Reference Detail

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@jax.org

Ref Type Abstract
PMID
Authors Alexander Spira; Valentina Gambardella; Shumei Kato; Cesar Batista Perez; Meredith Mckean; Maria Gonzalez Cao; Richard Kim; Chris T Chen; Antoine Italiano; Philippe Cassier; Janice Mehnert; Bartosz Chmielowski; Gerri Lee; Paul Severson; Caro Unger; Xiaowei Guan; Richard Williams; Georgina Long
Title Abstract CT032: Trials in progress: a global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma
Journal Vol Issue Date Pages Journal Short Title
Cancer Research April 14 2023 83 8_Supplement
URL https://aacrjournals.org/cancerres/article/83/8_Supplement/CT032/725198/Abstract-CT032-Trials-in-progress-a-global-phase-1
Abstract Text Background: Patients with cancers driven by BRAF Class II (C II) or C III alterations and/or NRAS mutations are unlikely to benefit from approved BRAF-targeted therapies and have few other treatment options. Exarafenib is a potentially best in class orally available pan-RAF inhibitor optimized for potency & high selectivity. It has differentiated dose-dependent activity across a broad range of cell lines & models driven by BRAF C I (inc. those with acquired resistance to 1st gen RAFi), C II, C III or NRAS alterations. Methods: KN-8701 (NCT04913285) is an ongoing Phase 1 dose escalation & dose expansion study at 35 sites in 7 countries evaluating exarafenib monotherapy in participants (pts) with advanced solid tumors harboring oncogenic BRAF or NRAS alterations. Results: Preliminary results as of 13 Dec 2022 are reported for 52 pts (median age 63, 51.9% male) with a median of 3 prior therapies treated in 6 dose levels. Treated pts included those with solid tumors driven by BRAF C I (38.5%), C II (19.2%), C III (28.8%) alterations or melanoma pts with NRAS mutations (13.5%). Steady state exarafenib exposure (Cmax and AUC) increased dose proportionally. Pathway inhibition & decreases in ctDNA were observed across BRAF classes & tumor types. Dose limiting toxicities observed at the highest dose level were Grade 3 (Gr3) acneiform rash & Gr3 macular rash. The maximum tolerated dose (MTD) was determined to be 300 mg bid. Treatment-related adverse events (TRAEs) (any grade) occurred in 69.2% of pts with 13.5% of pts having Gr ≥3 events. Skin AEs (any grade) were the most common TRAEs observed in 48.1% of pts with 7.7% of pts having Gr ≥ 3 skin events. GI TRAEs occurred in 19.2% pts (Gr 1-2 only), including diarrhea (1 pt, Gr 1). Reversible, asymptomatic Gr 3 increased ALT and/or increased AST AEs in 3 pts were the only non-skin Gr ≥ 3 TRAEs reported in ≥ 2 pts. At therapeutically relevant exposures, there was no cutaneous evidence of paradoxical activation. Of the 34 pts across all dose levels with at least 1 post-baseline tumor assessment, 6 pts (17.6%) had a partial response (5 confirmed at submission date) & 16 pts (47.1%) had stable disease including 8 pts (23.5%) with objective tumor shrinkage (up to 20%). The 6 responders all continue exarafenib therapy (treatment duration up to 12 months) and include 3 pts with BRAF C I alteration-driven cancers (inc. 1 RAFi + MEKi pre-treated melanoma pt) and 1 pt each with BRAF C II, BRAF C III-driven & NRAS-mutation driven cancers. For pts who achieved or confirmed their best response at MTD, the response rate was 33% (4/12) & included responses in pts with BRAF C I, C II, C III, and NRAS mutant tumors. Conclusions: Exarafenib achieves therapeutically meaningful drug exposures and demonstrates promising tolerability & clinical activity in BRAF or NRAS alteration-driven solid tumors. Pt enrollment & exarafenib treatment at 300 mg bid continues.

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.

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
NRAS act mut melanoma predicted - sensitive Exarafenib Case Reports/Case Series Actionable In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including a partial response in 1 melanoma patient harboring an NRAS mutation (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). detail...
BRAF class 2 Advanced Solid Tumor predicted - sensitive Exarafenib Case Reports/Case Series Actionable In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including a partial response in 1 patient harboring a BRAF class 2 mutation (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). detail...
BRAF class 3 Advanced Solid Tumor predicted - sensitive Exarafenib Case Reports/Case Series Actionable In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including a partial response in 1 patient harboring a BRAF class 3 mutation (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). detail...
BRAF class 1 Advanced Solid Tumor predicted - sensitive Exarafenib Case Reports/Case Series Actionable In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including 3 partial responses in patients harboring BRAF class 1 mutations (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). detail...