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|Authors||C. Lebbe G.V. Long C. Robert O. Hamid V.G. Atkinson A.N. Shoushtari A. Daud O.E. Bechter D. Schadendorf R.J. Sullivan R. Dummer J.J. Grob N. Lewis L. Fan S. Basu G. Caponigro V.G. Cooke A. Lau R. Amaria|
|Title||Phase II study of multiple LXH254 drug combinations in patients (pts) with unresectable/metastatic, BRAF V600- or NRAS-mutant melanoma|
|Abstract Text||Background The mitogen-activated protein kinase pathway is often dysregulated in melanoma. LXH254, an oral RAF inhibitor, inhibits BRAF and CRAF. We explore LXH254 combined with LTT462 (ERK1/2 inhibitor), trametinib (MEK1/2 inhibitor), or ribociclib (CDK4/6 inhibitor) in previously treated, BRAF V600 or NRAS-mutant melanoma. Methods Phase II, open-label study (NCT04417621) with a selection part followed by expansion. In selection, pts with melanoma (BRAF V600 and NRAS mutations separately allocated) were randomized to receive LXH254 (400 mg twice daily [BID]) + LTT462 (200 mg once daily [QD]; L+L), trametinib (0.5 mg QD; L+T), or ribociclib (400 mg QD; L+R). Based on Phase I expansion data, the L+T regimen was changed to LXH254 200 mg BID + trametinib 1 mg QD (L+T1). Pts had previously received ≥1 anti–PD-(L)1 inhibitor; pts with BRAF V600-mutant disease had prior treatment (Tx) with a BRAF inhibitor ± a MEK inhibitor as the most recent Tx line. The primary objective was to evaluate the efficacy of LXH254 combinations based on overall response rates. Key secondary objectives were safety and tolerability. Results As of May 2, 2022, 48 BRAF V600-mutant and 86 NRAS-mutant pts with advanced melanoma were enrolled; 77% had received ≥2 prior Txs. Table shows responses. Overall, 96% of pts had Tx-related adverse events (TRAEs) of any grade, most commonly rash (35%; L+L: 36%, L+T: 36%, L+T1: 40%, L+R: 23%), acneiform dermatitis (28%; L+L: 29%, L+T: 41%, L+T1: 27%, L+R: 14%), nausea (25%; L+L: 30%, L+T: 23%, L+T1: 10%, L+R: 27%), pruritus (24%; L+L: 25%, L+T: 21%, L+T1: 23%, L+R: 14%), and fatigue (21%; L+L: 17%, L+T: 14%, L+T1: 27%, L+R: 32%). Grade 3/4 TRAEs occurred in 46% of pts: rash (7%) was most common. Conclusion: These combinations exhibited tolerable safety profiles; most common toxicities were cutaneous. LXH254 in combination with LTT462 or trametinib shows promising efficacy in NRAS-mutant, immuno-resistant melanoma.|
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|NRAS mutant||melanoma||predicted - sensitive||LTT462 + LXH 254||Phase II||Actionable||In a Phase II trial, combination treatment with LXH 254 and LTT462 demonstrated tolerable safety in patients with NRAS-mutant melanoma, and led to a disease control rate of 62% (18/29), with a confirmed partial response in 6 patients and stable disease in 12 patients (Ann Oncol (2022) 33 (suppl_7): S197-S224; NCT04417621).||detail...|