Abstract 853P
Background
Immune checkpoints inhibitors (ICI) targeting CTLA-4 and PD-1 have achieved unprecedented results in advanced melanoma patients. Mechanisms of resistance are not fully understood and predictive biomarkers of response are to be identified. TNF is a pleiotropic cytokine whose role in cancer can be detrimental and TNF blockade potentiates ICI efficacy in preclinical models.
Methods
MELANFα (NCT03348891) is a translational proof-of-concept, open-label, prospective, multicenter, cohort study of 60 advanced melanoma patients (ipilimumab+nivolumab; pembolizumab or nivolumab). Its primary objective was to study whether the evolution of plasma TNF between baseline (W0) and week 12 (W12) could identify patients presenting non-progressive disease at W12. Exploratory objectives were to monitor the pharmacodynamics of ICI on plasma cytokines (Meso Scale) and circulating T cells (flow cytometry). The disease control rate (DCR) was defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥6 months.
Results
TNF plasma levels increased along therapy with a median of 0.804 pg/mL (range: 0.180-5.451) at W0 to 0.981 pg/mL (0.313-4.835) at W12 (p=0.0416) but the evolution from baseline was not associated with non-progressive disease at W12. Whereas TNF plasma levels at baseline did not differ in responders (R) and non-responders (NR), they were significantly higher at W12 (p = 0.0129) in NR (1.060 pg/mL; 0.403-4.835) versus R (0.713 pg/mL; 0.313-1.880). At W12, TNF and IL-6 plasma levels were positively correlated (r(s)=0.5769; p<0.0001) and IL-6 plasma levels tended (p=0.0562) to be increased in NR (2.016 pg/mL; 0.405-9.932) versus R (1.103 pg/mL; 0.314-8.813). At W12, the proportion of circulating central memory CD4 T cells was significantly increased in patients with DCR [median: 36.5% (22.1-55.1) versus 29.4% (7.6-47.2), p=0.0045].
Conclusions
Our results show that elevated TNF plasma levels along therapy is associated with a poorer clinical outcome and further point TNF as a putative target in combination with ICI in melanoma patients.
Clinical trial identification
NCT03348891.
Editorial acknowledgement
Legal entity responsible for the study
Institut Claudius Regaud.
Funding
Bristol Myers Squibb.
Disclosure
T. Filleron: Other, Consulting (compensated to my institution): Cellectis. B. Ségui: Non-Financial Interests, Institutional, Sponsor/Funding, Worked as investigator, consultant and speaker: BMS. N. Meyer: Non-Financial Interests, Institutional, Principal Investigator, investigator, consultant, speaker: BMS; Non-Financial Interests, Institutional, Other, investigator, consultant, speaker: MSD, Roche, Novartis, Pierre Fabre, Amgen, Incyte, AbbVie. All other authors have declared no conflicts of interest.