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Ref Type
PMID
Authors J. Wolf D. Planchard R.S. Heist B. Solomon M. Sebastian A. Santoro N. Reguart U. Stammberger L. Manganelli H. Wu A. Mais C. Dooms
Title Phase Ib study of LXH254 + LTT462 in patients with KRAS- or BRAF-mutant NSCLC
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 31 Supplement 4
URL https://www.annalsofoncology.org/article/S0923-7534(20)41697-7/fulltext
Abstract Text 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.

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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
BRAF V600E lung non-small cell carcinoma predicted - sensitive LTT462 + LXH 254 Case Reports/Case Series Actionable In a Phase Ib trial, LTT462 and LXH 254 combination therapy was well tolerated and resulted in an unconfirmed partial response (PR) in 4% (2/49) and stable disease (SD) in 33% (16/49) of patients with advanced or metastatic KRAS- or BRAF-mutant non-small cell lung cancer, with 1 patient harboring BRAF V600E achieving an unconfirmed PR and 1 achieving SD with over 25% tumor reduction (Ann Oncol 31 (suppl 4):S881-S882; NCT02974725). detail...
BRAF K601N lung non-small cell carcinoma predicted - sensitive LTT462 + LXH 254 Case Reports/Case Series Actionable In a Phase Ib trial, LTT462 and LXH 254 combination therapy was well tolerated and resulted in an unconfirmed partial response (PR) in 4% (2/49) and stable disease (SD) in 33% (16/49) of patients with advanced or metastatic KRAS- or BRAF-mutant non-small cell lung cancer, with 1 patient harboring BRAF K601N achieving an unconfirmed PR (Ann Oncol 31 (suppl 4):S881-S882; NCT02974725). detail...
BRAF G466A lung non-small cell carcinoma predicted - sensitive LTT462 + LXH 254 Case Reports/Case Series Actionable In a Phase Ib trial, LTT462 and LXH 254 combination therapy was well tolerated and resulted in an unconfirmed partial response (PR) in 4% (2/49) and stable disease (SD) in 33% (16/49) of patients with advanced or metastatic KRAS- or BRAF-mutant non-small cell lung cancer, with 1 patient harboring BRAF G466A achieving SD with over 25% tumor reduction (Ann Oncol 31 (suppl 4):S881-S882; NCT02974725). detail...