We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment.
Keywords: BRAF inhibitor; CBC, complete blood count; CR, complete response; CRP, c-reactive protein; CT, computed tomography; CTL, cytotoxic lymphocyte; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GrzB, granzyme B; HD, high dose; IFN, interferon; IL-2, interleukin 2; LDH, lactate dehydrogenase; M6P, manose 6 phosphate; MAPK, mitogen-activated protein kinase pathway; PD-1, programmed death 1; PDL-1, programmed death ligand 1; PDL-2, programmed death ligand 2; PET, positron emission tomography; PR, partial response; RT, radiation therapy; SLE, systemic lupus erythematosus; WBC, white blood cell count; cytotoxic therapy, immunotherapy, treatment of melanoma; interleukin-2; ipilimumab; metastatic melanoma.