Abstract 1387P
Background
LXH254 is a BRAF/CRAF inhibitor and LTT462 is an ERK1/2 inhibitor. Both have demonstrated preclinical activity in MAPK-pathway driven xenograft models and have been evaluated as single agents in phase I dose-finding studies.
Methods
This phase Ib open-label trial (NCT02974725) explored LXH254 combinations; here we report on LXH254 + LTT462 dose escalation. Patients (pts) with advanced/metastatic KRAS- or BRAF-mutant NSCLC received oral LXH254 (50–350 mg once daily [QD] or 300–600 mg twice daily [BID]) and oral LTT462 (100–300 mg QD). Objectives included evaluating the recommended dose for expansion (RDE), safety, pharmacokinetics (PK) and preliminary efficacy of LXH254 + LTT462.
Results
As of 20 Aug 2019, 49 pts had been treated. 45 (92%) discontinued, primarily due to progressive disease (PD; n=29; 59%). Median age was 62 yrs (range: 35–82), 67% had ≥stage IIIB disease, 82% received ≥2 prior therapies. Median duration of exposure to study treatment was 6 wks (range: 1–36). LXH254 + LTT462 PK parameters were consistent with single-agent data; exposure was approximately dose proportional for both. 5 DLTs were reported in 4 pts: Grade (G) 3 rash and G3 hand-foot syndrome; G4 asymptomatic amylase increase; G3 asymptomatic lipase increase; G3 retinal detachment. Treatment-related (tr) AEs were reported in 90% of pts, most commonly (≥20%) dermatitis acneiform, nausea (both 29%), pruritis (27%), diarrhea (24%). G3/4 trAEs were reported in 33% of pts, most commonly (≥4%) lipase increase, amylase increase (both 6%), acute polyneuropathy (4%). Maximum tolerated dose was not reached; the RDE was LXH254 400 mg BID + LTT462 200 mg QD. 2 pts (4%; BRAF-mutant: 1 typical [V600E], 1 atypical [K601N]) had an unconfirmed partial response (uPR) and received treatment >4 months at LXH254 doses ≥300 mg BID. 16 pts (33%; including the 2 uPRs) had stable disease; of those, 2 BRAF-mutant pts (V600E, G466A) had tumor shrinkage ≥25%. 19 pts (39%) had PD. Response was unknown in 13 pts due to discontinuation prior to first assessment and 1 pt due to insufficient data.
Conclusions
LXH254 + LTT462 was generally well tolerated and the RDE has been declared. Preliminary signs of efficacy were seen in pts with BRAF-mutant NSCLC; dose expansion is ongoing.
Clinical trial identification
NCT02974725.
Editorial acknowledgement
Editorial assistance was provided by Laura Hilditch, Articulate Science.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
J. Wolf: Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Ignyta; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Takeda. D. Planchard: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Celgene; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: prIME Oncology; Honoraria (self), Advisory/Consultancy: Peer CME; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Samsung; Research grant/Funding (institution): Medimmun; Research grant/Funding (institution): Sanofi-Aventis; Research grant/Funding (institution): Taiho Pharma; Research grant/Funding (institution): Novocure. R.S. Heist: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Genentech Roche; Research grant/Funding (institution): Mirati; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Debiopharm; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy: Apollomics; Honoraria (self), Advisory/Consultancy: Tarveda; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy: Roche. B. Solomon: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Roche/Genetech; Advisory/Consultancy: Loxo; Licensing/Royalties: Veristrat (Biodesix); Licensing/Royalties: UpToDate. M. Sebastian: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self): Biontech; Honoraria (self): CureVac; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Tesaro. A. Santoro: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Servier; Advisory/Consultancy, Speaker Bureau/Expert testimony: Gilead Sciences; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: ARQULE; Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: AbbVie; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Celgene; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Sandoz; Speaker Bureau/Expert testimony: Novartis. N. Reguart: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Boehringer Ingelheim. U. Stammberger: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. L. Manganelli: Full/Part-time employment: Novartis. H. Wu: Full/Part-time employment: Novartis. A. Mais: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. All other authors have declared no conflicts of interest.