Abstract 4165: Combined FGFR1 and PD-1 inhibition could enhance antitumor activity in lung cancer models

Abstract

Abstract FGFR1 and PD-1 - mediated signals are involved in growth and survival of lung cancer and should be considered as targets for therapeutic approaches. Here, we report the potential efficacy of an anti-FGFR1 humanized antibody OM-RCA-01, either alone or in combination with an anti-PD-1 antibody. To assess the activity of OM-RCA-01 on FGF-mediated signaling, A549 human adenocarcinoma cells expressing FGFR1 were incubated and dosed with OM-RCA-01. Control cells were left untreated. Six hours after dosing, FGF2 was added at a concentration of 100 ng/ml. Cell growth was determined using Promega’s Cell Titer-Glo assay. Thirty-five NCr nu/nu female mice (10-12 weeks of age) were used for A549 xenotransplantation. Twenty animals with measurable tumors were pair matched and selected on day 7 after tumor inoculation. Intravenous OM-RCA-01 (30 mg/kg, N=10) or saline (Vehicle, N=10) were administered every 3 days starting on day 7 after tumor inoculation. To evaluate the efficacy of co-inhibition, patient explants (adenocarcinoma with PD-L1 expression >50%, DAKO 22C3) were obtained from surgical lung specimens, and PDX models were generated by implantation of PDX into humanized NSG mice (Jackson Laboratory, Sacramento, CA, USA) as previously described (Wang, FASEB J., 2018). Treatment with intravenous OM-RCA-01 (30 mg/kg) with pembrolizumab (10 mg/kg) or pembrolizumab alone (10 mg/kg) or saline (vehicle) every 3 days was started when the tumors reached 70 mm3 in volume. Measurements of tumor volume were performed by digital calipers every 3 days during 31 days in xenograft and PDX studies. In vitro study showed that FGF2 significantly increased proliferation of the human lung cancer cells (P<0.001). OM-RCA-01 exerted dose-dependent inhibitory effects on FGF-triggered lung cancer cell proliferation in comparison with control (P=0.01). IC50 was 9.69 mcg/mL. In the xenograft model, treatment resulted in median tumor volume of 1,048.5 mm3 and 2,174 mm3 at day 31 in the OM-RCA-01 and vehicle groups, respectively (P<0.0001). All tumors reached the volume endpoint of 2,000 mm3 to day 31 in vehicle group in comparison with study group where maximum size of tumor was 1,309 mm3. In the PDX study, the differences between groups were also statistically significant (all P<0.001). Median tumor volume was 97.1 mm3 in the combination group (N=7), 417.1 mm3 in the pembrolizumab only group (N=7), and 863.5 mm3 in the vehicle group (N=7). No group mean body weight losses or clinical manifestations of toxicity were observed in both groups. In conclusion, OM-RCA-01 antibody has potent antitumor activity against lung cancer in vitro and in vivo. Our findings also support that the co-inhibition of FGFR1 and immune checkpoints can enhance antitumor activity compared to anti-PD-1 antibody monotherapy. Citation Format: Ilya Tsimafeyeu, Jonathan Smith, Wei Yin, Alex Fanelli, Dmitry Khochenkov, Evgenia Stepanova. Combined FGFR1 and PD-1 inhibition could enhance antitumor activity in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4165.