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).

Citation Format: 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. Phase Ib study of LXH254 + trametinib (TMT) in patients (pts) with NRAS-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT197.