LBA40 - Phase II study of multiple LXH254 drug combinations in patients (pts) with unresectable/metastatic, BRAF V600- or NRAS-mutant melanoma

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. Table: LBA40

Preliminary efficacy

a. NE, n=12; b. Received LXH254 200 mg due to a prescription error, n=1; c. NE, n=11. BOR, best overall response based on all patients; cPR, confirmed partial response; DCR, disease control rate; NE, not evaluable; PD, progressive disease; SD, stable disease.

Conclusions

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.

Clinical trial identification

CLXH254C12201, NCT04417621.

Editorial acknowledgement

Editorial assistance was provided by Manoshi Nath MSc, of Articulate Science Ltd, and was funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

C. Lebbe: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; Financial Interests, Personal, Funding: Roche, Bristol Myers Squibb; Non-Financial Interests, Advisory Role: Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; Honoraria, Speaker's Bureau: Roche; Honoraria, Speaker's bureau, Travel, Accommodations, Expenses: Bristol Myers Squibb; Honoraria, Speaker's Bureau, Travel, Accommodations, Expenses: Novartis, MSD; Honoraria, Speaker's Bureau: Amgen; Honoraria, Travel, Accommodations, Expenses: Pierre Fabre; Honoraria: Pfizer; Honoraria: Incyte; Travel, Accommodations, Expenses: Sanofi. G.V. Long: Financial Interests, Personal, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. C. Robert: Financial Interests, Personal, Advisory Board: BMS, Roche, Pierre Fabre, Novartis, Sanofi, Msd, AstraZeneca, Pfizer. O. Hamid: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Advisory Board: Aduro, Akeso, Amgen, Beigene, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, SEAGEN, Tempus, Zelluna, Bioatla, Alkermes, Instil Bio, Iovance; Financial Interests, Institutional, Invited Speaker: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, SEAGEN, Torque, Zelluna, Rubius. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Nektar, Novartis, Pierre fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS. A.N. Shoushtari: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, Immunocore; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Invited Speaker: Bristol-Myers Squibb, Immunocore, Polaris, Xcovery, Pfizer, Novartis, Targovax ASA, Checkmate Pharmaceuticals; Non-Financial Interests, Member: ASCO. A. Daud: Financial Interests, Personal, Advisory Board: Xencor; Financial Interests, Personal, Other, DSMB: Nektar; Financial Interests, Personal, Stocks/Shares: Trex, Neuvogen; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, Merck, Pfizer, Incyte, Checkmate; Financial Interests, Institutional, Funding: Genentech. O.E. Bechter: Financial Interests, Institutional, Advisory Board: Novartis, BMS, MSD, Sanofi. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi, Merck, Novartis, BMS, MSD, 4SC, Nektar; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Roche, Merck Serono, Immunocore, 4SC, Pierre Fabre, Sanofi/Regeneron, Array Biopharma, Pfizer, Philogen, NEKTAR, Sandoz, Neracare; Financial Interests, Institutional, Research Grant: Novartis, BMS, MSD, Array/Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, MSD, Pierre Fabre, Sanofi, Roche, Philogen, 4SC, Nektar; Non-Financial Interests, Invited Speaker: EORTC-MG. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, Pfizer, Sanofi, Moderna, Roche-Genentech, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Simcha Therapeutics, OnKure. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. J.J. Grob: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Roche, Pierre fabre, Novartis, Pfizer, Sanofi, Philogen, Iteos Therapeutics, Sunpharma; Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pierre Fabre, Sanofi, Novartis; Financial Interests, Institutional, Research Grant: Pierre fabre. N. Lewis: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation; Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. L. Fan: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation. S. Basu: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation; Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. G. Caponigro: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation; Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. V.G. Cooke: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation; Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. A. Lau: Financial Interests, Personal, Full or part-time Employment: Novartis Pharmaceuticals Corporation. R. Amaria: Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics, Novartis, Bristol Myers-Squibb; Financial Interests, Institutional, Invited Speaker: Merck, Bristol Myers Squibb, Novartis, Iovance.