Treatment of Advanced Melanoma With Concurrent Radiation and Programmed Cell Death 1 Inhibitors

Abstract

To report toxicity and clinical outcomes of patients with locally advanced unresectable or metastatic melanoma treated with concurrent radiation (RT) and programmed cell death 1 (PD-1) inhibitors. The medical records of all patients with locally advanced or metastatic melanoma from a single institution were reviewed. Fourteen patients between October 2014 and December 2016 underwent 18 courses of definitive or palliative RT while receiving a PD-1 inhibitor. RT was delivered concurrently with pembrolizumab (n=11), nivolumab (n=6), or ipilimumab/nivolumab (n=1). Most received a single course of RT (n=11) and three had multiple RT treatments concurrent with PD-1 inhibition. Patients were analyzed for toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The median age was 53 years (range, 30-81). The median follow up was 6.5 months (range, 1-27). Seven patients received PD-1 inhibitors as first line therapy. Prior to starting PD-1 inhibitors, four patients with BRAF V600E mutations had failed combination BRAF and MEK pathway inhibitors and six patients had progressive disease after ipilimumab. The median time from initiation of a PD-1 inhibitor to the start of RT was 55 days (range, 1-637). The following sites were irradiated: extremity/trunk (n=4), brain radiosurgery (n=4), abdomen/pelvis (n=4), head and neck (n=3), lung (n=1), spine (n=1), and liver (n=1). The most frequent RT dose was 30 Gy in 5 fractions (n=7). The median planning target volume (PTV) irradiated for non-radiosurgery treatments was 237.5 cm3 (range, 11-2807). One patient experienced a grade 3 gastritis, although this was a primary gastric melanoma and toxicity was confounded by tumor related symptoms. Grade 3 confluent desquamation was seen during RT of a vulvar melanoma treated with 48 Gy in 20 fractions to a 2807 cm3 PTV. Grade 2 toxicity was frequent and site dependent, but primarily consisted of radiation dermatitis and diarrhea for cutaneous and abdominal/pelvic sites, respectively. No acute toxicity was seen with concurrent PD-1 inhibitors and brain radiosurgery (n=4). The 1-year overall survival was 69.6%. The median local control of the irradiated lesion and progression free survival were 12.6 months and 5.3 months, respectively. Four patients have no evidence of progression after a median follow up of 5 months (range, 1-27) since completion of RT. One patient with an initially unresectable axillary lesion was treated with RT and pembrolizumab and had a pathologic complete response. Another patient experienced >50% radiographic response in a non-irradiated lesion after combination therapy suggesting a possible abscopal effect. Delivery of concurrent RT and PD-1 inhibitors was well tolerated. Further study is required to determine optimal dose, fractionation, and timing of RT and to define the long term clinical benefit of this approach.