{
  "abstract": "Background Colorectal cancer (CRC) is the third most prevalent cancer globally. 1 Approximately 20% CRC patients are diagnosed with metastatic CRC (mCRC), and up to half of those initially diagnosed with localized tumors eventually develop metastases.2 Microsatellite stable (MSS) tumors account for ~95% of mCRC characterized by inadequate immune cell tumor penetration and poor response to immunotherapy. Patients with MSS WT KRAS/BRAF receive frontline treatment of chemotherapy with anti-EGFR (left-sided mCRC) or anti-VEGF (left- and right-sided mCRC) therapies.3 4 However, efficacy of these treatments is limited by tumor heterogeneity, acquired drug resistance and an immunosuppressive tumor microenvironment (TME).5–8 Ficerafusp alfa, a bifunctional antibody targeting EGFR and TGF-β, overcomes key resistance mechanisms to cetuximab (anti-EGFR antibody) by blocking epithelial-mesenchymal transition and promoting tumor penetration of immune cells.9 Ficerafusp alfa also reduces VEGF,9 an important angiogenic factor in both left- and right-sided mCRC, opening a potential opportunity to expand anti-EGFR based therapy beyond left-sided mCRC. Ficerafusp alfa was evaluated in KRAS/BRAF WT MSS CRC cell lines to determine if dual targeting of EGFR and TGF-β can improve responses over cetuximab.Methods KRAS/BRAF WT MSS CRC cell lines (NCI-H508 and SNU-503) were characterized for EGFR expression and TGF-β secretion. Cells were treated with ficerafusp alfa or cetuximab and evaluated for cytotoxicity (cellTiter-Glo) at 72 hours. In-vitro tumor-PBMC coculture assays (with 1ng/mL TGF-β) were performed for 3-14 days and assessed for cell death (cytoTox-Glo), cell growth (real-time GFP+ tumor cell imaging using IncuCyte platform), and immune response (cytokines).Results The expression of EGFR and TGF-β was higher in SNU-503 compared to NCI-H508. In the absence of PBMCs, NCI-H508 cells were sensitive to ficerafusp alfa and cetuximab, whereas SNU-503 cells were largely resistant. However, in the presence of PBMCs (and TGF-β), ficerafusp alfa rescued the inhibitory effect of TGF-β, enhancing IFN-γ secretion and cytolytic activity of PBMCs against SNU-503 and NCI-H508. Ficerafusp alfa showed prolonged and significantly improved tumor cytotoxicity (>50%) and a two-fold increase in IFN-γ levels compared to cetuximab ( figure 1).Conclusions Ficerafusp alfa showed significantly improved and sustained anti-tumor effects compared to cetuximab in the presence of PBMCs, underscoring the importance of overcoming TGF-β-mediated drug resistance and facilitating immune cell tumor penetration with the TGF-β arm of ficerafusp alfa. This study supports the rationale for evaluation of ficerafusp alfa +/- immunotherapy in the Ph1b expansion cohort for MSS WT KRAS/BRAF mCRC ( NCT04429542).References Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45. Epub 20250116. doi: 10.3322/caac.21871. PubMed PMID: 39817679; PubMed Central PMCID: PMC11745215.Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72(4):372–401. Epub 20220426. doi: 10.3322/caac.21728. PubMed PMID: 35472088.Gmeiner WH. Recent advances in therapeutic strategies to improve colorectal cancer treatment. Cancers (Basel). 2024;16(5). Epub 20240302. doi: 10.3390/cancers16051029. PubMed PMID: 38473386; PubMed Central PMCID: PMC10930828.Cherri S, Oneda E, Zanotti L, Zaniboni A. Optimizing the first-line treatment for metastatic colorectal cancer. Front Oncol. 2023;13:1246716. Epub 20231016. doi: 10.3389/fonc.2023.1246716. PubMed PMID: 37909027; PubMed Central PMCID: PMC10614157.Parseghian C, Eluri M, Kopetz S, Raghav K. Mechanisms of resistance to EGFR-targeted therapies in colorectal cancer: more than just genetics. Front Cell Dev Biol. 2023;11:1176657. Epub 20230915. doi: 10.3389/fcell.2023.1176657. PubMed PMID: 37791069; PubMed Central PMCID: PMC10542118.Schmitt M, Greten FR. The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol. 2021;21(10):653–67. Epub 20210428. doi: 10.1038/s41577-021-00534-x. PubMed PMID: 33911231.Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15(2):81–94. Epub 20171108. doi: 10.1038/nrclinonc.2017.166. PubMed PMID: 29115304.Buikhuisen JY, Torang A, Medema JP. Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges. Oncogenesis. 2020;9(7):66. Epub 20200709. doi: 10.1038/s41389-020-00250-6. PubMed PMID: 32647253; PubMed Central PMCID: PMC7347540.Boreddy SR, Nair R, Pandey PK, Kuriakose A, Marigowda SB, Dey C, et al. BCA101 is a tumor-targeted bifunctional fusion antibody that simultaneously inhibits EGFR and TGFbeta signaling to durably suppress tumor growth. Cancer Res. 2023;83(11):1883–904. doi: 10.1158/0008-5472.CAN-21-4425. PubMed PMID: 37074042; PubMed Central PMCID: PMC10236157.Abstract 1180 Figure 1Ficerafusp alfa showed prolonged and significantly improved tumor cell death and enhanced IFNγ secretion over cetuximab. PBMC co-culture assays with SNU-503 rfluc-GFP. 56nM drug treatments followed by real time imaging of GFP+SNU-503 cells with IncuCyte (A) Representative images at Day 14 (B) Percentage tumor cells at Day 14 (C) IFNG in supernatant at 72h (D) One-wayANOVA",
  "authors": [
    {
      "affiliations": [
        "Syngene International Limited, Bengaluru, India"
      ],
      "name": "Anshu Kuriakose"
    },
    {
      "affiliations": [
        "Syngene International Limited, Bengaluru, India"
      ],
      "name": "Reshmi Nair"
    },
    {
      "affiliations": [
        "Syngene International Limited, Bengaluru, India"
      ],
      "name": "Pradip Nair"
    },
    {
      "affiliations": [
        "Bicara Therapeutics, Boston, MA, USA"
      ],
      "name": "Brenda C O’Connell"
    },
    {
      "affiliations": [
        "Bicara Therapeutics, Boston, MA, USA"
      ],
      "name": "Rachel Salazar"
    }
  ],
  "title": "1180 Dual targeting of TGF-β and EGFR with ficerafusp alfa shows superior anti-tumor activity over cetuximab in KRAS/BRAF wild-type MSS colorectal cancer",
  "uid": "78607409-c55d-5078-b2c4-41c9b28793f2"
}