IK-595（一种新型MEK-RAF分子胶）1期扩展研究在NRAS/KRAS突变晚期肿瘤患者中的单机构经验

Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. IK-595 is a novel MEK-RAF molecular glue designed to overcome resistance mechanisms by stabilizing MEK and all RAF isoforms in an inactive conformation. Anti-tumor activity was observed in KRAS-driven models when IK-595 was given alone and improved responses were seen when added to standard chemotherapy. Methods: Patients (pts) with metastatic RAS-mutant pancreatic adenocarcinoma (mPDAC) received Gemcitabine/nab-paclitaxel (1000/125 mg/m 2 i.v. weekly for 3 of 4 weeks in 28-day cycle) plus escalating doses of IK-595 p.o. (combo) as 1L or IK-595 (4mg twice p.o. weekly for 28 days) alone (mono) for 2L. Metastatic colorectal cancer (mCRC) with NRAS mutation was enrolled in dose escalation at 6mg twice weekly p.o. for 28 days. Primary objective was safety and tolerability. Secondary objective was antitumor activity. Here we describe our institution's experience. Results: At all participating sites, 51 total patients enrolled in monotherapy dose escalation, 5 in combo escalation and 19 with KRAS G12R mutation only in monotherapy expansion (4 mg twice weekly). 12 pts were treated at our institution, 7/12 in expansion monotherapy arm (1 prior line of treatment) and 4/12 with the combo (treatment-naïve). Objective response rate was 25% with mono and 50% with combo, including 1 complete response; disease control rate was 88% and 75%, respectively, and the responses were sustained for over 6 months in all responders. CA 19-9 responses ( > 20% decline in CA 19-9) were observed in 80% in mono and 100% in combo for those evaluable. Of note, 1 pt with NRAS mutant-mCRC, after with 2 prior lines, is still on study (on dose escalation) with on-going PR after 8 cycles. Treatment-related adverse events (TRAE, ≥ 15%) in the monotherapy arm were mostly mild, with rash (100%) being the most common, followed by diarrhea (57%), fatigue (43%), nausea/vomiting (28%), and ocular changes (28%). Grade 3 TRAE of elevated LFTs occurred in one mono pt and G3 elevated troponin in one combo pt. No Grade 4/5 TRAEs occurred. Conclusions: IK-595 showed an acceptable safety profile and compelling efficacy in both treatment-naïve mPDAC pts with KRAS mutation in combination with chemotherapy as well as 2L mPDAC and mCRC RAS mutant pts. These data support further treatment of this patient population with this novel agent.