Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Abstract

Background:There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic.Method:We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS).Results:A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8–24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93–17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039).Conclusions:IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+T cell trafficking

“…1C). Thus, the outcome of anti-PD-1/anti-CTLA-4 combination therapy was superior to the two monotherapies, which is in line with the reported intracranial response rate for anti-PD-1 monotherapy (21-25%) (12)(13)(14)(15) and anti-PD-1/anti-CTLA-4 combination therapy (50-55%) (15,16), as well as the 6 month progression-free survival rate of 28% and 46%, respectively (15). Due to these promising data, we focused on the anti-PD-1/anti-CTLA-4 combination therapy.…”

“…A handful of retrospective and prospective clinical studies indicated activity of ipilimumab in melanoma BrM with 16-25% intracranial response rate, but also suggested that only a subgroup of patients is likely to benefit (4,5,11). Pembrolizumab and nivolumab also showed efficacy in melanoma BrM with an ~21% response rate in the brain (12)(13)(14)(15). A very recent interim analyses from two clinical trials in drug-treatment naïve patients with melanoma BrM (ABC trial (15) and CheckMate 204 trial (16)) reported a 50% and 55%…”

Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab

“…Recently, it has been shown in a retrospective trial that nivolumab treatment in patients with MBM leads to a median overall survival of 9.9 months. Similar to the results with ipilimumab, patients who are corticosteroid independent and with asymptomatic MBM had a better progression‐free survival and median overall survival . A retrospective analysis of RT for MBM in a patient population treated with nivolumab has shown a good local and distant control and a median overall survival of about 12 months.…”

“…Similar to the results with ipilimumab, patients who are corticosteroid independent and with asymptomatic MBM had a better progressionfree survival and median overall survival. 42 A retrospective analysis of RT for MBM in a patient population treated with nivolumab has shown a good local and distant control and a median overall survival of about 12 months. Similar to the studies with ipilimumab, the performance status was predictive of a good overall survival.…”

Immuno-oncology for surgeons

“…Similarly, the use of corticosteroid, an immunosuppressive agent, particularly in patients with brain metastasis or glioblastoma, has been associated with poor outcome after immunotherapy. Keskin and colleagues demonstrated that patients with glioblastoma who received dexamethasone during administration of personalized neoantigen vaccines were unable to generate neoantigen‐specific CD4+ and CD8+ responses in both peripheral blood and the TME.…”