Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers)
Recommended Citation
Lee MS, Parikh AR, Spigel DR, Dayyani F, Spira AI, Atreya CE, Ulahannan SV, Strickler JH, Fakih M, Grierson P, Christenson E, Outlaw D, Khan G, Kopetz S, Bullock AJ, Li Z, Chen X, Patel H, Hazra S, Chiorean E. Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers). J Clin Oncol 2023; 41(16):3557.
Document Type
Conference Proceeding
Publication Date
6-1-2023
Publication Title
J Clin Oncol
Abstract
Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) has dramatically worse survival than non-BRAF V600E mutated CRCs, and novel therapies are needed. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. The combination of a BRAF plus EGFR inhibitor (EC) is approved for the treatment of pts with BRAF V600E mCRC; however, only 20% of pts experience an objective response. ERAS-007 alone or in combination with EC showed promising in vitro and in vivo activity in BRAF V600E CRC models to support the combinatorial clinical benefit of ERAS-007+EC in BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety and tolerability of escalating doses of ERAS- 007 + EC in pts with BRAF V600E CRC. Prior BRAF inhibitor and EGFR inhibitor treatment is neither required nor excluded to be enrolled in this study. Results: As of 30 November 2022, 12 patients were dosed with ERAS-007 twice daily-once a week (BID-QW) (75 and 100 mg; n = 10) or once daily once a week (QW) (150 mg; n = 2) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion once every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥20% of pts were fatigue (50%), headache (42%), constipation, diarrhea, nausea, dermatitis acneiform (33% each), and vomiting (25%). No TEAEs led to ERAS-007 discontinuation or death. Grade ≥3 TEAEs were reported in 3 pts (25%). Grade ≥3 treatment-related AEs reported in ≥ 2 patients (17%) include hypertension, headache, confusional state, and skin toxicity. Three pts (25%) died due to disease progression. No DLTs were reported. Out of 4 efficacy evaluable EC naïve pts, one confirmed partial response (PR) and one unconfirmed PR were observed. Evaluation of PK is ongoing and preliminary data will be presented. Conclusions: ERAS-007+EC in pts with BRAF V600E CRC shows acceptable preliminary safety/tolerability and evidence of clinical activity. The highest dose of ERAS-007 evaluated and cleared by the safety review committee to date is 100 mg BID-QW when combined with EC. Observed PK, toxicity, and preliminary activity support continued evaluation of this combination in pts with BRAF V600E CRC.
Medical Subject Headings
Hematology
PubMed ID
Not assigned.
Volume
41
Issue
16
First Page
3557
