Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 4, Pages 804-811Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-1223
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Funding
- NCI of the NIH [U10CA180821, U10CA180882, U24CA196171, U10CA180836, UG1CA189960, U10CA180863]
- Department of Defense Career Development Award [W81XWH-17-1-0265]
- NCI Cancer Clinical Investigator Team Leadership Award [P30 CA014599]
- Arthur J. Schreiner Family Melanoma Research Fund
- J. Edward Mahoney Foundation Research Fund
- Brush Family Immunotherapy Research Fund
- Buffet Fund for Cancer Immunotherapy
- Clinical Therapeutics Training Grant [NIH/NIGMS T32GM007019]
- Exelixis
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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 6.4months and 7.3months (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 tumormutational burden of 1.53mutations/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.
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