Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas.
Paul K PaikJia LuoNi AiRachel KimLinda AhnAnup BiswasCourtney CokerWanchao MaPhillip WongDarren J BuonocoreW Victoria LaiJamie E ChaftSwarnali AcharyyaJoan MassaguéMark G KrisPublished in: Nature communications (2022)
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.
Keyphrases
- chemotherapy induced
- small cell lung cancer
- clinical trial
- free survival
- squamous cell carcinoma
- locally advanced
- rheumatoid arthritis
- oxidative stress
- study protocol
- phase iii
- advanced non small cell lung cancer
- transcription factor
- randomized controlled trial
- emergency department
- electron microscopy
- radiation induced
- rectal cancer
- adipose tissue
- insulin resistance
- room temperature
- type diabetes
- open label
- anti inflammatory
- metabolic syndrome
- skeletal muscle
- adverse drug
- electronic health record
- ionic liquid