Feasibility and safety of nintedanib in combination with nivolumab in pretreated patients with advanced or metastatic adenocarcinoma of the lung - An AIO phase Ib/II trial.

[OBJECTIVES] Nivolumab and nintedanib are both established agents for pre-treated NSCLC of adenocarcinoma histology. Hypothesizing that the combination of immune checkpoint inhibition (nivolumab) and anti-angiogenesis (nintedanib) increases efficacy, we intended to determine a safe and efficacious dose for the combination.

[MATERIALS AND METHODS] Our multi-center, open-label, single arm, phase Ib/II study enrolled patients with histologically confirmed stage IIIB/IV adenocarcinoma NSCLC and one or two previous lines of systemic treatment with platinum-based chemotherapy +/- checkpoint inhibitors (CPI). A traditional 3 + 3 design was used to determine a recommended phase II dose (RP2D) for nintedanib combined with nivolumab. Primary endpoints were safety and tolerability together with 6- and 9-month rates of progression-free survival (PFS).

[RESULTS] The RP2D was determined as 200 mg nintedanib twice daily (bid) with 240 mg nivolumab biweekly (Q2W). No new safety signals were detected. PFS milestone rates at 6 and 9 months for the 52 patients who received this dose were 25% [95% CI 14.3-37.3%] and 11.5% [4.7-21.8%], respectively. Median overall survival (mOS) was 12.2 months [95% CI: 8.13-18.37]. Central biomarker analysis based on combined positive score (CPS) revealed that high PD-L1 and low PD-L1/low FGFR1 identified patients with prolonged OS at 36 months (70% and 40%, respectively), while low PD-L1/high FGFR1 was associated with shorter OS (p = 0.0195). CPI-rechallenged patients had better OS outcomes than those who were CPI-naïve (mOS 8.13 months [95% CI 2.03-15.2] vs. 14.7 months [95% CI 8.2-NR]; logrank p = 0.0493).

[CONCLUSION] Combination of nivolumab and nintedanib was shown to be safe and feasible. Despite missing synergistic effects on efficacy for the overall population, promising OS was observed for patients with high PD-L1 expression and for patients with previous immunotherapy. Therefore, CPI responsiveness may have been restored in some cases. Inhibition of FGFR-mediated tumor progression seems relevant in tumors with lower levels of both PD-L1 and FGFR1 expression and might be effectively inhibited by nintedanib. The combination nivolumab/nintedanib might warrant further exploration in selected patients.