Yanhong Deng

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: To evaluate retlirafusp alfa (an anti–PD-L1/transforming growth factor-β bispecific antibody) plus standard chemotherapy as first-line treatment for unresectable, locally advanced or metastatic, human epidermal growth factor receptor 2 (HER2)–negative gastric or gastroesophageal junction adenocarcinoma in the first-line setting. METHODS: In this randomized, double-blind (RELIGHT), phase III study, 731 patients with previously untreated, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive retlirafusp alfa or placebo intravenously every 3 weeks plus capecitabine and oxaliplatin (CAPOX). The primary end point was overall survival (OS), assessed in patients with PD-L1 combined positive score (CPS) ≥5 and the intention-to-treat analysis set. RESULTS: Retlirafusp alfa plus CAPOX significantly prolonged OS versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 16.8 vs 10.4 months; stratified hazard ratio [HR], 0.53 [95% CI, 0.40-0.68]; one-sided P < .0001) and the intention-to-treat analysis set (median, 15.8 vs 11.2 months; stratified HR, 0.66 [95% CI, 0.53-0.81]; one-sided P < .0001). Progression-free survival benefit was observed with retlirafusp alfa plus CAPOX versus placebo plus CAPOX in both patients with PD-L1 CPS ≥5 (median, 7.6 v 5.5 months; stratified HR, 0.52 [95% CI, 0.42 to 0.66]) and the intention-to-treat analysis set (median, 7.0 v 5.5 months; stratified HR, 0.57 [95% CI, 0.48 to 0.69]). Grade ≥3 treatment-related adverse events were generally comparable between patients treated with retlirafusp alfa plus CAPOX (62.6% [228 of 364]) and those treated with placebo plus CAPOX (59.0% [216 of 366]). CONCLUSION: Retlirafusp alfa plus CAPOX represents a first-line treatment option for unresectable, locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma. A key limitation is that chemotherapy alone served as the comparator, given that the study protocol was finalized before PD-1 inhibitor plus chemotherapy became the approved standard-of-care regimen in China.

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.

Microsatellite-stable (MSS) colorectal cancers (CRCs) are largely refractory to immune checkpoint inhibitors (ICIs) due to immunologically “cold” tumor microenvironments (TMEs) characterized by limited T-cell infiltration. While RecQ-mediated genome instability 2 (RMI2) is known for regulating DNA repair, its role in anti-tumor immunity remains unclear. Here, we demonstrate that RMI2 deficiency impairs homologous recombination repair, causing cytosolic DNA accumulation, cGAS-STING pathway activation, and type I interferon signaling that boosts anti-tumor immunity. Notably, RMI2 knockout in mice synergizes with PD-1 blockade and fluorouracil to induce robust tumor regression and prolonged survival. Our data reveal that RMI2 loss derepresses the cGAS-STING pathway by disrupting DNA repair homeostasis, thereby reversing immune evasion. This paradigm shift converts MSS CRCs into “hot” tumors and renders them responsive to ICI therapy, establishing RMI2 inhibition as a novel therapeutic avenue.