Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.