Adding first-line PD-1 inhibition to anti-VEGF and XELOX in pMMR metastatic colorectal cancer: Steppingstones, stumbling blocks, and next phase.

In the randomized, double-blind, multicenter study by Wang et al.,1 the addition of serplulimab (a PD-1 antibody) to anti-VEGF (HLX04; a bevacizumab biosimilar) together with chemotherapy (XELOX) was deemed to be tolerable and safe and may improve progression-free survival. However, even if adverse events were comparable, oncological endpoints including survival need to be confirmed in the next phase 3 study.

Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, the role of ICI in patients with early-stage, operable CRC remains unclear. The aim of this study was to investigate trials on neoadjuvant ICI in operable CRC. MATERIALS AND METHODS: Scoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on neoadjuvant ICI for operable CRC was done up to December 2022. RESULTS: Some 40 trials investigating neoadjuvant ICI for early-stage, operable CRC were identified, including five published trials and three conference abstracts. Preclinical phase I/II trial predominated with only three clinical phase III trials. Few trials investigated neoadjuvant ICI as the only intervention (monotherapy). Trials in rectal cancer were designed for combined ICI with chemo(radio)therapy, only 8 trials stating an MSI/dMMR status for inclusion, one designed for MSS/pMMR only and, the rest agnostic for MMR status. Thirty-eight (95%) trials investigated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PD-1/PD-L1 inhibitors were combined with vascular endothelial growth factor (VEGF) inhibitor or with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, in two trials each, respectively. Pathological complete response as primary outcome after surgery was the most frequently used study endpoint. In rectal cancer, six trials included a "watch and wait" strategy for patients with complete clinical response. No "watch and wait" study design for colon cancer after neoadjuvant ICI were identified. CONCLUSION: High response rates from neoadjuvant ICI in early-stage colon and rectal cancer are reported in phase I/II studies. Contemporary trial designs are heterogeneous, with few comparable inclusion criteria, use of several drug combinations and durations and, wide variation of endpoints reported. Harmonizing clinical and translational aspects including survival data is needed for improved future trial designs with clinical impact.

Neoadjuvant immunotherapy in colorectal cancer beyond immune checkpoint inhibitors: emerging from bench to bedside.

Colorectal cancer (CRC) is the second most frequent cancer in both men and women, and of concern increasing in the younger population. Despite the progress in treatment, still up to half of CRC patients will develop metastasis. Immunotherapy consists of an arsenal of different managements that in many aspects has revolutionized cancer therapy. Monoclonal antibodies, chimeric antigen receptor (CAR) T-cell receptor gene modified T-cells and immunization and/or vaccination are different immunotherapies used in cancer treatment. Large trials in metastatic CRC, such as CheckMate 142 and KEYNOTE-177, have proven the efficacy of immune checkpoint inhibitors (ICI). The ICI drugs, targeting the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are now part of first-line treatment of dMMR/MSI-H metastatic CRC. However, ICIs are gaining a novel role in management of primary operable CRC after preliminary results from early-phase clinical studies in both colon and rectal cancer. Neoadjuvant ICI in operable colon and rectal cancer is hence becoming a clinical reality, while not quite yet adopted as a routine use. However, with some answers comes more questions and challenges. In this review article we aim to give an overview over different modes of immunotherapy to treat cancer with an emphasis on ICIs and their relevance to CRC, describe some of the progresses made in immunotherapy overall, with potential mechanisms, some of the concerns and, some highlight for the way forward.

Histopathological Growth Pattern in Colorectal Liver Metastasis and The Tumor Immune Microenvironment.

Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted.

Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis?

In resectable colorectal liver metastasis (CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases (both resectable and non-resectable) and the shift in indication from "what is taken out" (e.g., how much liver has to be resected) to "what is left behind" (that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.

Qualitative and quantitative issues of lymph nodes as prognostic factor in colon cancer.

For patients undergoing curative resections for colon cancer, the nodal status represents the strongest prognostic factor, yet at the same time the most disputed issue as well. Consequently, the qualitative and quantitative aspects of lymph node evaluation are thus being scrutinized beyond the blunt distinction between 'node positive' (pN+) and 'node negative' (pN0) disease. Controversy ranges from a minimal or 'least-unit' strategy as exemplified by the 'sentinel node' to a maximally invasive or 'all inclusive' approach by extensive surgery. Ranging between these two extremes of node sampling strategies are factors of quantitative and qualitative value, which may be subject to modification. Qualitative issues may include aspects of lymph node harvest reflected by surgeon, pathologist and even hospital performance, which all may be subject to modification. However, patient's age, gender and genotype may be non-modifiable, yet influence node sample. Quantitative issues may reflect the balance between absolute numbers and models investigating the relationships of positive to negative nodes (lymph node ratio; log odds of positive lymph nodes). This review provides an updated overview of the current controversies and a state-of-the-art perspective on the qualitative and quantitative aspects of using lymph nodes as a prognostic marker in colon cancer.