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A retrospective analysis of patients with metastatic melanoma treated with sequential metronomic temozolomide after immune therapy failure
Abstract   Peer reviewed

A retrospective analysis of patients with metastatic melanoma treated with sequential metronomic temozolomide after immune therapy failure

Jason Chen, Aditya Alluri, Matthew Gao, Raghuram Inturi, Christopher Jun, Spencer Pham, Isabella Phillips, Sarah L. Mott and Mohammed M. Milhem
Journal of clinical oncology, Vol.44(16_suppl), pp.e21515-e21515
06/01/2026
DOI: 10.1200/JCO.2026.44.16_suppl.e21515

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Abstract

e21515Background: Melanoma is a skin malignancy that results in the deaths of around 60,000 people globally per year. Although metastatic melanoma historically carried a poor prognosis, breakthroughs such as pembrolizumab, a monoclonal antibody targeted against PD-1 receptor, have led to significant improvements in therapy. Despite this, studies have shown that more than 60% of patients show resistance to anti-PD-1 therapies. Multiple mechanisms, such as lack of presentation of antigenic proteins, insensitivity to T cells, and presence of immunosuppressive cells, have been implicated in this resistance. Temozolomide, a DNA alkylating agent, has been shown in a rat glioma model to reduce the number of circulating T regulatory cells. In a recent case series, three patients with metastatic melanoma showed responsiveness to metronomic temozolomide after pembrolizumab therapy failure. This study intends to provide a retrospective chart review of patients with metastatic melanoma to evaluate different factors that could influence the use of sequential metronomic temozolomide as a treatment option in patients who did not derive benefit from initial immunotherapy. Methods: Using TriNetX, patients with metastatic melanoma who received metronomic temozolomide after immunotherapy failure and received care at the University of Iowa Health Care were identified. Patients who did not receive prior immunotherapy or had ocular melanoma were excluded from analysis. Factors analyzed include age, gender, location of melanoma, stage, location of metastasis, disease burden, and receipt of prior definitive or palliative radiation. The key outcomes investigated were progression-free survival (PFS) and overall survival (OS) using Cox regression. Results: A cohort of 73 (58% male, median age 62) patients was identified. Median PFS and OS were 1.8 and 4.6 months, respectively. On univariate analysis, increased M stage (Hazard ratio [HR]: M1b 3.27, M1c 2.53, M1d 3.55, M1a referent; p = 0.04), presence of brain metastasis (HR: 1.82; p = 0.02), and receipt of palliative radiation (HR: 1.78; p = 0.02) were significantly associated with decreased PFS. While associated with decreased PFS, they were not found to have statistically significant differences in OS. Conclusions: In patients with metastatic melanoma who received metronomic temozolomide following immunotherapy failure, advanced M stage, presence of brain metastasis, and reception of palliative radiation were shown to have statistically significant decreases in PFS. Although this study does not demonstrate any specific factors associated with improved PFS or OS, therapies for immunotherapy-refractory metastatic melanoma remain exceptionally limited, and this study can help inform the risk-benefit analysis utilized by clinicians when considering the use of temozolomide in patients with varying disease presentations.

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