PO.CT01.05 · 临床试验
新型BRAF抑制剂plixorafenib（FORE8394）在BRAF V600突变晚期结直肠癌（CRC）中的临床活性和安全性
Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
BRAF V600突变型CRC是一个预后较差、生存期较短的侵袭性亚组。当前的BRAF抑制剂（BRAFi）受限于快速耐药和副作用。在BRAFi联合方案进展的患者中存在很高的未满足需求。
Plixorafenib是一种"悖论阻断剂"，旨在破坏RAF二聚体，选择性抑制V600和非V600 BRAF变异而不激活MAPK通路。PLX120-03是一项已完成的单臂1/2a期研究，评估了plixorafenib单药治疗在BRAF变异实体瘤中的最佳剂量、安全性和疗效。总体人群的初步数据此前已报告。
在这项针对BRAF V600突变CRC（N=14）预设疗效分析的首次披露中，中位年龄为60岁，57%为女性，100%为白人。参与者（pts）既往接受的中位治疗线数为2线，其中1例既往接受过含MAPK抑制剂（MAPKi）的方案。在13例无既往MAPKi治疗的患者中，plixorafenib单药的疾病控制率为62%，中位PFS为3.5个月（mos）。有1例经确认的PR（ORR 8%），持续3.7个月（治疗持续时间6个月）；MAPKi预处理患者则为PD。7例为SD（治疗持续时间范围：3.7-28.7个月），其中4例持续治疗≥6个月。临床获益与既往治疗线数较少相关。安全性令人鼓舞，与总体人群一致；治疗中出现的不良事件（TEAE）主要为低级别肝功能指标（LFT）升高、胃肠道疾病和乏力。5例患者中出现11起3级TEAE，其中8起无关、3起相关（食欲下降、腹泻、高血糖），无因TEAE导致的停药。
对基线及后续时间点的血浆ctDNA变异进行了分析（n=12）。观察到给予plixorafenib后BRAF变异等位基因频率（VAF）和瘤内ERK磷酸化下降，证实了直接的PD效应。BRAF VAF在整个治疗期间下降，并在PD时反弹，与肿瘤体积变化的动态相匹配。
在治疗结束时，与已获批BRAFi相比，我们发现MAPK通路（KRAS、MAP2K1、MET AMP）和PI3K通路（PIK3CA、AKT2、AKT3）内获得性突变的发生率更低。未观察到NRAS突变或BRAF外显子缺失。在>2例患者中发现的其他获得性突变为NF1（n=2）、雄激素受体（AR；n=2）和CDKN2A/B CNV（n=3）。在对plixorafenib无应答的患者中，识别出RTK、NF1和PI3K通路（PTEN、PIK3CA、AKT）的基线突变，这些可能与耐药有关。
Plixorafenib单药治疗在既往经过多线治疗的BRAF V600突变CRC患者中显示出与已获批BRAFi单药相当的活性，且安全性显著改善。ctDNA数据显示出与已获批BRAFi不同的耐药模式，获得性MAPK通路和PI3K通路突变更少。这些数据支持探索plixorafenib与靶向药物或化疗的联合方案。
查看英文原文 English abstract
BRAF V600 mutant CRC is an aggressive subset with shorter survival. Current BRAF inhibitors (BRAFis) are limited by rapid resistance and side effects. There is a high unmet need in patients who progress on BRAFi-containing regimens.
Plixorafenib is a paradox breaker designed to disrupt RAF dimers, selectively inhibiting V600 and non-V600 BRAF alterations without activating the MAPK pathway. PLX120-03, a completed single-arm phase 1/2a study assessed optimal dose, safety, and efficacy of plixorafenib monotherapy in BRAF-altered solid tumors. Preliminary data for the total population were reported previously.
In this first disclosure of a prespecified efficacy analysis for BRAF V600 mutated CRC (N=14), median age was 60 years, 57% were female, and 100% were White. Participants (pts) received a median of 2 prior lines of treatment, and one received a prior MAPK inhibitor (MAPKi)-containing regimen. For 13 pts with no prior MAPKi, disease control rate with plixorafenib monotherapy was 62% and median PFS was 3.5 months (mos). There was confirmed PR (ORR 8%) lasting 3.7 mos (treatment duration 6 mos); the MAPKi pretreated pt had PD. Seven pts had SD (treatment duration range: 3.7-28.7 mos) with 4 remaining on treatment ≥6 mos. Clinical benefit correlated with fewer lines of prior therapy. Safety was encouraging and consistent with the total population; TEAEs were primarily low-grade LFT elevations, GI disorders, and fatigue. There were 11 grade 3 TEAEs in 5 pts, 8 unrelated and 3 related (decreased appetite, diarrhea, hyperglycemia), and no discontinuations due to TEAEs.
Plasma ctDNA alterations at baseline and subsequent timepoints were analyzed (n=12). Decreases in BRAF variant allele frequency (VAF) and intratumor ERK phosphorylation after administration of plixorafenib were observed, confirming direct PD effects. BRAF VAF decreased throughout treatment and rebounded at PD, matching the dynamics of tumor volume changes.
At the end of treatment, we identified lower rates of acquired mutations within the MAPK (KRAS, MAP2K1, MET AMP) and PI3K (PIK3CA, AKT2, AKT3) pathways compared to that for approved BRAFis. NRAS mutations or BRAF exon deletions were not observed. Other acquired mutations found in >2 pt were NF1 (n=2), androgen receptor (AR; n=2), and CDKN2A/B CNV (n=3). In pts who did not respond to plixorafenib, baseline mutations in RTKs, NF1, and PI3K pathway (PTEN, PIK3CA, AKT) were identified and may have contributed to resistance.
Plixorafenib monotherapy in heavily pre-treated pts with BRAF V600 mutated CRC demonstrated activity comparable to approved BRAFi monotherapy with a markedly improved safety profile. ctDNA data showed a pattern of resistance distinct from that of approved BRAFis, with lower acquired MAPK pathway and PI3K pathway mutations. These data warrant exploration of combination approaches of plixorafenib with targeted drugs or chemotherapy.
利益披露 Disclosure
R. Yaeger,
Mirati Therapeutics Independent Contractor, ).
Revolution Medicines Independent Contractor, ).
Eli Lilly Independent Contractor, ).
Merck Independent Contractor.
Erasca Independent Contractor.
Parabilis Medicines Independent Contractor, ).
Alterome Independent Contractor.
Bayer Independent Contractor.
Pfizer ).
Boundless Bio Independent Contractor, ).
Daiichi Sankyo ).
CytoDyn Independent Contractor.
S. Sharma,
Cure CRC Summit Travel.
Iterion Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Tisch Cancer Institute Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Mirati Therapeutics (BMS) Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Black Canyon Bio g., Board of Directors, non-salaried role), Stock.
Stingray Therapeutics g., Board of Directors, non-salaried role), Stock.
Bonneville Bio g., Board of Directors, non-salaried role), Stock.
A. Parikh,
C2i Genomics; Khora; OneCell; XGenomes; Cadex; Parithera Stock.
Zola; CVS; Phesi; Xilio; 3T Biosciences; Do More Diagnostics; Summit Therapeutics; Pfizer; Regeneron; GSK; Foundation Medicine; Careset; Value Analytics Labs; Naterara; Adroya; AstraZeneca; Scare; Other, Consultant/Advisor.
Hookipa; Guardant; Abbvie; Seagen; Mirati; Takeda; PMV; Kahr; Sirtex; Eli Lilly; Merck; Amgen; Delicate; Exact; Caris; BMS; Incyte; Pheon; Neogenomics; J & J; Exact; Boehringer Ingelheim; Novartis; Other, Consultant/Advisor.
Third Rock Ventures; MPM Capital; Science For America Other, Consultant/Advisor.
Science For America Other, Chief Scientist of Reversing Early Recurrence.
Up to Date Other, Receives Fees.
Karkinos Healthcare Travel.
PMV Pharmaceuticals; BMS; Mirati; Erasca; Genentech; Daiichi Sankyo; Syndax; Revolution Medicine; Lily; Xilio; Parthenon Other, Received research funding to the institution.
S. Peacock Shepherd,
Fore Biotherapeutics Employment, Stock, Stock Option, Patent.
Corcept Therapeutics Patent.
AbbVie Stock, Stock Option.
Abbott Stock, Stock Option.
BridgeBio Stock, Stock Option.
Moderna Stock, Stock Option.
M. Monga,
Fore Biotherapeutics Employment, Stock Option.
P. Jiang,
Fore Biotherapeutics Employment.
J. Jang,
Fore Biotherapeutics Employment, Stock Option, Patent.
Cellectis, Inc Stock.
M. Paz,
Fore Biotherapeutics Employment, Stock Option, Other, Study management.
F. Tsai,
FhRma Foundation ).
CME Horizon Other, Payment or honoraria for lectures, presentations, speakers
bureaus, abstract writing or educational events.
Sphinx Health Solutions Corp g., Board of Directors, non-salaried role).
Salarius Pharmaceuticals Stock, Stock Option.
U. Vaishampayan,
Fore Biotherapeutics Other, Payment to institution.
BMS Other, Consulting.
Merck Other, Consulting.
Bayer Other, Consulting.
Janssen Other, Consulting.
Novartis Other, Consulting.
AstraZeneca Other, Consulting.
Pfizer Other, Consulting.
MI Society of Hematology/Oncology Other, Board Member.
J. Rodon,
European Society for Medical Oncology; American Society of Medical Oncology; Dava Oncology; STOP Cancer Travel, Other, non-financial support.
Ellipses Pharma; Lonctura; Amgen; Merus; MonteRosa; Bridgebio; Debio; Bristol Myers Squibb; BioHybrid Solutions Travel, Other, Consulting, (including serving on the scientific advisory board).
Vall d'Hebron Institute of Oncology; AstraZeneca; Boxer Capital LLC; Ecor1; Tang Advisors, LLC; Guidepoint Other, Consulting.
Blueprint Medicines; Merck Sharp & Dohme; Hummingbird; AstraZeneca; 280 Bio; Vall d'Hebron Institute of Oncology/Cancer Core Europe; Bristol Myers Squibb Other, Research funding.
Cancer Core Europe; Pfizer; Kelun-Biotech; Roche Pharmaceuticals; 280 Bio; Bicycle Therapeutics; ForeBio; Ideaya; Amgen; Tango Therapeutics; Bristol Myers Squibb; MonteRosa; Debio; Beigene; Relay; Other, investigator in clinical trials.
Novartis; Scorpion Therapeutics; Incyte; Parabilis Pharmaceuticals; Tyra; Nuvectis Pharma; Adcentrix; Vividion; AstraZeneca; Alnylam; Immuneering Corp; Alterome; Exelixis; Ensem; Bridgebio; Cogent; Other, investigator in clinical trials.
Biohaven; Insilico Medicines; Ipsen; Eli Lilly; Seed; Zai Labs Other, investigator in clinical trials.