lung cancer (NSCLC). Meanwhile, afatinib is one of the standard treatments in NSCLC with EGFR mutation, but the toxicities often require dose reduction. Recently, it is suggested that reducing afatinib doses can decrease treatment-related adverse events without affecting efficacy. We aimed to examine efficacy of DFP-14323 with low-dose afatinib by conducting phase II study in patients with metastatic NSCLC harboring EGFR mutation. Methods: The study was a multi-center, single-arm, open-label phase II trial. Stage III/IV and treatment-naïve patients with common EGFR mutation-positive (L858R/19del) NSCLC were treated with DFP-14323 at a fixed dose of 10mg/day and afatinib at a starting dose of 20 mg/day until disease progression or intolerable toxicity. The primary endpoint was disease control rate (DCR), defined by sum the CR, PR and SD. The secondary endpoints were progression-free survival(PFS), overall response rate(ORR), N/L ratio, and safety. A sample size of 26 patients was determined, assuming a threshold DCR 70% and an expected DCR 90% with a two sided α error of 0.05 and a β error of 0.20, based on the Simon’s two stage design. Results: From July 2018 to March 2020, 26 patients were enrolled. A median age was 72 years (range, 53-82), 21(81%) were female, and 16 (62%) were never-smokers. Half of patients had Del-19 and other half had L858R. An efficacy analysis provided a DCR of 100% (previously reported) with 18 responders (ORR : 69%). Independent imaging evaluation at 72 weeks provided a median PFS was confirmed to be 16.6mts (95% CI 10.2, 22.9, median follow-up time for censored cases: 16.3mts). According to updated exploratory follow-up by physicians, as of the data cut-off of Dec 2021, median PFS was calculated 20.6 mts (95% CI, 12.6, 28.5, median follow-up time for censored case: 20.9mts). Seven Grade 3 adverse events were observed in 6patient(23%), and paronychias in 3 patients and diarrhea, stomatitis, dermatitis, and lymphocytopenia in 1 patient each. One paronychia was considered to be related to DFP-14323 and the other events to afatinib. No grade 4 or 5 adverse events were observed. One Grade 1 ILD was observed but recovered soon without treatment. Conclusions: Combination of DFP-14323 and low-dose afatinib has shown comparable potential as a first-line treatment for EGFR mutation positive NSCLC with feasible efficacy and good safety profile. We are planning a phase III study to evaluate this combination therapy as compared with other EGFR-TKIs. Clinical trial information: UMIN000033062.