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Risk Factors and Comparative Safety of Anti-PD-1 Combination Therapies in Advanced Melanoma: A Nationwide Real-World
Yuan Qiao1,2,3, Xiao Fu4, Sundus Shukar1,3
1School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Backgroud:
Different anti-PD-1 combination therapies are used to improve response rate and combat drug resistance for melanoma in the real world of China. While the reported safety data has remained scarce, especially for the controversial use of interferon. Identification of risk factors and comparative safety of different therapies will be beneficial for physicians to make decisions on rational usage of immunotherapy.
Methods:
A nationwide retrospective cohort study consecutively collected advanced melanoma patients treated by anti-PD-1 based therapies between July 1, 2018 and June 30, 2023. Univariate and multivariable logistic regression analysis was performed to identify the association between the potential risk factors and the occurrence of immune-related adverse events (irAEs).
Results:
A total of 508 advanced melanoma patients receiving PD-1 monotherapy (n = 181), PD-1 + tyrosine kinase inhibitors (TKI, n = 131), PD-1 + anti-vascular endothelial growth factor (anti-VEGF, n = 56), PD-1 + interferon Alfa-1b (IFN-α1b, n = 99) and PD-1 + IFN-α1b + TKI (n = 41) were included. There was no significant difference in irAEs across subtypes of melanoma. While for patients with autoimmune disease of psoriasis and lichen planus, recurrence was observed after immunotherapy. Baseline renal or hepatic dysfunction and prior TKI therapy were risk factors for grade 3-5 irAEs. Multivariate logistic regression model found that compared with PD-1 monotherapy therapy, PD-1 based combination therapies had greater toxicity but were tolerated, except PD-1 + IFN-α1b + TKI group. Notably, the triple therapy was associated with the highest risk of grade 3-5 irAEs (OR, 3.1; 95% CI: 1.2-8.1; p = 0.019), which led to a high rate of hospitalization and permanent treatment discontinuation.
Conclusion:
Our results suggested that PD-1 + TKI, PD-1 + anti-VEGF, PD-1 + IFN-α1b combination therapies have some adverse events but are generally tolerated sufficiently for continuation of treatment. While the triple therapy PD-1 + IFN-α1b + TKI is not recommended because the benefits do not outweigh the risks.
Insights
This study evaluated anti-PD-1 combination therapies for advanced melanoma in China. While most combinations were tolerated, triple therapy with PD-1, interferon, and tyrosine kinase inhibitors showed unacceptable toxicity.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Treatment
Background:
- Anti-PD-1 combination therapies are crucial for advanced melanoma in China, aiming to improve response rates and overcome resistance.
- Safety data for these combinations, particularly those involving interferon, is limited, necessitating further investigation.
- Understanding risk factors and comparative safety profiles is vital for optimizing immunotherapy decisions.
Purpose of the Study:
- To assess the safety and tolerability of various anti-PD-1 based combination therapies in advanced melanoma patients.
- To identify risk factors associated with immune-related adverse events (irAEs) in patients receiving immunotherapy.
- To compare the toxicity profiles of different anti-PD-1 combination strategies.
Main Methods:
- A nationwide retrospective cohort study included 508 advanced melanoma patients treated between July 2018 and June 2023.
- Patients received anti-PD-1 monotherapy or combinations including tyrosine kinase inhibitors (TKI), anti-vascular endothelial growth factor (anti-VEGF), or interferon Alfa-1b (IFN-α1b).
- Univariate and multivariable logistic regression analyses were used to identify risk factors for irAEs.
Main Results:
- No significant differences in irAEs were observed across melanoma subtypes, but recurrence occurred in patients with psoriasis and lichen planus.
- Baseline renal/hepatic dysfunction and prior TKI therapy were risk factors for severe irAEs (grade 3-5).
- Compared to PD-1 monotherapy, combination therapies increased toxicity, with PD-1 + IFN-α1b + TKI showing the highest risk of severe irAEs (OR, 3.1), leading to hospitalization and treatment discontinuation.
Conclusions:
- PD-1 + TKI, PD-1 + anti-VEGF, and PD-1 + IFN-α1b combinations are generally tolerated for advanced melanoma treatment.
- The triple therapy PD-1 + IFN-α1b + TKI is not recommended due to a high risk of severe irAEs where benefits do not outweigh the risks.
- Identifying patients at risk for irAEs and carefully selecting combination therapies are crucial for safe and effective melanoma treatment.
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