BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Based on promising results from pre-clinical and clinical studies demonstrating potential synergy between immunotherapy and targeted therapy for melanoma, clinical trials are underway to investigate the efficacy and safety of combining targeted therapy and immunotherapy in patients with melanoma positive for BRAF mutations (Table 8.1).
There are several clinical trials studying the combination of BRAF-directed therapy with the FDA-approved agent aldesleukin (interleukin-2). The first of these trials was developed at the Massachusetts General Hospital (Boston, Massachusetts) and is a phase II trial (NCT01754376) of BRAF-directed therapy (vemurafenib) and immunotherapy using aldesleukin (IL-2) in patients with metastatic melanoma harboring a BRAFV600E mutation. In this trial, patients receive a 2 week “lead-in” with vemurafenib and then receive high dose IL-2. The primary endpoints for this trial include efficacy (as measured by progression-free survival and durable response rate) and toxicity and comparisons will be made to historic controls of vemurafenib alone and aldesleukin alone. Importantly, this trial also includes correlative studies to assess for treatment response and immunologic parameters. The target accrual for this clinical trial is 42 patients over a 2 year time period.
A similar study is being run by the cytokine working group (CWG) (NCT01683188), examining the complete response rate to combination therapy of vemurafenib and high dose IL-2 in two cohorts: (1) BRAF V600 mutation-positive metastatic melanoma patients (n = 135) who receive vemurafenib < 7 weeks before treatment with high dose IL-2 and (2) BRAF V600 mutation-positive metastatic melanoma patients (n = 50) who receive vemurafenib > 7–18 weeks before treatment with IL-2.
In addition to IL-2 and vemurafenib combination strategies, clinical trials are also assessing the investigational use of adoptive cell therapy (ACT) in patients with metastatic melanoma. A pilot trial (NCT01585415) at the National Cancer Institute (Bethesda, Maryland) is investigating the safety of vemurafenib in combination with the investigational use of ACT of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma. In this interventional study, investigators will first biopsy or resect melanoma tumors from patients (n = 25) in order to generate and expand autologous TILs ex vivo. Patients will first undergo non-myeloablative lymphocyte depletion by chemotherapeutic agents: cyclophosphamide (60 mg/kg/day IV) on days seven and six and fludarabine (25 mg/day IV) on days five until one. On day zero, patients will receive up to 1011 TILs and aldesluekin (a total of 15 doses of 720,000 IU/kg IV every 8 hours). Patients will then start vemurafenib (960 mg) regimen on day one. Similarly, a single-center, Phase II Trial (NCT01659151) has commenced at H. Lee Moffitt Cancer Center and Research Institute (Tampa, Florida) to improve: (1) drop-out rates from ACT and (2) 12 monthPR and CR in patients with metastatic melanoma (n = 60) that receive a combination of vemurafenib, lymphodepletion using cyclophosphamide and fludarabine plus adoptive cell transfer and high dose IL-2.
Table 8.1. Clinical trials investigating the combination of targeted therapy and immunotherapy
There are also several clinical trials of BRAF-directed therapy in combination with immune checkpoint inhibitors. The first of these trials was a phase I/II trial of vemurafenib and ipilimumab given concurrently in patients with BRAF mutant melanoma (NCT01400451). This trial involved a run-in of 1 month of BRAF-directed therapy (vemurafenib) alone followed by four infusions of ipilimumab. The primary goal of this trial was to assess safety and to define a schedule that could be used for further clinical trials. The target accrual for this trial was 50 patients, though the trial was stopped early due to toxicity (see discussion below). After the trial was stopped, another trial was opened with sequential (i.e. non-overlapping) administration of these agents. The target accrual for this trial is 45 patients.
Another trial is currently underway investigating the combination of BRAF-directed therapy with immune checkpoint blockade using anti-PD-L1 (NCT01656642). This trial aims to enroll 44 patients with BRAF-mutant melanoma with the primary endpoint of safety and tolerability.
Given the encouraging findings of combined BRAF-directed therapy with MEK inhibition, efforts are also underway to use combined BRAF + MEK inhibition with immune checkpoint blockade using ipilimumab (anti-CTLA-4). A phase I trial is currently underway and involves a 25 day lead-in of dabrafenib, trametinib, or both followed by ipilimumab (NCT01940809). The primary endpoint of this study is safety and tolerability, with a secondary endpoint of disease control rate and response rate. Importantly, biomarkers will also be studied with the goal of identifying potential predictors of response.
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