Sequential Decitabine and Carboplatin Induced Stabilisation of Tumour Burden in a Patient with Immunotherapy-Resistant Metastatic Melanoma

Despite significant progress in the treatment of metastatic melanoma in recent years with targeted and immune checkpoint inhibitor therapy, there is no effective treatment option once resistance to all of these treatments occurs. Here, we report stabilisation of disease in a patient with anti-PD1 immunotherapy resistance after sequential low-dose decitabine and carboplatin. Stable disease allowed for re-challenge with anti-PD1 immunotherapy. Stable disease with no disease progression was seen in a 47-year old Caucasian male diagnosed with metastatic melanoma with unknown primary who had progressed on previous BRAF/MEK inhibitors (dabrafenib and trametinib) and anti-PD1 immunotherapy (pembrolizumab) after 9 weeks on the novel Phase 2 study (PRIME001: Pilot early phase II study of decitabine and carboplatin in patients with advanced melanoma ACTRN12616000440426). The patient received two 4-week cycles of decitabine 7 mg/ m2 intravenous infusion (IVI)/day for 5 days (D1-D5) followed by Carboplatin AUC 5 IVI on day 8 (D8) and Week 3 and Week 4 no treatment. There were no toxicities >grade 2. Stable disease (RECIST 1.1) was recorded at week 9, the patient re-commenced Pembrolizumab and continued to have stable disease for a further 9 months. Tumour biopsies at baseline and at disease progression 9 months post re-commencing Pembrolizumab both showed high PD-L1 expression and moderate tumour infiltrating lymphocytes, predominately restricted to the tumour periphery. Genomic analysis identified high tumour mutation load and 4 mutations in common to the 2 biopsies. Peripheral immune cell profiles displayed an increase and stabilisation of CD4+ and CD8+ T-cells, particularly with the expression of CXCR6. Sequential decitabine and carboplatin is a feasible priming regime, with a tolerable safety profile for patients with advanced melanoma who are resistant to prior immunotherapy. The priming treatment limits the burden of disease to allow effective ongoing treatment with immune checkpoint inhibitors.