Nivolumab serum concentration in metastatic melanoma patients could be related to outcome and enhanced immune activity: a gene profiling retrospective analysis.

BACKGROUND: Nivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes. METHODS: In this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient's genetic profile plays a role in this association. RESULTS: We observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways. CONCLUSIONS: In conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.

Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization.

BACKGROUND: The clinical observation showed a potential additive effect of anti-PD-1 agents and cetirizine in patients with advanced melanoma. METHODS: Clinical outcomes of concomitant cetirizine/anti-PD-1 treatment of patients with stage IIIb-IV melanoma were retrospectively collected, and a transcriptomic analysis was performed on blood samples obtained at baseline and after 3 months of treatment. RESULTS: Patients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28-0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29-0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p < 0.05). The expression of FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p < 0.0001), IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005). CONCLUSIONS: This retrospective study suggests that M1 macrophage polarization may be induced by cetirizine through the interferon-gamma pathway. This effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents.