Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.

3517 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Patients (pts) with metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) have dramatically poorer survival rates than those with non-BRAF V600E mutated CRC, highlighting the need for novel therapies. The combination of a BRAF plus EGFR inhibitor is approved for the treatment of pts with BRAF V600E mCRC; however, objective response occurs in only 20% of pts. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. ERAS-007 alone or in combination with encorafenib and cetuximab (EC) showed promising in vitro and in vivo activity in BRAF V600E CRC models, supporting investigation of the potential clinical benefit of ERAS-007 + EC in pts with BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (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, tolerability, PK, and preliminary clinical activity of the combination of ERAS-007 + EC in pts with EC-naïve BRAF V600E CRC. Results: As of 30 November 2023, 19 (EC-naïve and EC-pretreated) pts have been dosed with ERAS-007 100 mg twice daily-once a week (BID-QW) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥25% of pts were dermatitis acneiform (52.6%); nausea and fatigue (47.4% each); diarrhea (42.1%); constipation, headache, and hematuria (31.6% each); and vomiting, anemia, and infusion-related reaction (26.3% each). There were no Grade 4 TEAEs. One pt suffered a Grade 5 unrelated event of respiratory failure. There were no Grade 3 treatment-related AEs that occurred in more than 1 pt. There were no ERAS-007-related AEs that led to discontinuation of ERAS-007. Of the 19 pts, 11 were EC naïve and 10 of 11 were efficacy evaluable. In the EC naïve efficacy evaluable pts, the ORR was 40% with 3 of the 4 responses confirmed. The maximum duration of response is > 15 months; updated data will be presented. Conclusions: ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .