Abstract
Anti-programmed cell death protein 1 (PD-1) monoclonal antibody therapy is becoming a standard treatment for advanced melanoma that produces durable responses and prolonged survival, but the prognosis of patients with liver metastases is still unsatisfactory. Here, we analyzed five clinical studies (second-line or later, JS001-I-PK, CT4, KN151, BGB-A317-102, and SHR-1210-102; performed between 2015 and 2018) of anti-PD-1 monotherapy for advanced melanoma to explore prognostic variables for patients with liver metastases. A total of 168 patients with stage IV melanoma were included, among which 47 had liver metastasis and 121 did not. The objective response rate (ORR) of the no liver metastasis group was significantly higher than that of the liver metastasis group (20.7 vs. 4.3%, P < 0.05). The median progression-free survival (PFS) time was 3.6 months for the patients with liver metastasis and 7.4 months for those without liver metastasis (P < 0.05). The no liver metastasis group also had a longer median overall survival (OS) time than the liver metastasis group (22.8 vs. 15.7 months, P < 0.05). Multivariate analysis showed that liver metastasis was negatively associated with PFS. In the liver metastasis group, compared to metastases in other sites (lymph node, subcutaneous, and lung), liver metastases responded worse to anti-PD-1 monotherapy and were most likely to progress. Intrahepatic progression (defined as an increase in liver metastasis by more than 20% from baseline or having new liver metastases, P < 0.05) was negatively associated with OS, which indicates the need to find a more effective therapy that can target liver metastases. Interestingly, with a median PFS and OS time of 6.0 and 30.9 months, respectively, previous oncolytic virotherapy might bring more benefits to patients with liver metastasis, but confirmation is needed because of the limited number of samples. These findings emphasize that liver metastasis is a poor prognostic factor for advanced melanoma treated with anti-PD-1 monotherapy. Further exploration is still needed to find a new treatment approach for these patients.
Highlights
RESULTSProgrammed cell death protein 1 (PD-1) is a highly expressed protein on tumor-infiltrating lymphocytes that reduces the activity of T cells and blocks the immune response upon interaction with programmed death ligand-1 on the surface of tumor cells, leading to immune escape [1]
The type of prior immunotherapy was not included in the univariate and multivariate analyses because of the small sample size. Univariate analysis of this group suggested that the baseline LDH level and age were risk factors for progression-free survival (PFS)
Multivariate analysis confirmed that an age ≥65 was significantly and negatively associated with the PFS of patients with liver metastases (Figure 5A), with a much shorter median PFS time seen in older patients than in younger patients
Summary
Programmed cell death protein 1 (PD-1) is a highly expressed protein on tumor-infiltrating lymphocytes that reduces the activity of T cells and blocks the immune response upon interaction with programmed death ligand-1 on the surface of tumor cells, leading to immune escape [1]. PD-1 is an important target in immunotherapy treatment for melanoma [2,3,4] Given their abilities to produce durable responses and prolonged survival, two anti-PD-1 monoclonal antibodies, pembrolizumab and nivolumab, have been approved in the United States for use in advanced melanoma [5,6,7,8,9,10,11]. In phase 1b clinical trials of pembrolizumab including 655 patients with advanced melanoma, the overall objective response rate (ORR) was 33%, and the median overall survival (OS) time was 23 months [7]. With a median OS time of 16.8 months, nivolumab produced an ORR of 31% in a study of 107 patients with advanced melanoma [9]. We summarize five clinical studies for advanced melanoma performed at our clinical research center between 2015 and 2018, describing the clinical characteristics of patients with melanoma liver metastases treated with antiPD-1 monoclonal antibody therapy, trying to explore possible prognostic factors
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