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Ref Type Abstract
Authors Filippo de Braud; Christophe Dooms; Rebecca S. Heist; Celeste Lebbe; Martin Wermke; David Planchard; Dirk Schadendorf; Piotr Rutkowski; Jürgen Wolf; Paolo A. Ascierto; Ignacio Gil-Bazo; Shumei Kato; Maria Wolodarski; Meredith McKean; Eva Muñoz Couselo; Martin Sebastian; Armando Santoro; Vesselina Cooke; Luca Manganelli; Kitty Wan; Anil Gaur; Tanay S. Samant; Jaeyeon Kim; Giordano Caponigro; Xuân-Mai Couillebault; Michele Moschetta; Adil Daud
Title Phase Ib study of LXH254 + trametinib (TMT) in patients (pts) with NRAS-mutant melanom
Journal Cancer Research
Vol 82
Issue 12_Suppl
Date June 15 2022
Abstract Text Background: MAPK pathway dysregulation is a characteristic molecular abnormality of melanoma. NRAS mutations in melanoma lead to constitutive MAPK activation and subsequent MEK and ERK activation. Inhibiting the pathway with a combination of BRAF/CRAF and MEK inhibitors (LXH254 and TMT, respectively) has demonstrated synergistic activity in preclinical models of NRAS-mutant melanoma. Methods: We report data from an open-label, Phase Ib study (NCT02974725), that tested LXH254 + TMT combination in a dose-escalation (ESC) part in pts with KRAS- or BRAF-mutant NSCLC or NRAS-mutant melanoma and in a dose-expansion (EXP) part in NRAS-mutant melanoma pts. In ESC, five dose levels were explored: LXH254 200 mg twice daily (BID) + TMT (1 mg or 0.5 mg) daily (QD); LXH254 400 mg BID + TMT (1 mg or 0.5 mg) QD; LXH254 400 mg BID + TMT 1 mg (QD, 2 wk on/2 wk off). Primary objectives were to evaluate safety and tolerability, and determine the recommended dose for expansion (RDE). Secondary objectives were to characterize pharmacokinetics and pharmacodynamics of LXH254 + TMT, and evaluate antitumor activity. Results: As of Dec 9, 2021, 36 and 30 pts were enrolled in ESC and EXP, respectively; median age was 63.5 and 69 y, respectively. Pts in ESC and EXP received a median of 3 (range: 1-6) and 2 (range: 1-7) prior treatments, respectively, including IO (ESC: 88.9% pts; EXP: 96.7% pts). All pts from ESC and 24 pts from EXP discontinued, mainly due to progressive disease (61.1% and 60%, respectively); 6 pts were ongoing in EXP at data cut-off. In ESC, Grade ≥3 (G≥3) DLTs were reported in 6 pts: dermatitis acneiform (n=2), maculopapular rash (n=2), increased lipase (n=1), and Stevens-Johnson syndrome (n=1). The RDEs were LXH254 200 mg BID + TMT 1 mg QD and LXH254 400 mg BID + TMT 0.5 mg QD. Treatment-related adverse events (TRAEs) were reported in 34 pts (94.4%) in ESC and all pts in EXP. G≥3 TRAEs in ESC and EXP were experienced by 19 (52.8%) and 24 (80%) pts, respectively; the most common being rash or dermatitis acneiform (13.9% each) in ESC and rash (33.3%) in EXP. One fatal TRAE (hypovolemic shock) was reported in the LXH254 400 mg BID + TMT 0.5 mg QD group. The ORR in EXP was 46.7% (7 pts; 95% CI: 21.3-73.4) for LXH254 200 mg BID + TMT 1 mg QD and 13.3% (2 pts; 95% CI: 1.7-40.5) for LXH254 400 mg BID + TMT 0.5 mg QD; overall in EXP, 9 pts (30%) achieved PR and 13 pts (43.3%) reported SD. In EXP the median DOR was 3.8 months (95% CI: 2.6-7.4). Exposures of LXH254 (200 mg or 400 mg BID) + TMT (0.5 mg or 1 mg QD) vs LXH254 single agent were comparable, indicating no apparent LXH254-TMT interactions. Limited paired tumor biopsy data (n=8) showed substantial MAPK pathway inhibition (DUSP6). Conclusions: LXH254 in combination with TMT has shown preliminary antitumor activity in the pretreated, NRAS-mutant melanoma population. A Phase II trial of LXH254 combinations in pts with pretreated BRAF- or NRAS-mutant melanoma is currently ongoing (NCT04417621).


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS mutant melanoma predicted - sensitive LXH 254 + Trametinib Phase I Actionable In a Phase Ib trial, combination treatment with LXH 254 and Mekinist (trametinib) resulted in an overall response rate of 30% (9/30) and stable disease in 43.3% (13/30) of patients with melanoma harboring NRAS mutations (Cancer Res 2022;82(12_Suppl):Abstract nr CT197; NCT02974725). detail...