CAPability-01: Success of anti-PD-1, HDAC inhibitor, and anti-VEGF combination in colorectal cancer

Abstract

The CAPability-01 trial, led by Feng Wang et al.,¹ was published in Nature Medicine on March 04, 2024. This study highlighted that a triplet regimen of the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab significantly improved the progression-free survival (PFS) and response in microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC).

CAPability-01 trial is a randomized, open-label, multicenter, Phase 2 clinical trial, that evaluated the efficacy of a triplet therapy (sintilimab, chidamide, and bevacizumab) versus a doublet (sintilimab with chidamide) in patients with unresectable, chemotherapy-refractory, locally advanced or metastatic MSS/pMMR CRC. Forty-eight patients were enrolled and randomly assigned in a 1:1 ratio to receive the triplet or doublet treatment.

The study found that the triplet regimen outperformed the doublet regimen in most key endpoints. More than 50% of the patients presented with liver metastases or lung metastases at baseline. Treatment histories were diverse, with almost half of the patients, particularly in the doublet group, receiving third-line or later treatment. The triplet treatment group exhibited a significantly higher PFS rate and improved overall response rate (ORR) and disease control rate (DCR) compared to the doublet group, with 44% achieving partial response and 28% maintaining stable disease. Subgroup analysis revealed that patients with liver metastases benefited more from the triplet treatment, showing significantly notably better outcomes in PFS (7.3 months vs. 1.4 months, p = 0.001), ORR (50.0% vs. 8.3%), and DCR (71.4% vs. 8.3%) compared with those on the doublet regimen. In this study, the incidence rates of treatment-related side effects (TEAEs) occurred in 60.0% of patients in the triplet group and 30.4% in the doublet therapy. Grade 3 or higher adverse events included thrombocytopenia, reported in 16.0% of patients receiving triplet therapy compared to 8.7% in the doublet group, and neutropenia, which was reported at 28.0% for the triplet therapy and not at all for the doublet. The triplet regimen appeared promising for patients with MSS/pMMR unresectable advanced or metastatic CRC, providing longer progression-free survival and manageable toxicity.

Despite the advancements in chemotherapy and target therapy, the prognosis of most patients with unresectable locally advanced or metastatic CRC remains poor. Several studies are currently evaluating the effectiveness of immune checkpoint inhibitors (ICIs), antiangiogenesis therapy, and HDAC inhibitors in treating microsatellite instability-high/deficient mismatch repair phenotypes (MSI-H/dMMR) CRC (Table 1). ICIs, like PD-1 antibodies and CTLA-4 antibodies, have demonstrated impressive clinical benefits in CRC patients such as MSI-H/dMMR.² These patients often have numerous genomic mutations, where mutated peptides activate immune cell priming and infiltration. MSI-H/dMMR CRCs typically exhibit increased levels of CD8+ T cell infiltration, T helper 1 (TH1), CD4+ T cell infiltration, tumor-associated macrophage infiltration, and IFNγ secretion. Conversely, patients with MSS/pMMR phenotype often develop an immunosuppressive tumor environment marked by a low tumor mutation burden, limited effector T cell infiltration, and an influx of immunosuppressive cells. Moreover, in this environment, tumor cells often increase the expression of T cell inhibitory ligands, such as CD80 and CD86 of the B7 family and PDL1, allowing tumors to evade immune destruction. ICIs target these signaling to enhance the destruction of tumor cells by cytotoxic T-cells. However, MSS/pMMR tumors, which account for over 90% of advanced CRC cases, generally fall to generate immunostimulatory neoantigens and exhibit low levels of immune-inhibitory ligands, resulting in T-cell exclusion. Therefore, patients with MSS/pMMR tumors respond differently to ICI therapies, whether used alone or in combination. The main challenge in treating these tumors is the lack of immune cell recruitment and the absence of immunostimulatory neoantigens, both are crucial for effective treatment responses.

Recent studies indicated that resistance to ICIs in pMMR/MSI-L mCRC may be mitigated by combining ICIs with antiangiogenesis therapies, such as anti-VEGF monoclonal antibody (mAb), decoy VEGF-trap receptor, anti-VEGFR2 mAb, and tyrosine kinase inhibitor (TKI). These combination therapies are believed to improve T-cell infiltration and reduce regulatory T cells and myeloid-derived suppressor cells by normalizing vascular structures and decreasing hypoxia, potentially converting tumor-associated macrophages to a more immune-stimulatory state while reducing immunosuppressive signals.³

Motivated by encouraging preclinical results, various clinical trials have been conducted to assess the effectiveness of this combination. The REGONIVO study, for example, evaluated the combination of nivolumab and regorafenib in MSS/pMMR advanced CRC patients, showing an mPFS of 7.9 months, and a 41.8% PFS rate at 1 year, reflecting positive outcomes.⁴ Nonetheless, results from other trials have shown variability. For example, the phase I/Ib clinical trial NCT03712943, examined the safety and effectiveness of regorafenib combined with nivolumab in pMMR mCRC, reported a PR in 10% of patients, with 53% maintaining SD, and DCR of 63%. The mPFS and OS were 4.3 and 11.1 months, respectively. In contrast, another trial, NCT04126733, reported a disease control rate of 39% with mPFS and OS at 1.8 months and 11.9 months, respectively. These findings underscore the pressing need for optimized treatment strategies that combine ICIs with targeted therapies.

HDACi have demonstrated promise in fostering an antitumor immune microenvironment by modulating PD-L1 expression and epigenetic of immune cell activation, differentiation, and effector function. Although HDACi combined with PD-1/PD-L1 inhibitors have yielded encouraging responses in lymphoma, their effectiveness in solid tumors such as non-small cell lung cancer and breast cancer has been modest, with overall response rates ranging from 6.7% to 10%.

The combination of HDACi, anti-VEGF, and anti-PD-1 therapies, known as triplet therapy, has demonstrated enhanced efficacy in treating MSS/pMMR advanced CRC, especially in those with liver metastases. This improvement has been confirmed in both in preclinical studies and clinical trials. For example, in a Phase 2 study on a pMMR mCRC cohort treated with regorafenib and nivolumab, patients with liver metastases had lower ORR (4% vs 25%), shorter PFS (median: 2.3 vs. 8.9 months) and shorter OS (median: 9.7 months vs. not reached) compared to those without liver metastases. Furthermore, in the REGONIVO study, the ORR for all enrolled CRC patients was 36%, but only 15.4% for those with liver metastases.⁴ Similarly, the REGOTORI study found that patients with liver metastases exhibited a lower response rate compared to those without liver metastasis (8.7% vs. 30.0%).⁵ However, the CAPability-01 trial showed that triplet therapy provides superior efficacy in mCRC regardless of liver metastases.

Although the study yielded encouraging outcomes, its small size and absence of long-term follow-up data are notable limitations. Consequently, further studies are required to confirm these results and gain a deeper understanding of the underlying mechanisms. Building on these findings, a multicenter, randomized, Phase III trial—CAPability-02—has been launched to study patients with MSS-type CRC who have failed first-line treatment including oxaliplatin-based chemotherapy. With more clinical trials conducted, it is believed that they will provide conclusive evidence for the effectiveness of the triplet therapy regimen in treating various malignancies, including triple-negative breast cancer.

The CAPability-01 trial found that triplet therapy with sintilimab, chidamide, and bevacizumab significantly improved PFS, ORR, and DCR in chemotherapy-refractory MSS/pMMR CRC with doublet therapy. The triplet combination also created a more immunologically active tumor microenvironment, enhancing CD8 + T cell infiltration. The findings suggest that this combination could be a promising approach for treating advanced CRC, particularly in patients with liver metastasis, who traditionally have poorer outcomes.

Yujie Tan: Conceptualization (lead); project administration (equal); writing—original draft (equal); writing—review and editing (equal). Yunfang Yu: Conceptualization (equal); funding acquisition (equal); project administration (equal); supervision (lead). Both authors have read and approved the final manuscript.

The authors declare no conflict of interest.

The authors have nothing to report.