PO.CT01.05 · 临床试验
Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC)
作者与单位
摘要 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.