Hongming Pan

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.

Background: Comprehensive genomic profiling (CGP) holds the potential as a diagnostic tool to identify the primary tissue site of patients with cancer of unknown primary (CUP). This study aims to evaluate the effectiveness of patient-centered precision therapy (PCPT) directed by CGP, relative to conventional chemotherapy, in previously untreated patients with CUP. Methods: Patients diagnosed with CUP between July 2017 and January 2022 were screened for analysis. A comprehensive 90-gene expression assay was utilized to identify tissue-of-origin, while CGP was performed on the Illumina NextSeq 500 system. Survival analysis was performed using Kaplan-Meier method. Significant OS variables were further investigated through multivariate analysis using the Cox proportional hazard model. A P-value of less than 0.05 was considered significant. Results: 48 patients were identified for final analysis. The 90-gene assay was able to predict 11 different tumor types. The most common types of cancer were lung cancer (n = 10, 20.8%). The median OS was 19.2 months (95% CI, 13.6–24.7). CGP analyses were performed on 36 samples. The mean number of non-silent mutations detected per sample was 8.2 (range: 1 to 30). The most commonly mutated genes included TP53, KRAS, KMT2D, BRAF, CIC, SMAD4, KEAP1, SMARCA4, and STK11. PCPT for CUP was significantly associated with significant longer OS compared with empirical therapy (median OS: 23.8 vs. 9.7 months; HR, 0.39; 95% CI, 0.24–0.63; P < 0.001). Multivariate analysis identified PCPT as initial therapy (HR = 0.21, p = 0.02), female (HR = 0.33, p = 0.02), and favorable performance status (HR = 0.32, p < 0.001) as prognostic indicators that correlate with prolonged OS. Conclusion: Comprehensive genomic profiling contributes to CUP origin prediction and patient-centered precision therapy, and the data support a significant association between PCPT and longer OS compared to empirical chemotherapy. This treatment strategy deserves further research.

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.

Colorectal cancer (CRC) is one of the most frequently diagnosed malignant tumors. However, clear evidence explaining the regulatory mechanisms of programmed death ligand 1 (PD-L1) in CRC has been limited. To illustrate the function of YTH N ⁶ -methyladenosine (m ⁶ A) RNA binding protein F2 (YTHDF2), we conducted a comprehensive evaluation of expression profiling datasets from online databases and clinical samples. We used a subcutaneous immunodeficient mouse model to investigate the impact of YTHDF2 on CRC. Western blots, flow cytometry, PD-1/PD-L1 binding assay, and cell killing assay were used to assess the relationship between YTHDF2 and PD-L1. We used RNA sequencing, along with methylated RNA immunoprecipitation (MeRIP) and RNA binding protein immunoprecipitation (RIP) sequencing to analyze mRNA expression, m ⁶ A methylation levels, and YTHDF2 target transcripts. The m ⁶ A methylation locations of mRNAs were verified using sequence-based RNA adenosine methylation site predictor (SRAMP), MeRIP-qRT-PCR, RIP-qRT-PCR, and a dual-luciferase reporter system. YTHDF2 was upregulated in CRC tissues, and patients with higher YTHDF2 expression had a worse prognosis. The in vivo model showed that YTHDF2 promoted CRC growth, whereas in vitro experiments showed that inhibiting YTHDF2 expression did not affect cell proliferation, migration, or invasion. Mechanistically, interference with YTHDF2 reduced PD-L1 expression and the binding ability between PD-1 and PD-L1. The use of RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics tools confirmed that the speckle type BTB/POZ protein ( SPOP ) mRNA was a YTHDF2 target and validated its m ⁶ A methylation sites. After YTHDF2 knockdown, SPOP mRNA stability increased, causing an increase in SPOP expression and a decrease in PD-L1 expression. This study demonstrated that YTHDF2 might upregulate PD-L1 expression by destabilizing m ⁶ A-containing SPOP mRNA and promote CRC development. The biological effect of the YTHDF2-SPOP-PD-L1 axis presented a promising target for CRC treatment and provided an approach to enhance the efficacy of anti-PD-1/PD-L1 therapy.