Abstract The liver is the primary target organ for hematogenous metastasis of colorectal cancer, and colorectal cancer liver metastasis is one of the key and challenging aspects in its treatment. In order to improve the diagnosis and comprehensive treatment of colorectal cancer liver metastasis, the guideline development group has summarized advanced experiences and the latest achievements from both domestic and international sources, and has once again revised and updated the Guideline for the diagnosis and comprehensive treatment of colorectal cancer liver metastases (2025 edition) to continuously provide guidance and reference for clinical practice in this field.
Abstract Background Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (a bevacizumab biosimilar) in patients with first-line HCC. Methods In this phase II, multicenter, randomized, multi-arm, open-label trial, patients with advanced HCC received ociperlimab and tislelizumab plus BAT1706 (Arm A) or tislelizumab plus BAT1706 (Arm B). The primary objective was to evaluate efficacy using objective response rate (ORR) assessed by the investigator per RESIST v1.1 for Arms A and B. Results 94 patients were randomized to Arm A (N = 62) and Arm B (N = 32). Confirmed ORR (95% confidence interval) was 37.1% (25.2–50.3) for Arm A and 40.6% (23.7–59.4) for Arm B. In Arms A and B, respectively, 90.3% and 80.6% of patients experienced treatment-related treatment-emergent adverse events (TEAEs), 59.7% and 32.3% experienced Grade ≥ 3 treatment-related TEAEs and 22.6% and 9.7% experienced treatment-related TEAEs leading to treatment discontinuation. Immune-mediated adverse events were reported in 50.0% of patients in Arm A and 45.2% of patients in Arm B. Infusion-related reactions occurred in a single patient in Arm A. Conclusion In patients with advanced HCC, tislelizumab plus BAT1706 demonstrated promising ORR, while adding ociperlimab was not associated with improved efficacy. The safety profile of ociperlimab and tislelizumab plus BAT1706 was tolerable and manageable, with no new safety signals identified. Trial registration ClinicalTrials.gov: NCT04948697 (September 20, 2021).
Colorectal cancer remains a major cause of cancer-related morbidity and mortality globally, with 30% to 40% of cases developing metastasis, mainly to the liver. Although immunotherapy has shown promise for colorectal cancer treatment, patients with colorectal cancer liver metastasis (CRLM) experience limited therapeutic benefits, potentially because of an immunosuppressive tumor microenvironment. Thus, an urgent need exists to identify the key players that drive CRLM and potentiate immunotherapeutic resistance. In this study, we established liver metastatic cells through continuous passaging in vivo, allowing the screening of RNA expression profiles related to CRLM. A combination of spatial transcriptomic sequencing and single-cell analysis revealed a substantial upregulation of SPP1 expression and secretion in CRLM. SPP1 induced immunotherapeutic resistance by stimulating CXCL12 production by cancer-associated fibroblasts through activation of β-catenin/HIF1α-related transcription. CXCL12 promoted epithelial-mesenchymal transition of colorectal cancer cells but suppressed CD8+ T-cell infiltration. Treatment with a CXCL12 receptor antagonist or anti-SPP1 antibody markedly activated intratumoral CD8+ T-cell infiltration and enhanced the efficacy of anti-PD-1 antibody treatment. Elevated SPP1 and CXCL12 corresponded to immunotherapy resistance in patients with CRLM. Together, this study highlights the potential of the SPP1/CXCL12 axis as a target and a biomarker for precise cancer immunotherapy in CRLM. The intricate interactions within the tumor microenvironment offer promising avenues for improving therapeutic outcomes in patients with CRLM. SIGNIFICANCE:SPP1 orchestrates development of an immunosuppressive tumor microenvironment that supports liver metastasis of colorectal cancer cells, offering insights into potential strategies for improving immunotherapy efficacy in liver metastatic colorectal cancer.
BACKGROUND:Savolitinib combined with osimertinib is a potential novel therapy for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) harbouring MET amplification after progression on EGFR tyrosine kinase inhibitor (TKI) therapy. We aimed to evaluate the efficacy and safety of savolitinib-osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population. METHODS:SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals. Eligible adults with locally advanced or metastatic EGFR mutation-positive NSCLC and MET amplification after EGFR TKI failure were randomly assigned (1:1) to once daily oral savolitinib-osimertinib or intravenous chemotherapy (pemetrexed plus either cisplatin or carboplatin), both in 21-day cycles. Central randomisation was implemented through an interactive web-response system with stratification based on the presence of brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype, using a mixed block-size methodology. The primary endpoint, investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours version 1.1, was tested using a hierarchical procedure: first in the third-generation EGFR TKI-naive population, and if positive, the intention-to-treat (ITT) population. Safety analysis was performed in all patients who received at least one dose of the study treatment. Interim analysis data cutoff was Aug 30, 2024. This study is registered with ClinicalTrials.gov (NCT05015608) and is complete. FINDINGS:Between Oct 15, 2021, and Aug 30, 2024, 211 patients were enrolled, 106 were randomly assigned to savolitinib-osimertinib and 105 were randomly assigned to chemotherapy, including 137 (65%) of 211 who were third-generation EGFR TKI-naive (69 in the savolitinib-osimertinib group; 68 in the chemotherapy group). In 106 patients in the savolitinib-osimertinib group, the median age was 59·4 years (IQR 54·3-65·8), 62 (58%) were female, and 44 (42%) were male. In 105 patients in the chemotherapy group, the median age was 61·9 years (IQR 56·3-69·1), 55 (52%) were female, and 50 (48%) were male. All participants were Asian. Median PFS was significantly prolonged with savolitinib-osimertinib versus chemotherapy in the third-generation EGFR TKI-naive (9·8 months [95% CI 6·9-12·5] vs 5·4 months [4·2-6·0]; hazard ratio 0·34 [0·21-0·56]; p<0·0001) and ITT populations (8·2 months [6·9-11·2] vs 4·5 months [3·0-5·4]; 0·34 [0·23-0·49]; p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in the same proportion of patients in both groups who received the study drugs (60 [57%] of 106 patients in the savolitinib-osimertinib group and 55 [57%] of 96 patients in the chemotherapy group). INTERPRETATION:The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population. FUNDING:HUTCHMED and AstraZeneca.
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapy for advanced, EGFR-mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co-existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third-generation EGFR-TKI aumolertinib in combination with carboplatin-pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with EGFR mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy (n = 62) or monotherapy (n = 64). The primary end point was median progression-free survival (PFS). At a median follow-up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34-0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co-existing tumor protein p53 (TP53) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug-related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype-directed, chemotherapy-targeted intensification approach favoring aumolertinib plus carboplatin-pemetrexed for this molecularly defined population.
