Zhiyu Chen

Purpose:EMB-01 is a novel epidermal growth factor receptor × mesenchymal–epithelial transition factor bispecific antibody. The phase Ib/II study (NCT05176665) presents the safety and antitumor activity of EMB-01 in patients predominantly with heavily pretreated metastatic colorectal cancer (mCRC). Patients and Methods:EMB-01 was administered at 1,600 mg intravenously weekly. Primary endpoints were safety and tolerability in phase Ib and antitumor activity in phase II. Secondary endpoints included cross-phase validation of antitumor activity and safety. Exploratory endpoints included biomarker analysis. Results:Fifty-two patients were enrolled (phase Ib, n = 27; phase II, n = 25). All patients (100%) experienced at least one treatment-emergent adverse event, and 98.1% experienced treatment-related adverse events (TRAE). Grade ≥3 TRAEs occurred in 63.5% of patients, with rash (25%) and dermatitis acneiform (17.3%) most frequently. Among the 48 patients with mCRC, the confirmed objective response rate (cORR) was 12.5% [95% confidence interval (CI), 4.7%–25.2%], with a median duration of response of 32 weeks (95% CI, 16–not estimable). All responses were observed in a favorable mCRC subgroup with evaluable response [left-sided, RAS/RAF wild-type, naïve to fruquintinib/regorafenib/trifluridine–tipiracil (TAS-102); n = 29]. In this subgroup, the unconfirmed ORR (uORR) and the cORR were 24.1% (95% CI, 10.3%–43.5%) and 20.7% (95% CI, 8%–39.7%), respectively. Median progression-free survival was 19 weeks (95% CI, 12.3–24.1 weeks). Conclusions:EMB-01 demonstrated a manageable safety profile and promising antitumor activity in heavily pretreated mCRC, particularly in the RAS/RAF wild-type, left-sided mCRC subgroup naïve to late-line therapies, warranting further clinical development.

PFS in mCRC patients with different genomic aberration.

Representativeness of Study Participants.

Hematological Toxicities in Patients Treated with EMB-01 (Phase Ib/II).

Subgroup Analysis of Objective Response Rate (ORR), Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) in mCRC patients.

Subgroup Analysis of Progression-Free Survival (PFS) in mCRC patients.

Purpose: EMB-01 is a novel epidermal growth factor receptor × mesenchymal–epithelial transition factor bispecific antibody. The phase Ib/II study (NCT05176665) presents the safety and antitumor activity of EMB-01 in patients predominantly with heavily pretreated metastatic colorectal cancer (mCRC). Patients and Methods: EMB-01 was administered at 1,600 mg intravenously weekly. Primary endpoints were safety and tolerability in phase Ib and antitumor activity in phase II. Secondary endpoints included cross-phase validation of antitumor activity and safety. Exploratory endpoints included biomarker analysis. Results: Fifty-two patients were enrolled (phase Ib, n = 27; phase II, n = 25). All patients (100%) experienced at least one treatment-emergent adverse event, and 98.1% experienced treatment-related adverse events (TRAE). Grade ≥3 TRAEs occurred in 63.5% of patients, with rash (25%) and dermatitis acneiform (17.3%) most frequently. Among the 48 patients with mCRC, the confirmed objective response rate (cORR) was 12.5% [95% confidence interval (CI), 4.7%–25.2%], with a median duration of response of 32 weeks (95% CI, 16–not estimable). All responses were observed in a favorable mCRC subgroup with evaluable response [left-sided, RAS/RAF wild-type, naïve to fruquintinib/regorafenib/trifluridine–tipiracil (TAS-102); n = 29]. In this subgroup, the unconfirmed ORR (uORR) and the cORR were 24.1% (95% CI, 10.3%–43.5%) and 20.7% (95% CI, 8%–39.7%), respectively. Median progression-free survival was 19 weeks (95% CI, 12.3–24.1 weeks). Conclusions: EMB-01 demonstrated a manageable safety profile and promising antitumor activity in heavily pretreated mCRC, particularly in the RAS/RAF wild-type, left-sided mCRC subgroup naïve to late-line therapies, warranting further clinical development.

Background: Cytotoxic agents remain the mainstay treatment for advanced gastrointestinal cancer. However, the number of cytotoxic agents is limited, and the treatment effect is not satisfactory. Therefore, new agent and combination strategies are to be explored.Methods: The antitumor efficacy of low‐dose epigenetic modifiers (LD‐EMs) of 5‐azacytidine and entinostat, cytotoxic agents of paclitaxel, cisplatin, oxaliplatin, 5‐fluorouracil, and a novel cytotoxic agent TIC10, and the combination of LD‐EMs and cytotoxic agents was investigated in vivo. Flow cytometry and immunohistochemistry were conducted to analyze the immune phenotype in the tumor microenvironment. The proliferation and apoptosis analyses were performed in vitro.Results: LD‐EM therapy demonstrated superior tumor inhibition compared with commonly used chemotherapy in gastrointestinal cancer. A novel cytotoxic agent TIC10 resulted in weak to moderate tumor growth inhibition (TGI). LD‐EMs exhibited a more pronounced antitumor effect than TIC10 alone (CT26: TGI of 74.5% vs. 46.2%, respectively; p < 0.05; HNM007: TGI of 52.0% vs. 21.4%, respectively; p < 0.05; AKR: TGI of 53.8% vs. 10.1%, respectively; p < 0.05). The combination of TIC10 and LD‐EMs led to a more pronounced tumor reduction with tolerable toxicity. Analysis of the immune profiles showed increased percentages of CD45⁺ lymphocytes, CD3⁺ and CD8+ T cells, M1 macrophages, and dendritic cells, whereas decreased percentages of M2 macrophages and myeloid‐derived suppressor cells under treatment with LD‐EMs and combination therapy. Mechanistic studies revealed that LD‐EMs activated the RIG‐I–MAVS pathway, stimulated type I interferon responses, and subsequently promoted chemokine secretion. In contrast, TIC10 suppressed cell viability and induced cell apoptosis.Conclusions: LD‐EMs remodeled the tumor microenvironment to an immune‐promoting environment. Although TIC10 could suppress cell viability and induce cell apoptosis. A combination of LD‐EMs and TIC10 indicated a rational strategy through complementary mechanisms.

Cetuximab therapy is the major treatment for colorectal cancer (CRC), but drug resistance limits its effectiveness. Here, we perform longitudinal and deep proteomic profiling of 641 plasma samples originated from 147 CRC patients (CRCs) undergoing cetuximab therapy with multi-course treatment, and 90 healthy controls (HCs). COL12A1, THBS2, S100A8, and S100A9 are screened as potential proteins to distinguish CRCs from HCs both in plasma and tissue validation cohorts. We identify the potential biomarkers (RRAS2, MMP8, FBLN1, RPTOR, and IMPDH2) for the initial response prediction. In a longitudinal setting, we identify two clusters with distinct fluctuations and construct the model with high accuracy to predict the longitudinal response, further validated in the independent cohort. This study reveals the heterogeneity of different biomarkers for tumor diagnosis, the initial and longitudinal response prediction respectively in the first course and multi-course cetuximab treatment, may ultimately be useful in monitoring and intervention strategies for CRC.