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

Paul K. Paik (), Jia Luo, Ni Ai, Rachel Kim, Linda Ahn, Anup Biswas, Courtney Coker, Wanchao Ma, Phillip Wong, Darren J. Buonocore, W. Victoria Lai, Jamie E. Chaft, Swarnali Acharyya, Joan Massagué and Mark G. Kris
Additional contact information
Paul K. Paik: Memorial Sloan Kettering Cancer Center
Jia Luo: Memorial Sloan Kettering Cancer Center
Ni Ai: The Ohio State University
Rachel Kim: Memorial Sloan Kettering Cancer Center
Linda Ahn: Memorial Sloan Kettering Cancer Center
Anup Biswas: Columbia University
Courtney Coker: Columbia University
Wanchao Ma: Columbia University
Phillip Wong: Memorial Sloan Kettering Cancer Center
Darren J. Buonocore: Memorial Sloan Kettering Cancer Center
W. Victoria Lai: Memorial Sloan Kettering Cancer Center
Jamie E. Chaft: Memorial Sloan Kettering Cancer Center
Swarnali Acharyya: Columbia University
Joan Massagué: Memorial Sloan Kettering Cancer Center
Mark G. Kris: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33719-6

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