Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas Journal Article
| Authors: | Paik, P. K.; Luo, J.; Ai, N.; Kim, R.; Ahn, L.; Biswas, A.; Coker, C.; Ma, W.; Wong, P.; Buonocore, D. J.; Lai, W. V.; Chaft, J. E.; Acharyya, S.; Massagué, J.; Kris, M. G. |
| Article Title: | 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. © 2022, The Author(s). |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; treatment response; aged; unclassified drug; gene mutation; clinical trial; constipation; drug tolerability; fatigue; neutropenia; cisplatin; diarrhea; drug efficacy; drug safety; nonhuman; side effect; antineoplastic agents; cancer staging; outcome assessment; antineoplastic agent; anorexia; mouse; progression free survival; multiple cycle treatment; pharmacodynamics; anemia; cell infiltration; leukopenia; nausea; neuropathy; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; epidermal growth factor receptor 2; animal experiment; animal model; maintenance therapy; smoking; creatinine; hemoglobin; creatinine blood level; in vivo study; pathology; enzyme linked immunosorbent assay; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; dyspnea; hypomagnesemia; lung tumor; alanine aminotransferase; aspartate aminotransferase; bilirubin; hyponatremia; cytokine; lung adenocarcinoma; karnofsky performance status; gene rearrangement; tumor necrosis factor-alpha; cd11b antigen; paracrine signaling; maximum tolerated dose; phase 1 clinical trial; oncogene k ras; lung infection; cxcl2 chemokine; pemetrexed; bilirubin blood level; b raf kinase; bioluminescence; immunocompetent cell; lewis carcinoma; cxcl1 chemokine; heart arrest; skin infection; tumor necrosis factor; non small cell lung cancer; adenocarcinoma of lung; metastasis inhibition; tumor necrosis factor inhibitor; infliximab; tumor necrosis factor antibody; adalimumab; cytokine response; humans; human; male; female; article; absolute neutrophil count; myeloid-derived suppressor cell; alk protein; ex-smoker; certolizumab pegol; doublet chemotherapy; experimental metastasis; llc cell line; tumor necrosis factor inhibitors |
| Journal Title: | Nature Communications |
| Volume: | 13 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-10-15 |
| Start Page: | 6095 |
| Language: | English |
| DOI: | 10.1038/s41467-022-33719-6 |
| PUBMED: | 36241629 |
| PROVIDER: | scopus |
| PMCID: | PMC9568581 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
