Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas

Nat Commun. 2022 Oct 15;13(1):6095. doi: 10.1038/s41467-022-33719-6.


We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic propagation in breast and lung cancer models. Therefore, we sought to further validate and translate these findings into patient care by coupling the anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy. Here we first validate the anti-metastatic effect of certolizumab in a liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety, efficacy, and pharmacodynamic effects of certolizumab with cisplatin and pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen adult patients with stage IV lung adenocarcinomas. The primary outcome is maximum tolerated dose. Secondary outcomes are response rate and progression-free survival (PFS); pharmacodynamic changes in blood and tumor are evaluated as a correlative outcome. There were nine partial responses among 16 patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was 9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3 to NR). The standard 400 mg dose of certolizumab, added to cisplatin and pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates potent pharmacodynamic inhibition of peripheral cytokines associated with the paracrine inflammatory loop.

Publication types

  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / drug therapy
  • Adult
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Certolizumab Pegol / therapeutic use
  • Cisplatin / therapeutic use
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / pathology
  • Pemetrexed / therapeutic use
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha / therapeutic use


  • Antineoplastic Agents
  • Certolizumab Pegol
  • Cisplatin
  • Pemetrexed
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha