RESUMO
Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.
Targeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of BRAF-mutant melanoma. Additionally, immunotherapy in combination with targeted therapy has been shown to improve patient outcomes. In this study, the authors assess the efficacy and safety of a combination of a BRAF-inhibitor (encorafenib), an MEK-inhibitor (binimetinib) and an anti-PD-1 (pembrolizumab) in patients with metastatic BRAF-mutant melanoma. Clinical Trial Registration: NCT04657991 (ClinicalTrials.gov).
Assuntos
Melanoma , Segunda Neoplasia Primária , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Carbamatos , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Segunda Neoplasia Primária/etiologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , SulfonamidasRESUMO
PURPOSE: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy. RESULTS: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed > or =50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed. CONCLUSION: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.