Rui-hua Xu and Feng Wang team develops an original immunotherapy strategy to break the dilemma of colorectal cancer treatment

March 07, 2024

Colorectal cancer is one of the most common malignancies with a high incidence in China. The 2020 China Cancer Registry shows that the incidence and mortality rate of colorectal cancer in China ranks second and fifth among all malignant tumors. For patients with permanent metastatic colorectal cancer (mCRC), the survival period is limited after receiving standard treatment of chemotherapy ± targeted therapy. Although the emergence of immunotherapy is beneficial for dMMR/MSI-H patients, pMMR/MSS patients, who account for more than 90% of metastatic colorectal cancer, cannot benefit from the treatment of immunotherapy alone. In recent years, how to solve the treatment dilemma of immunotherapy in pMMR/MSS colorectal cancer has always been a popular exploration direction.

On March 4, 2024, an article entitled “Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial” was published in the top international medical journal "Nature Medicine". The article presented the detailed data from the national multicenter clinical trial, Capability 01, led by Prof. Ruihua Xu and Prof. Feng Wang. This trial introduced new treatment options for patients with pMMR/MSS colorectal cancer. The results of the study indicate that the triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a higher overall response rate (ORR) of 44.0% and longer median median progression-free survival (PFS) of 7.3 months. This study addresses clinical issues and guided clinical practice through basic research, thereby benefiting patients and showcasing the innovative strength of Chinese physician scientists.

CAPability-01 is a national multi-center, randomized phase 2 trial. It is carried out among four centers in China (Sun Yat-sen University Cancer Center, the First Affiliated Hospital of the School of Medicine of Zhejiang University, the First Affiliated Hospital of Guangxi Medical University and Harbin Medical University Cancer Hospital). In this study, 48 eligible patients were enrolled, with 23 randomly assigned to the doublet arm (sintilimab and chidamide) and 25 to the triplet arm (sintilimab, chidamide and bevacizumab) in the intention-to-treat (ITT) population and safety analysis set. The primary endpoint was the progression-free survival rate at 18 weeks (18wPFS rate) of the entire study population. Secondary endpoints included overall survival (OS), PFS, ORR, disease control rate (DCR), duration of response (DOR) and safety of the entire study population.

The primary endpoint of 18wPFS rate was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a higher 18wPFS rate (64.0% versus 21.7%) and longer median PFS (7.3 months versus 1.5 months) (Figure 1).

Figure 1

Similarly, the ORR and DCR was also higher in the triplet arm compared to the doublet arm (44.0% versus 13.0% and 72.0% versus 39.1%) (Figure 2).

Figure 2

Specifically, among the 26 patients with liver metastasis, those in the triplet arm exhibited higher 18wPFS rate (64.3% versus 8.3%), longer median PFS (7.3 months versus 1.4 months) (Figure 3), higher ORR (50.0% versus 8.3%,) and higher DCR (71.4% versus 8.3%) compared to those in the doublet arm.

Figure 3

Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, cytotoxic lymphocytes and monocytic lineage, coupled with a concomitant decrease in intratumoral B lineage, endothelial cells and fibroblasts following treatment. Gene set variation analysis (GSVA) provided further insights into the molecular mechanisms. Among the responders in the triplet therapy group after treatment, a stronger antitumor immune response was observed across the entire process from antigen presentation to effector cell killing ability (Figure 4).

Figure 4

In order to break the dilemma of immunotherapy in colorectal cancer, the team was devoted in this field for many years, from laboratory to clinical transformation, and boldly proposed the original innovative strategy of the triplet combination. The triplet combination showed superior therapeutic efficacy than the doublet regimen, and the potential underlying mechanism of this observed efficacy involves the infiltration and the activation of CD8+ T cells.

CAPability-01 studies the novel combination of epigenetic drug + immune check point inhibitor + anti-angiogenic drug, with high potential in the treatment in more cancer types. Based on the results of CAPability-01 research, CAPability-02 has been started with larger sample size. The exploration of the triplet combination in the second line treatment of metastatic colorectal cancer has been carried out in 17 centers across China. 

Professor Ruihua Xu and Professor Feng Wang from Sun Yat-sen University Cancer Center are the corresponding authors of this paper. Professor Feng Wang, Assistant Chief Physician Jin Ying, Dr. Wang Min and Chief Physician Luo Huiyan from Sun Yat-sen University Cancer Center, and Professor Weijia Fang from the First Affiliated Hospital, Zhejiang University School of Medicine are the first authors of this paper.

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