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PurposeCombination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy.Patients and methodsIn a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety.ResultsA total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated.ConclusionCombination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Vaccination using dendritic/tumor cell hybrids represents a novel and promising cancer immunotherapy. We have developed a technology that can instantly purify the hybrids (dendritomas) from the fusion mixture of dendritic cells (DCs) and tumor cells. Our animal studies and a phase I study of stage IV melanoma patients demonstrated that dendritoma vaccination could be conducted without major toxicity and induced tumor cell-specific immunological and clinical responses. In this pilot study, ten stage IV renal cell carcinoma patients were studied. Dendritomas were made from autologous DCs and tumor cells and administered by subcutaneous injection. After initial vaccination, three escalating doses of IL-2 (3, 6, and 9 million units each) were followed within five days. This treatment regimen was tolerated well without severe adverse events directly related to the dendritoma vaccine. Most adverse events were related to IL-2 administration or pre-existing disease. Patient-specific immune responses were evaluated by flow cytometric measurement of interferon-gamma-producing T-cells before and after vaccination in response to stimulation with tumor antigens. Nine out of nine patients eligible for the analysis showed an increase of IFN-gamma-expressing CD4+ T cells after vaccination(s); while five out of eight patients eligible for the analysis showed an increase of IFN-gamma-expressing CD8+ T cells. Clinical responses were documented in 40% of the patients, three with stabilization of disease and one with a partial response documented by a reduction in tumor size. This pilot study demonstrated that dendritoma vaccines could be administered safely to patients with metastatic renal cell carcinoma, while producing both clinical and immunologic evidence of response.

A pilot clinical trial using dendritomas, purified hybrids from the fusion of dendritic/tumor cells combined with a low dose of IL-2, in metastatic melanoma patients was conducted in order to determine its safety and potential immunological and clinical responses. Ten metastatic melanoma patients were enrolled into this study. Dendritoma vaccines were created by fusing dendritic cells stained with green fluorescent dye with irradiated autologous tumor cells stained with red fluorescent dye and purifying the hybrids using immediate fluorescent-activated cell sorting. Initial vaccine was given subcutaneously and followed by IL-2 in serially elevated doses from 3-9 million units/m2 for 5 days. Repeated vaccinations were administered without IL-2, at 3-month intervals for a maximum of 5 times. Immune reactions were measured by the increase of interferon-gamma (IFN-gamma) expressing T cells. Vaccine doses ranged from 250,000 to 1,000,000 dendritomas. There was no grade 2 or higher toxicity directly attributable to the vaccine. All patients experienced toxicity due to IL-2 administration (9-grade 2, 3-grade 3, 1-grade 4). Eight of nine evaluable patients demonstrated immunologic reactions by increased IFN-gamma expressing T cells. One patient developed partial response at 12 weeks after the first vaccine. Nine months later, this patient achieved a complete response. In addition, two patients had stable disease for 9 and 4 months, respectively; one patient had a mixed response. Our findings demonstrated that dendritoma vaccines with a low dose of IL-2 can be safely administered to patients with metastatic melanoma and induce immunological and clinical responses.