Editor's Note: Neoadjuvant therapy for locally advanced colorectal cancer has made significant progress over the past 20 years, but it still faces limitations such as adverse reactions, organ dysfunction, and unsatisfactory control of distant metastasis. In recent years, with the improvement of surgical techniques and further development of tumor molecular typing research, how to further improve local control rates, reduce distant metastasis rates, and even spare surgery and preserve organs based on clinical response has become the current patient needs and research objectives.

At the 27th National Clinical Oncology Conference and the 2024 CSCO Academic Annual Meeting, we conducted an exclusive interview with Dr. Kai-Keen Shiu from University College London Cancer Institute on the current status of immunotherapy for locally advanced colorectal cancer. The content is now organized as follows for the benefit of our readers.

Oncology Frontier: Could you please discuss the current status and trends of neoadjuvant therapy for locally advanced colorectal cancer?

Dr. Kai-Keen Shiu: In treating early-stage colorectal cancer, we now distinguish between MMR-proficient and MMR-deficient/MSI-high subtypes, as they require different therapeutic approaches. Traditionally, for MMR-proficient colon cancer, we recommend surgical resection followed by adjuvant chemotherapy, typically for three to six months, using either a single agent or a combination regimen. For rectal cancer, treatment has evolved towards a neoadjuvant approach, involving either chemoradiotherapy or, more recently, total neoadjuvant chemotherapy combined with chemoradiotherapy.

Excitingly, for the MMR-deficient group, immunotherapy has shown remarkable efficacy, particularly in metastatic settings, and is now being explored as a first-line neoadjuvant treatment. In Phase II trials, the results have been extraordinary: a significant proportion of patients experience complete pathological responses, ranging from 50% to 80%. This is a paradigm shift, as these patients are not only seeing tumor downstaging but also achieving excellent surgical outcomes with minimal complications. These trials consistently demonstrate that patients respond well and have low relapse rates.

Oncology Frontier: Could you talk about how to select the optimal population for neoadjuvant immunotherapy?

Dr. Kai-Keen Shiu: Patient selection is indeed crucial. Accurate diagnosis of MMR-deficiency or MSI-high status is the first step, followed by careful radiological staging to avoid overstaging, as MMR-deficient tumors can present with inflammatory lymph nodes. This collaborative approach involves pathologists for diagnosis, gastroenterologists for initial assessments, and surgeons for optimal timing of intervention.

In the UK, I currently offer these therapies within clinical trials, which enables strict criteria for patient eligibility. However, educating pathologists to perform reflex testing and preparing surgeons for neoadjuvant timing are essential steps toward broader implementation. Outside clinical trials, I still advocate surgery as the standard of care for eligible patients, especially given that immunotherapy is most effective in MMR-deficient cases. Administering immunotherapy to MMR-proficient patients offers little benefit, highlighting the need for accurate diagnostics.

Oncology Frontier: Could you delve into the application prospects of neoadjuvant immunotherapy in MSI-H locally advanced colorectal cancer and the specific clinical benefits it brings to patients?

Dr. Kai-Keen Shiu: The clinical benefits of neoadjuvant immunotherapy in MSI-high cases are substantial. Although current evidence comes primarily from Phase II trials, the NICHE-2 trial, led by Dr. Myriam Chalabi in the Netherlands, reported 100% disease-free survival at three years. This was presented at ASCO and ESMO and, while not a randomized trial, would likely have ended the control arm early if it had been. The data is compelling: even without a Phase III confirmation, these findings suggest tremendous potential for durable outcomes. Other Phase II trials, such as NEOPRISM, NEOSHOT, and IMHOTEP, reinforce this benefit.

Our next steps involve collaboration—between oncologists, pharmaceutical companies, and regulatory bodies—to bring these therapies to patients. If optimized, this approach could allow us to cure over 90% of MSI-high patients with brief treatment durations. Patients are increasingly informed about immunotherapy’s benefits and often initiate discussions on their own, highlighting the demand and the need for our teams to remain updated.

Oncology Frontier: Could you share your views on future research directions for neoadjuvant immunotherapy in the field of MSI-H locally advanced colorectal cancer?

Dr. Kai-Keen Shiu:  Many ongoing trials integrate extensive biomarker analysis, including liquid biopsies, cDNA, TCR complexity, whole-exome and whole-genome sequencing, and even patient-derived organoids from biopsies for personalized drug testing.

We’re gaining insights that not only help in MSI-high settings but also might apply to more advanced cases. Some of our research focuses on biomarkers that predict resistance, potentially allowing us to extend the benefits of immunotherapy to the MMR-proficient population. Additionally, circulating DNA (cDNA) could support non-operative management strategies—a crucial factor for patients who are resistant to surgery, like some with Lynch syndrome who may wish to preserve their bowel function.

Ultimately, these biomarkers will not only enhance treatment precision for MSI-high tumors but could also expand immunotherapy’s reach.