A Phase I Trial Of Certolizumab Plus Chemotherapy In Patients With Stage Iv Lung Adenocarcinomas.

9080 Background: We previously identified a paracrine inflammatory loop (TNF-α, CXCL1/2, S100A8/9) involving both tumor and stroma that develops in response to chemotherapy, engendering chemoresistance and metastatic propagation in breast and lung adenoca models (Acharyya, Cell 2012). Interruption of this loop at any point, including inhibition by TNF-α monoclonal antibodies (mabs), leads to chemo-resensitization and abrogation of metastases, supporting a new approach to improve the efficacy of chemotherapy. Methods: This was a phase 1 study of certolizumab pegol (Cimzia), a TNF-α mab, added to cisplatin + pemetrexed (C+P) in patients (pts) with untreated stage IV lung adenocas. The primary endpoint was identification of the RP2D by safety and pharmacodynamic criteria (suppression of TNF-α). Pts were treated with C 75mg/m2 and P 500mg/m2 q3wks for 6 cycles. Pts also received Cimzia in 2 dose cohorts (200mg, 400mg) every 2 wks x 1 month then monthly thereafter. Serial blood was collected for cytokine analysis by ELISA. Response was assessed using RECIST v1.1. Results: 18 pts were treated (N = 3,200mg, N = 15,400mg). Median age = 63; female = 61%; smoker = 94%; median KPS = 80%. The most common any-grade related AEs were nausea (67%), anemia (61%), constipation (61%), and leukopenia (50%). Grade ≥ 3 related AEs occurred in 61% of pts, mostly hematologic: decreased neutrophils (22%), anemia (6%), thrombocytopenia (6%). No febrile neutropenia was seen. No DLTs were present. There were 3 unrelated SAEs (gr3 lung infection, gr2 skin infection, gr5 cardiac arrest). No pt had CTCAE wt loss; 16% had grade 1 wt gain. Safety was similar across Cimzia doses. 16 pts were evaluable for response: 9 PR (56%), 6 SD (38%), and 1 PD (6%). With a median f/u of 8.2mo, 66% of pts remain on maintenance peme. All pts had a significant decrease in [TNF-α] from baseline (8.5 fold mean decrease, p < 0.001), which is different from a control group treated with chemo alone (16 fold mean increase, p = 0.001). Conclusions: Cimzia 400mg is tolerable when given with C+P with promising anti-tumor efficacy and TNF-α suppression. A phase 2 study of this combination in pts with early stage disease is planned to assess the effect of TNF-α blockade on cure rate and metastatic propagation. Clinical trial information: NCT02120807.