The goal of this clinical trial is to see if adding a weight loss medication (GLP-1 receptor drug) to patients with an increased BMI receiving treatment for rectal cancer prior to surgery (total neoadjuvant chemoradiotherapy) improves cancer outcomes. The main questions it aims to answer is

1. Does the drug increase weight loss in rectal cancer patients with a high BMI
2. Does the drug improve response rates to chemotherapy and radiotherapy
3. Does the drug improve survival outcomes and if cancer returns

Researchers will compare this drug in one group against a group of patients receiving preoperative total neoadjuvant chemoradiotherapy without the drug

Patients will be required to

1) take the GLP-1 receptor agonist drug during TNT or just having TNT alone as per standard hospital protocols

Body weight will be measured at three predefined time points:

1. Baseline: Prior to initiation of semaglutide or TNT
2. Pre-TNT: Start of TNT (for the intervention arm, this is 4 weeks after semaglutide initiation)
3. Post-TNT: Within 7 days following completion of TNT and prior to definitive surgery

Patients will complete their treatment and go on to have surgery as per standard methods for treating rectal cancer

This Phase II multicentre, open-label randomized controlled trial aims to determine whether adding a GLP-1 receptor agonist (GLP-1RA) to standard Total Neoadjuvant Therapy (TNT) improves oncological outcomes in Locally Advanced Rectal Cancer (LARC). We will evaluate whether metabolic modulation through GLP-1RA increases pathological complete response (pCR) rates, accelerates the clearance of circulating tumour DNA (ctDNA), and reduces the risk of recurrence. Secondary outcomes include toxicity profiles, surgical parameters and outcomes, ctDNA dynamics, and 2-year disease-free (DFS) and overall survival (OS). By combining innovative metabolic therapy with biomarker-driven monitoring, this study pioneers a precision oncology approach in the management of LARC.

Immune metabolism refers to the bioenergetic and biosynthetic processes that support immune cell function. Obesity significantly alters this metabolic programming. Obesity has a significant impact on cancer development and progression, in part due to its effects on the tumour microenvironment (TME) and immune metabolism. Understanding this connection is key in cancer biology and can also inform therapeutic strategies. There are many consequences of obesity-induced TME alterations, including immune suppression, increased tumour progression, metastasis, and resistance to immunotherapy.

Obesity is linked to an increased risk of developing 13 different cancers, including CRC cancer. 1 The mechanisms are complex, but elevated systemic inflammation and dysregulated immunity are major factors. Emerging evidence is beginning to show the potential benefits of GLP-1 therapies in cancer treatment; since this class of medications improves obesity, they might also help improve cancer outcomes. In a large retrospective cohort study with a 15-year follow-up, GLP-1 medication use was associated with a significant risk reduction in 10 of the 13 obesity-related cancers. 1 Mechanistically, the reasons for this reduction are unknown, but decreased inflammation and immune dysregulation are likely key factors in lowering this risk.

Our research group has extensively documented the harmful effects of obesity on the immune system, including its impact on anti-cancer immunity. Additionally, we have provided clinical and experimental evidence that GLP-1 therapy reduces inflammation and can significantly enhance anti-tumor immune cell populations. In this study, we will precisely assess the effects of two specific interventions-either TNT combined with GLP-1 RA (intervention group) or TNT alone (control group)-on the systemic inflammatory profile and circulating/tumor immune phenotype in stage III rectal cancer.

GLP-1-based treatments originally developed for type 2 diabetes and obesity, are now gaining attention for their potential impact on immune metabolism and even cancer therapy. There has been direct links between GLP-1 treatment and immune metabolism, with GLP reducing inflammation and improving systemic metabolism enhancing immune fitness. Some studies have also shown that GLP treatment can also indirectly modulate the TME by lowering leptin and insulin levels, reducing tumour-promoting signalling and reducing immunosuppressive cells in the TME. It is important to note that different cancers may respond differently to GLP-1 modulation based on the complexity, composition and level of immune infiltration. In this current study, we will profile the metabolic profiles and inflammatory profiles in the complex TME across the two defined interventions (either TNT + GLP-1 RA (intervention group) or TNT alone (control group)) in stage III rectal cancer patents enrolled in the trial.

GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide, have demonstrated strong effects on weight loss in individuals with obesity. In the STEP 1 trial, semaglutide led to an average weight loss of 14.9%, compared to 2.4% with placebo, over 68 weeks. Recent epidemiologic data also suggest a link between GLP-1 RA use and a reduced incidence of obesity-related cancers, including colorectal cancer. 3 Additionally, GLP-1 RAs may have anti-inflammatory and metabolic effects that could be beneficial in the context of cancer therapy.

Total neoadjuvant therapy (TNT) is increasingly utilized in managing locally advanced rectal cancer (LARC) to improve pathological complete response (pCR) rates, facilitate surgical downstaging, and support organ preservation. This trial aims to determine whether combining GLP-1 RAs with TNT leads to meaningful weight loss and better oncological outcomes compared to TNT alone in patients with BMI ≥30 and LARC.

Inclusion Criteria:

• Written informed consent according to local guidelines obtained prior to any study-related activities.
• Histologically confirmed mismatch repair protein proficient adenocarcinoma of the rectum.
• BMI ≥25 kg/m²
• Radiological confirmed >T2, Node positive, Threatened Surgical Margin and/or EMVI+ by MRI
• Imaging available for radiomics analysis
• Absence of metastatic disease at registration.
• Adequate renal function is defined as calculated creatinine clearance (CrCl) >50ml/min.
• ANC > 1.5 cells/mm3, HGB > 8.0 gm/dl, PLT > 150,000/mm3, total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's Syndrome who must have total bilirubin ≤ 3.0 x ULN), AST≤ 3 x ULN, ALT ≤ 3 x ULN
• Able to tolerate medication.
• ECOG 0-2

Exclusion Criteria:

• Received prior chemotherapy or radiotherapy
• Previous or concurrent active malignancy ≤ 5 years prior to registration, with the exception of non-melanotic skin cancer or carcinoma in situ of any type, or other cancers that the treating investigator does not feel will impact the study objectives.
• Locally advanced disease T3N+ or T4 disease.
• Recurrent rectal cancer
• Metastatic disease at presentation
• Patients unable to undergo MRI
• Patients having already received weight-loss intervention (pharmacological or surgical)

De identified data will not be available to anyone outside the study. This is in line with our ethics department and GDPR