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Ref Type Abstract
Authors Macarena Ines De La Fuente, Jordi Rodon Ahnert, Rona Yaeger, Frank Yung-Chin Tsai, Filip Janku, Nicholas A. Butowski, Carl E. Allen, Natraj Reddy Ammakkanavar, Jennie Webster Taylor, Glenn Michelson, Irina Kline, Michael Paz, Alexia Tussay-Lindenberg, Kongming Wong, Stacie Peacock Shepherd, Ping Jiang, Eric Jeffrey Sherman
Title Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study
Abstract Text Background: FORE8394 is an investigational inhibitor (i) of class 1 (V600) and 2 (activating non-V600) BRAF-altered tumors. FORE8394 did not have paradoxical activation of the MAPK pathway in nonclinical studies. Methods: In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). CNS metastases and prior treatment with other BRAFi were allowed. Besides standard safety assessments, skin and eye exams were required. Objective response was assessed by RECIST v1.1 or RANO criteria. Efficacy was evaluated in pts with class 1/2 BRAF alterations and ≥1 post-baseline assessment, with mg/m2 dosing (n=4) reported separately. Results: On 21Nov2022, 110 pts had received ≥1 dose of FORE8394. 85% completed ≥1 4-week cycle. 10 (9%) and 3 (3%) received FORE8394 ≥2 and ≥6 years, respectively; 14 (13%) are ongoing. Pts included 61 (55%) class 1 mutations, 19 (17%) class 2 mutations (excluding fusions), and 17 (15%) BRAF fusions. 64 pts (58%) had ≥2 prior lines of systemic therapy; 28 (25%) received prior MAPKi. Increased ALT (39%), increased AST (35%), fatigue (34%), nausea (27%), diarrhea (22%), and vomiting (20%) were the most frequently reported treatment-emergent adverse events (TEAEs); most were grade (G) 1/2. G3+ TEAEs were reported in 49% (54/110), the most common being increased ALT (9%), increased blood bilirubin (6%), and hyponatremia (5%). Transient G1 pyrexia was observed in 8 (7%) pts. All rashes were G1; none required a dose change. No TEAE of hyperkeratosis, papilloma, uveitis, retinal detachment, or LVEF reduction were reported. 1 pt discontinued due to FORE8394-related TEAE. Antitumor activity was observed in pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]), 39% (9/23) having a PR (median duration of response [DoR]: 32 months). In 17 pts with V600 mutated tumors (excluding CRC) treated with prior MAPKi, 3 (18%) had PR and 5 (29%) had SD. In V600 mutated tumors, PRs occurred in 6 (55%) gliomas, 3 (100%) ovarian cancers, and 1 each in CRC (7%), small bowel (50%), papillary thyroid (13%) and anaplastic thyroid (25%) cancers. Of pts with BRAF-fusions, a pt with AGK-BRAF-fused melanoma had CR (DoR 51.8+ months); 46% (6/13) had SD. Of note, 1 child with V600E mutated Langerhans cell histiocytosis had SD with improvement in neurodegenerative changes and a progression-free survival of 55.8+ months. Conclusions: As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394. Clinical trial information: NCT02428712


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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 V600X Advanced Solid Tumor predicted - sensitive PLX8394 Phase Ib/II Actionable In a Phase I/II trial, PLX8394 treatment resulted in a partial response in 39% (9/23) of patients with MAPK inhibitor-naive advanced solid tumors (excluding colorectal cancer) harboring BRAF V600X with a median duration of response of 32 months, and resulted in a partial response in 18% (3/17) and stable disease in 29% of patients previously treated with a MAPK inhibitor (J Clin Oncol 41, 2023 (suppl 16; abstr 3006); NCT02428712). detail...
BRAF fusion Advanced Solid Tumor predicted - sensitive PLX8394 Phase Ib/II Actionable In a Phase I/II trial, PLX8394 treatment resulted in stable disease in 46% of patients with advanced solid tumors harboring BRAF fusions and a complete response with a duration of response of at least 51.8 months in a patient with melanoma harboring AGK-BRAF (J Clin Oncol 41, 2023 (suppl 16; abstr 3006); NCT02428712). detail...