Safety And Efficacy Of Nintedanib (Bibf 1120) Plus Pemetrexed In Japanese Patients With Advanced Or Recurrent Non-Small Cell Lung Cancer (Nsclc): A Phase I Study

8056 Background: Nintedanib (N) is a potent, orally bio-available triple angiokinase inhibitor that targets VEGFRs, PDGFRs and FGFRs, as well as RET and Flt3. The open-label phase I part of this phase I/II study was designed to determine the maximum tolerated dose (MTD) of N when combined with standard-dose pemetrexed (PEM), and to investigate safety and efficacy in Japanese patients (pts) with advanced/recurrent NSCLC. Methods: Eligible pts had histologically/cytologically confirmed stage IIIB/IV or recurrent NSCLC (any histology) after failure of first-line chemotherapy. Pts received PEM 500 mg/m2 iv on day 1 followed by N twice daily (bid) po on days 2–21 every 21 days using a standard 3+3 design. N was started at 100 mg bid and escalated to 200 mg bid in 50 mg bid intervals. Pts received ≥4 cycles of combination therapy with an option of continuing with single-agent N until disease progression or undue adverse events (AEs). Primary endpoints were MTD, defined as the highest dose at which incidence of dose-limiting toxicities (DLTs) was <33.3%, and safety. DLTs were defined as grade 3 non-hematologic or grade 4 hematologic AEs. Secondary endpoints included objective tumor response and pharmacokinetics (PKs). Results: 18 pts (14 male) were treated: 3 at N 100 mg bid, 6 at N 150 mg bid, and 9 at N 200 mg bid. DLTs were observed in 0/3, 1/6, and 2/9 pts in each cohort, respectively; 2 of these pts had liver enzyme elevations. The MTD for N (plus PEM) was 200 mg bid. The most common drug-related AEs were increased GGT, increased AST, decreased appetite, and diarrhea. Grade 3 AEs included neutropenia (22.2%), increased AST, increased ALT, and lymphopenia (each 11.1%); no pts experienced grade 4/5 AEs. Two pts (11.1%) achieved a partial response and 12 (66.7%) had stable disease. At the MTD, N exposure after PEM administration was similar to that seen with N monotherapy in a previous Japanese study. Co-administration of N did not affect the PKs of PEM. Conclusions: The combination of N and standard-dose PEM had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese pts with advanced/recurrent NSCLC. As in Caucasian pts, the MTD of N was 200 mg bid. Clinical trial information: NCT00979576.