Development of immunity-related adverse events correlates with baseline clinical factors, survival and response to anti-PD-1 treatment in patients with inoperable or metastatic melanoma.

BACKGROUND: The relationship between immune related adverse events (irAEs) and efficacy is not definitively proven, and data on the relationship between irAE and treatment efficacy are contradictory. MATERIAL AND METHODS: Five hundred ninety-three consecutive patients with unresectable or metastatic melanoma treated in the first line with anti-PD-1 (nivolumab or pembrolizumab) between January 2016 and December 2019 were enrolled in the study. RESULTS: Statistically significant differences were demonstrated between the group of patients without and with irAE in median OS and PFS (p < .0001 both) and also in OS between the group of patients without irAE and patients with irAE within 3, 6, and 9 months from the start of anti-PD-1 therapy (p = .0121, p = .0014, p < .0001; respectively) and PFS (p = .0369, p = .0052, p = .0001; respectively). A statistically significant relationship was demonstrated between the occurrence of irAE and the location of the primary tumor (skin vs. mucosa vs. unknown; p = .0183), brain metastasis (present vs. absent; p = .0032), other locations (present vs. absent, p = .0032), LDH (normal vs. elevated; p = .0046) and stage according to TNM (p = .0093). CONCLUSION: The occurrence of irAE was associated with longer OS, PFS, and more frequent response to treatment. IrAE occurred statistically significantly more often in patients with mucosa primary tumor, with normal LDH levels, without brain metastases, stages III, M1a, and M1b.

First-line treatment of advanced/metastatic melanoma with anti-PD-1 antibodies: multicenter experience in Poland.

Aim: To evaluate treatment results in advanced/metastatic melanoma patients treated with anti-PD-1 immunotherapy in routine practice in oncology centers in Poland. Methods: Multicenter retrospective analysis included 499 patients with unresectable/metastatic (stage IIIC-IV) melanoma treated with anti-PD-1 in first-line therapy. Results: Estimated median overall survival (OS) and progression-free survival (PFS) were 19.9 and 7.9 months, respectively. Multivariate analysis confirmed that ECOG 0, no brain metastases, normal lactate dehydrogenase level and occurrence of immune-related adverse events (irAEs) were statistically significantly associated with improved OS and PFS. Any irAE occurred in 24% of patients. Grade 3 or Grade 4 irAEs occurred in 6% of patients. Conclusion: Analysis revealed a slightly worse OS in real-world treatment in comparison to clinical trials (KEYNOTE-006 and CheckMate 066). Polish population treatment results are similar to other studies of real-world data. PFS and ORR are similar in our research and clinical trials.

Anti-programmed cell death-1 therapy in octogenarian and nonagenarian advanced/metastatic melanoma patients.

Immunotherapy with anti-programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Octogenarians and nonagenarians represent a significant cohort of melanoma patients. This multicenter retrospective analysis enrolled 499 patients treated with nivolumab or pembrolizumab. Seventy-three patients were aged 80-100, 218 patients were aged 65-79, and 208 patients were <65 years old. Baseline parameters were comparable. The median overall survival (OS) was 14.7, 18.7, 25.9, and the median progression-free survival (PFS) was 8.7, 7.7, and 6.2 months in the age groups of 80-100, 65-79, and <65 years, respectively. The median melanoma-specific survival (MSS) was 22.5, 27.8, and 31.6 months in the age groups of 80-100, 65-79, and <65 years, respectively. There was no statistically significant difference in OS (P = 0.2897), PFS (P = 0.7155), and MSS (P = 0.9235) between the group of 80-100 years old vs. 65-79 and vs. <65 years old patients. Overall response rate and disease control rate was similar in all groups (P = 0.06974 and P = 0.89435, respectively). Overall, the immune-related adverse event (irAE) rate was comparable in the three age groups (41, 34, and 37.5% in the groups of patients aged 80-100, 65-79, and <65 years, respectively). Also, the rates of G3 and G4 irAEs were comparable (4, 6, and 7% in the groups of patients, respectively). The efficacy and toxicity of anti-PD-1 therapy in octogenarians and nonagenarians with metastatic melanoma are similar as in patients aged <65 years and 65-79 years. The patients' age should not be considered as an exclusion criterion for anti-PD-1 treatment.

Tissue MicroRNA Expression as a Predictor of Response to Immunotherapy in NSCLC Patients.

INTRODUCTION: Expression of PD-L1 protein on tumor cells, which is so far the only validated predictive factor for immunotherapy, is regulated by epigenetic and genetic factors. Among the most important ones that regulate gene expression are microRNAs. MATERIALS AND METHODS: The study included 60 patients with NSCLC who underwent first or second line immunotherapy with pembrolizumab or nivolumab. FFPE materials were collected before the start of immunotherapy. We examined relative expression of microRNAs (miR-141, miR-200a, miR-200b, miR-200c, miR-429, miR-508-3p, miR-1184, miR-1255a) and PD-L1 mRNA expression. Copy number variation (CNV) of PD-L1 gene by qPCR and FISH methods were assessed. Two single nucleotide polymorphisms (SNPs) in promoter region of PD-L1 gene (rs822335 and rs822336) were examined. Expression of PD-L1 protein on tumor cells was assessed by immunohistochemistry (IHC). The response rate to immunotherapy and progression free survival (PFS) measured in weeks and overall survival (OS) measured in months from the start of immunotherapy were evaluated. RESULTS: Response to immunotherapy was observed in nine patients (15%, including one complete response), disease stabilization in 22 patients (36.7%), and progression in 29 patients (48.3%). Significantly higher (p=0.015) expression of miR-200b and significantly lower (p=0.043) expression of miR-429 were observed in responders compared to patients who did not respond to immunotherapy. The median PFS in the whole group of patients was 16 weeks, and the median OS was 10.5 month. In univariate analysis, the median PFS was significantly higher in patients with high miR-200b expression (HR=0.4253, 95%CI: 0.1737-1.0417, p=0.05) and high miR-508 expression (HR=0.4401, 95%CI: 0.1903-1.0178, p=0.05) and with low expression of miR-429 (HR=0.1288, 95%CI: 0.01727-0.9606, p=0.0456) compared to patients with low and high expression of these molecules, respectively. The median OS was higher in patients with low expression of miR-429 (HR=0,6288, 95%CI: 0,3053-1,2949, p=0.06) compared with patients with high expression of this microRNA. In multivariate analysis, we found that patients with PD-L1 expression on ≥1% of tumor cells compared to patients without PD-L1 expression on cancer cells had a significantly lower risk of progression (HR=0.3857, 95%CI: 0.1612-0.9226, p=0.0323) and death (HR=0.377, 95%CI: 0.1636-0.8688, p=0.022). CONCLUSION: The miR-200b and miR-429 molecules in tumor cells seem to have greatest impact on the effectiveness of immunotherapy in NSCLC patients.