Overcoming immunotherapy resistance in advanced melanoma through radiotherapy: A prospective observational study.

Abstract

e21501 Background: Outcomes for patients with advanced melanoma have improved since the integration of immune checkpoint inhibitors (ICIs). Despite these advances, most experience disease progression and succumb to their illness, making strategies to overcome resistance to immunotherapy an area of active investigation. Radiotherapy can induce an immune-mediated abscopal effect resulting in regression of non-irradiated tumors after localized radiotherapy. However, in melanoma, response rates and benefits with concurrent ICIs remain unclear. This prospective study assessed radiotherapy’s impact on advanced melanoma patients receiving immunotherapy, evaluating responses in both irradiated and non-irradiated lesions using RECIST 1.1. Methods: This ongoing IRB approved study enrolls adult patients with metastatic melanoma receiving standard of care immunotherapy. Upon disease progression, stereotactic radiotherapy was delivered to a selected target lesion (TL). Additional non-targeted lesions (NTL) were identified for monitoring. Radiation regimens included either 8–10Gy x 3 fractions or a single fraction of 8 Gy. Tumor responses were evaluated using RECIST 1.1 criteria. Objective response was defined as a ≥30% reduction in the sum of diameters of the lesions. Results: Five patients with metastatic melanoma were included in this interim analysis. All patients received nivolumab; one patient also received pembrolizumab, and two patients received ipilimumab. The median follow-up duration was 8.2 months (range 5.8– 34.5 months). In three patients (60%), TL remained stable in size following radiotherapy for a median duration of 6.9 months. Two patients (40%) demonstrated a reduction >30%. For NTL, four patients (80%) showed stable or decreased in size, with a median duration of response of 4.2 months. Four patients developed new metastatic lesions, resulting in the designation of progressive disease. The median time to progression due to new lesions was 4.8 months. Three patients died from disease progression at 5.8, 10.1, and 17.4 months from consent. Two patients remain alive at 34.5 months. Conclusions: Combining radiotherapy with ICIs represents a promising strategy to overcome immunotherapy resistance by augmenting antitumor responses. In this interim analysis, our small cohort demonstrated evidence of clinical benefit following combined therapy, with stabilization or reduction of both irradiated target lesions (100%) and non-irradiated lesions (80%). These findings suggest a transient synergistic effect in disease control, as most patients later developed metastatic lesions. The emergence of metastases may reflect the outgrowth of tumor clones with antigenic profiles distinct from the irradiated lesions suggesting sequential or repeated radiotherapy targeting new lesions could be explored as a strategy to re-induce local and systemic responses.