Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 15, 2022
- Source ID
- 10.1038/s41467-022-33719-6
Entities
People
- Anup Biswas
- Courtney Coker
- Darren J. Buonocore
- Jamie E. Chaft
- Jia Luo
- Joan Massagué Solé
- Linda Ahn
- Mark G. Kris
- Ni Ai
- Paul K. Paik
- Phillip Wong
- Rachel Kim
- Swarnali Acharyya
- W. Victoria Lai
- Wanchao Ma
Organizations
- National Cancer Institute
- United States Department of Defense
- United States Department of Health and Human Services