Effect of Radiotherapy Combined With Pembrolizumab on Local Tumor Control in Mucosal Melanoma Patients

Abstract

Objective: Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy of radiotherapy (RT), especially combined with immune checkpoint inhibitors (ICIs), for this rare melanoma subtype remains unknown. We investigated the reciprocal effect of RT and ICI on mucosal melanoma patients.Materials and Methods: We identified 23 patients with 31 tumors who were treated with RT between July 2008 and February 2017. All patients received RT for primary or metastatic gross tumor mass with a median dose of 4 Gy per fraction (range 1.8–12 Gy). Eleven patients (14 lesions) were treated with RT alone, whereas 12 (17 lesions) were administered pembrolizumab combined with RT (ICI+RT group). The local control (LC) and adverse event (AE) rates were compared between the groups. Eight patients with metastatic mucosal melanoma treated with ICI alone during the same study period were included as a comparison group.Results: The median follow-up period was 17.4 (range 3.7–95.2) months. The target lesion control rate at 1-year was significantly higher in the ICI+RT group than in the RT-alone group or ICI-alone group (94.1% vs. 57.1% vs. 25%; P < 0.05). No abscopal effect was observed in our cohort. Treatment-related AEs were not significantly increased in the combined treatment group compared with the RT-alone group (P > 0.05). No grade ≥3 AEs occurred in the ICI+RT group.Conclusions: Besides RT acting as an immune adjuvant, ICI might have a radiosensitizing effect and may increase LC without severe toxicity. We have initiated a phase II study to determine the effects of RT in patients with melanoma undergoing anti-PD1 (NCT04017897).

The Combination of Radiotherapy with Pembrolizumab in the Treatment of Metastatic Melanoma Patients: a Systematic Review

“…In a study by Kim et al [44], pembrolizumab was shown to have radiosensitizing effect when combined with RT, thereby increasing local control (LC) without severe toxicity. The 1-year LC rate was 94.1% for the RT+ pembrolizumab group compared with the RT-alone group with 25%.…”

The emerging role of myeloid-derived suppressor cells in radiotherapy

“…When combined with ICI treatment, RT have shown improved efficacy in preclinical studies [17][18][19][20] and clinical trials [21][22][23][24][25]. In TUBO and MC38 tumor models, high levels of radiation (12 Gy for TUBO and 20 Gy for MC38) combined with PD-L1 blockade synergistically amplified the antitumor effect, which was correlated with a reduction of MDSCs mediated by tumor infiltrating CD8+ T cells [17].…”

“…Thus, the combination of RT and ICIs could enhance antitumor responses more potently than either treatment alone. The combined effect of RT and ICIs have been evaluated and have shown promising results in preclinical studies [17][18][19][20] and clinical trials [21][22][23][24][25]. Furthermore, abscopal effects which seldom occur after RT alone have been increasingly reported in patients treated with the combination of RT and immunotherapy [26].…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…A prospective study comparing external beam irradiation combined with ipilimumab to radiation only in prostate cancer-associated bone metastases found no significant difference among groups [187]. Further trials combining radiotherapy with checkpoint blockade are currently being initiated for patients with advanced stage head and neck squamous cell carcinoma, breast cancer, and mucosal melanoma [188][189][190][191]. Studies are still ongoing exploring the synergistic effects of radiation and checkpoint blockade in various malignancies [192].…”