IntroductionEpigenetic modifications play an important role in progression and development of resistance in V600EBRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with V600EBRAF positive metastatic melanoma with or without any prior treatment.Experimental DesignThe study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line.ResultsFourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity.ConclusionsThe combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in V600EBRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.
Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m2 daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.
Background Use of immune checkpoint inhibitors in advanced melanoma is challenging in patients with a history of immune therapy related colitis or pre-existing inflammatory bowel disease (Crohn's disease or ulcerative colitis). 1 Vedolizumab is a gut-selective, anti-integrin antibody that binds to the a4b7 integrin on circulating leukocytes and inhibits their trafficking into the intestinal epithelium (figure 1). 2 There is limited clinical experience of using Vedolizumab in combination with anti-PD1 antibody in melanoma patients with inflammatory enterocolitis. 3 We present outcomes of a cohort of advanced melanoma patients with inflammatory enterocolitis who concurrently received Vedolizumab and anti-PD1 antibody. Methods In this retrospective single-institution study, records of advanced melanoma patients with a history of inflammatory enterocolitis were reviewed. Patients who received anti-PD1 antibody (Pembrolizumab, Nivolumab), concurrently with Vedolizumab were selected for analysis. Results Nine patients with stage III/IV cutaneous melanoma and pre-existing enterocolitis received Vedolizumab plus anti-PD1 antibody (table 1). A total of 96 doses of anti-PD1 antibody were administered concurrently with Vedolizumab (56 doses), with each patient receiving at least 7 doses of anti-PD1 antibody. Vedolizumab was administered intravenously (300 mg at weeks 0, 2 and 6 weeks and then every 8 weeks) along with Pembrolizumab (200 mg every 3 weeks) or Nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks). Patients had a history of grade 3-4 colitis from prior checkpoint inhibitor therapy (n=4), Crohn's disease (n= 4), and ulcerative colitis (n= 1). Seven patients were negative for BRAF V600 mutation. Six patients had no recurrence of colitis symptoms while on anti-PD1 antibody therapy. Three patients with recurrence of colitis had a prior history of Crohn's disease (n=2), and grade 3 check-point inhibitor related colitis (n=1). All patients with recurrence of colitis symptoms did not have melanoma progression while receiving Vedolizumab plus anti-PD1 antibody. Overall, seven patients did not experience melanoma progression on therapy. One patient had a complete response. Two patients were able to complete adjuvant treatment with anti-PD1 antibody, without melanoma recurrence on follow-up. Vedolizumab infusions were well tolerated, and no treatment related side effects were noted.Conclusions Concurrent Vedolizumab appears to allow treatment with anti-PD1 antibody in advanced melanoma patients with pre-existing inflammatory enterocolitis. Prospective studies are needed to definitively determine the safety and anti-melanoma efficacy of this combination.Ethics Approval This study was reviewed and approved by the University of Iowa Institutional Review Board IRB 01, under IRB# 202202583. A waiver of informed consent was granted by the IRB per 45 CFR 46.116 (f)(3)
BackgroundIn the United States, melanoma is the fifth leading cancer in men and the seventh in women. Immunotherapy has improved antitumor activity and survival. Overall response rate (ORR) with single agent PD-1 inhibitor is 35%, and 55% with the combination of PD-1/CTLA-4 inhibitors but with significant grade 3–4 toxicity.1 2 Cabozantinib inhibits multiple receptor tyrosine kinases, including c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), and has been shown to have immunomodulatory effects in vitro and in murine models.3 In addition, c-Met has been found to induce overexpression of PD-L1.4 We hypothesize that combination treatment with these two drugs has the potential to improve response rate in metastatic or recurrent melanoma, without significant regimen-limiting toxicities.MethodsThis trial in progress is an open-label, single center Phase 1b/2 study of the combination of cabozantinib and pembrolizumab in patients with advanced melanoma. Eligible patients have stage IV or recurrent/medically inoperable melanoma, treatment naïve for immunotherapy. Prior BRAF and MEK inhibitor is allowed in metastatic setting. Exclusion criteria includes those with ocular or mucosal melanoma or uncontrolled CNS metastases. The trial is currently recruiting.The phase 1b study is based on a 3+3 design with a fixed dose of pembrolizumab (200 mg IV every 3 weeks) and three dose levels of cabozantinib (40, 20 and 60 mg), administered orally daily. The primary endpoint of the phase 1b study is safety of the combination in metastatic melanoma patients. The phase 2 study will be conducted in two stages to evaluate the preliminary efficacy of combination cabozantinib and pembrolizumab, with up to a total of 44 subjects. The study will be terminated early if five or fewer subjects respond in the first stage; otherwise, additional subjects will be accrued. The primary endpoint is best ORR. The secondary endpoints are disease control rate (DCR), duration of DCR, time to response, progression-free survival and overall survival. Exploratory endpoints include assessing biomarkers as a measure of clinical efficacy.ResultsN/AConclusionsN/ATrial RegistrationNCT03957551Ethics ApprovalThe study was approved by The University of Iowa’s Institutional Review Board, approval number 201904712.ReferencesHodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. The Lancet Oncology 2016;17:1558–68.Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nature reviews Clinical oncology 2016;13:473–86.Ilangumaran S, Villalobos-Hernandez A, Bobbala D, Ramanathan S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions. Cytokine 2016;82:125–39.Balan M, Mier y Teran E, Waaga-Gasser AM, et al. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. The Journal of biological chemistry 2015;290:8110–20.
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