Dataset Information

Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201).

ABSTRACT: PURPOSE:The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. PATIENTS AND METHODS:Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. RESULTS:Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3-4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ? or >1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. CONCLUSIONS:MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

SUBMITTER: Luke JJ

PROVIDER: S-EPMC7055933 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201).

Luke Jason J JJ Olson Daniel J DJ Allred Jacob B JB Strand Carrie A CA Bao Riyue R Zha Yuanyuan Y Carll Timothy T Labadie Brian W BW Bastos Bruno R BR Butler Marcus O MO Hogg David D Munster Pamela N PN Schwartz Gary K GK

Clinical cancer research : an official journal of the American Association for Cancer Research 20190926 4

<h4>Purpose</h4>The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy.<h4>Patients and methods</h4>Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either ...[more]

PMID: 31558480

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Project description:LESSONS LEARNED:Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. BACKGROUND:Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). METHODS:This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. RESULTS:A total of 53 patients were enrolled in cohort 1 (n?=?24) and cohort 2 (n?=?29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. CONCLUSION:Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

Dataset Information

Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201).

Publications

Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201).

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