Combined RAF- and MEK-inhibition in solid cancers with kinase-impaired BRAF mutations (SORATRAM phase I trial).

3119 Background: BRAF is a frequently mutated gene in cancer, with most mutations (mut) at the activating hotspot V600 codon. Recently, kinase-inactive class III BRAF mut emerged as oncogenic driver and potential therapeutic target, as they lead to paradoxical cross-activation of RAF1- and RAS-dependent downstream signaling. Here we report the Phase I toxicity results of combinatory inhibition of RAF kinases by sorafenib (S), a multi-kinase inhibitor (e.g. RAF1, BRAF, c-KIT, FLT-3) and MEK/ERK signaling by trametinib (T) in patients (pts) with inactivating BRAF mut. Methods: SORATRAM is a prospective, molecularly stratified, multicenter phase I trial. Primary objective is to determine the maximal tolerated dose (MTD) of T combined with S and the recommended phase II dose (RP2D). Adult pts with metastatic malignancies, confirmed or known impaired kinase BRAF mut (according to in vitro testing), ECOG ≤ 2 and no available therapy options were eligible. S was given in the approved dose (800 mg) from day (d)1 cycle (c)1, combined with T on c1d8 for max 12c or until progression or unacceptable toxicity. Dose levels (DL) are defined by T dose (0.5mg DL1, 1.0mg DL2 and 1.5mg DL3) and escalated in a conventional 3 + 3 design. MTD is defined as highest dose at which 0/3 pts or < 2/6 pts experience a dose limiting toxicity (DLT) during c1. DLT is defined as toxicity related to S+T combination, unrelated to disease progression, intercurrent illness or concomitant medications, that requires dose reduction or drug withdrawal. Results: Since 2020, 236 cases from 9 sites were classified for mutational SORATRAM eligibility with 42% being kinase impaired (e.g. D594G, N581I, G466E), 21% known intermediate/high activity (excluding V600E/K) (e.g. L597V, K601E) and 36% with novel/unclear/unknown kinase activity (e.g. G469I, W531S). Eligible pts with inactivating BRAF mut proceeded to SORATRAM screening. 15 pts received dose finding treatment: 3 in DL1 and DL2 and 9 in DL3. Median age was 57 years (34-75) with 12f/3m pts. Included entities were colorectal cancer (60%), duodenal carcinoma/carcinoma of papilla vateri (20%), lung adenoid cystic carcinoma (6.7%), bone sarcoma (6.7%) and ovarian cancer (6.7%). 3/3 pts in DL1 and DL2 and 6/9 pts at DL3 fulfilled the minimum safety evaluation requirements (≥ 80% of S+T doses in c1; 28ds observation). No DLT was observed in DL1 and DL2. 1/6 pts in DL3 developed a DLT (reduction of left ventricular ejection fraction (LVEF)). 5/15 pts (33.3%) experienced grade 3 adverse events (AEs) during c1: Hypertension (13.3%), gastrointestinal bleeding (6.7%; rated as SAE), anemia (6.7%), LVEF reduction (6.7%), diarrhea (6.7%) and fatigue (6.7%). 79 AEs grade 1/2 were reported in c1. Conclusions: Combination of sorafenib/ trametinib is feasible and can be safely administered to pts. MTD was determined as DL3 (800mg S + 1.5mg T), RP2D as DL2 (800mg S + 1mg T). Dose expansion part of SORATRAM is open for enrollment. Clinical trial information: EU – CT No. 2024-512887-77-00 .