Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients

Abstract

Information on the role of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma patients is limited. We report on a prospective cohort of advanced melanoma patients treated simultaneously with radiotherapy and anti-PD-1 therapy between 01/01/15 and 30/06/16. Tumor evaluations (RECIST 1.1) were performed every 3 months on radiated and non-radiated lesions. Twenty-five advanced melanoma patients (64% AJCC stage IV M1c, 64% on second-line treatment or more, 60% with elevated LDH serum levels) were included. Radiotherapy was performed early (median: 24 days) after the first anti-PD-1 dose in 15 patients with rapidly progressing symptomatic lesion(s) or later (median: 5.4 months) in 10 patients with progressive disease (PD) despite PD-1 blockade. Radiotherapy was limited to one organ in 24 patients and consisted mainly of hypo-fractioned radiotherapy (median dose 26 Gy in 3–5 fractions, 17 patients) or brain radiosurgery (5 patients). Median follow-up after first anti-PD-1 dose was 16.9 m (range 2.7-27.4), with 44% of patients alive at last follow-up. For radiated lesions, rates of complete (CR), partial (PR) responses, stable disease (SD) or PD were 24%, 12%, 24%, and 32%, respectively. For non-radiated lesions, rates of CR, PR, SD, and PD were 20%, 19%, 12%, and 40%, respectively. Responses achieved after radiotherapy for radiated and non-radiated areas were correlated (Pearson correlation r: 0.89, P<0.0001) suggesting an abscopal effect. Five patients with CR remained disease-free after discontinuation of anti-PD-1 for a median of 9.5 months. No unusual adverse event was recorded. Hypo-fractionated radiotherapy may enhance efficacy of anti-PD1 therapy in difficult-to-treat patients. Controlled studies are needed.

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients

“…This benefit might be related to a synergic effect between radiotherapy and immunotherapy that has been demonstrated both in preclinical and clinical studies. [19][20][21][22][23] The combination of radiation and immune checkpoint inhibitors seems to be effective both in the irradiated and non-irradiated lesions, and this effect might be associated with the activation of cytotoxic T-cells and reduction of myeloid-derived suppressor cells. 18 24 25 The benefit of combining local and systemic therapy in MBM has been previously shown by our group and others, with mOS that range from 14 to 25 months and 1-year OS rates between 58% and 78% in the groups that received local and systemic therapy, clearly superior to the outcomes of patients receiving only systemic therapy (mOS between 6 and 13 months and 1-year OS rates ranging from 34% to 53%).…”

Extracranial abscopal effect induced by combining immunotherapy with brain radiotherapy in a patient with lung adenocarcinoma: A case report and literature review

“…Immunotherapy can liberate and activate CD8+ T cells from an immunosuppressed state, thereby increasing the probability of abscopal effects . Reports of abscopal effects have increased along with the development of combined radiotherapy and immunotherapy, but these have mainly occurred in patients with highly immunogenic melanomas …”

Pembrolizumab and concurrent hypo-fractionated radiotherapy for advanced non-resectable cutaneous squamous cell carcinoma

“…However, the association between immunotherapy (anti-CTLA-4 or anti-PD-1 mAb) and radiotherapy has proven its effectiveness in the local and distant control (abscopal effect) of melanoma, a skin cancer that, like cSCC, is characterized by a high mutational load, which is believed to be associated with anti-PD-1 mAb efficacy [5]. Radiotherapy might increase the efficacy of anti-PD-1 mAb treatment by changing the tumour microenvironment, increasing the level and activation of CD8+ T cells [20,22], promoting homing and extravasation of effector T cells at the tumour site, up-regulating tumour-associated antigen-MHC complex expression, or enhancing antigen cross-presentation in the draining lymph nodes [22,23]. Pembrolizumab lacked efficacy in two patients, which might be explained by its use as third-line treatment in one of them.…”

“…However, consent was obtained orally from all patients. The study was conducted according to the principles of the declaration of Helsinki [20].…”