For more than two decades, the treatment pathway for localized colon cancer has remained largely unchanged. Most patients undergo surgery first, followed by a decision on adjuvant chemotherapy based on the pathological stage and risk of recurrence.
Myriam Chalabi, MD, discussed how neoadjuvant immunotherapy could begin to challenge this established sequence not only for patients with microsatellite instability, or MSI, tumors, but potentially for the much larger population with microsatellite-stable, or MSS, colon cancer.
While immunotherapy has already produced exceptional responses in MSI colon cancer, its role in MSS disease has historically been far less certain. Emerging evidence from early-stage disease, however, suggests that this resistance may not be absolute.
A Treatment Pathway That Has Changed Little
The standard approach for patients with operable colon cancer continues to begin with surgery. Once the tumor and regional lymph nodes have been removed, pathological findings are used to determine whether adjuvant chemotherapy is required.
Chemotherapy is generally recommended for patients with stage III disease and for selected patients with high-risk stage II MSS tumors. Treatment is still largely based on clinical and pathological risk rather than molecular subtype, meaning that patients commonly receive similar chemotherapy regimens regardless of whether their tumors are MSI or MSS.
Despite surgery and, in some cases, up to six months of adjuvant chemotherapy, recurrence remains a major concern. Approximately 20% to 40% of patients may experience disease recurrence, emphasizing the need for treatments that can improve long-term outcomes while reducing the burden of therapy.
The toxicity of chemotherapy must also be considered. Oxaliplatin-based treatment can cause peripheral neuropathy, which may persist long after treatment has ended. Improving outcomes, therefore, is only part of the challenge. Reducing treatment-related complications and preserving quality of life are equally important goals.
Could Neoadjuvant Immunotherapy Change the Treatment Pathway for MSS Colon Cancer?
FOxTROT Opens the Door to Preoperative Treatment
Neoadjuvant therapy has not traditionally been considered standard treatment for colon cancer. The FOxTROT study, however, provided important evidence that chemotherapy can be administered safely before surgery in patients with operable, locally advanced disease.
In the study, patients were assigned to receive either perioperative chemotherapy—treatment before and after surgery—or postoperative chemotherapy alone. Patient selection was based on clinical tumor staging rather than MSI or MSS status.
FOxTROT demonstrated that preoperative chemotherapy was feasible and did not result in higher rates of surgical complications. The study also found histopathological downstaging, fewer incomplete resections and improved disease control among patients who received chemotherapy before surgery.
These findings helped establish that systemic treatment does not always need to wait until after surgery. They also created an important foundation for evaluating neoadjuvant immunotherapy in colon cancer.
The Biological Divide Between MSI and MSS Disease
The response to neoadjuvant treatment differs significantly according to tumor biology.
Patients with MSI or mismatch repair-deficient colon cancer can experience exceptionally high response rates with neoadjuvant immunotherapy. In the NICHE-2 study, nearly all evaluable patients achieved a pathological response following short-course nivolumab and ipilimumab treatment.
However, MSI tumors represent only a minority of localized colon cancers. Most patients have MSS or mismatch repair-proficient disease, for which chemotherapy remains the principal systemic treatment.
In MSS colon cancer, the pathological response rate to neoadjuvant chemotherapy is approximately 20% to 25% when the FOxTROT findings are considered alongside other studies. Alternative chemotherapy approaches have not fundamentally changed outcomes for this population, leaving considerable room for improvement.
Testing Immunotherapy Earlier
Immunotherapy has shown limited activity in metastatic MSS colorectal cancer. Professor Chalabi and colleagues proposed that the timing of treatment might influence its effectiveness.
Early-stage tumors may have a different immune environment from heavily treated metastatic disease. A subset of MSS colon cancers may also possess sufficient immunogenicity to respond when immune checkpoint inhibition is introduced before surgery.
The phase II NICHE study was the first clinical trial to investigate neoadjuvant immunotherapy in patients with early-stage mismatch repair-proficient colon cancer.
Thirty-one patients received a short course of treatment consisting of two doses of nivolumab and one dose of ipilimumab. This was the entire preoperative treatment regimen, and patients proceeded to surgery within six weeks.
The results challenged the assumption that MSS colon cancer is uniformly resistant to immunotherapy.
Deep Responses After Only Two Treatment Cycles
A pathological response was observed in 26% of patients following neoadjuvant nivolumab and ipilimumab. Responses included major pathological responses and complete responses, despite the interval between the first immunotherapy dose and surgery being only approximately four and a half weeks.
These were not minor reductions in tumor size. Some patients experienced deep pathological tumor regression after only two cycles of nivolumab and one cycle of ipilimumab.
The findings suggest that a clinically meaningful subgroup of patients with MSS colon cancer can respond to immune checkpoint blockade when treatment is administered at an earlier stage of disease.
They also raise the possibility that more active immune combinations, including next-generation CTLA-4–directed treatments, could increase the proportion of patients who respond.
Pathological Response May Carry Long-Term Meaning
The importance of neoadjuvant treatment extends beyond shrinking a tumor before surgery. Pathological response may also provide an early indication of long-term benefit.
In the NICHE cohort, patients who achieved a pathological response after the short course of immunotherapy had excellent outcomes without observed recurrences during follow-up. Patients who did not respond appeared to face a significantly greater risk of disease recurrence.
The group was small, and the results require confirmation in larger randomized studies. Nevertheless, the association between pathological response and favorable long-term outcomes is consistent with observations from neoadjuvant immunotherapy studies in melanoma and MSI colon cancer.
This could make pathological response an important early measure of treatment effectiveness while researchers await mature disease-free and overall survival results.
From Proof of Concept to Randomized Evidence
The NICHE results provide an important proof of concept: MSS colon cancer is not universally unresponsive to immunotherapy.
The next step is to determine whether these responses can be reproduced in larger patient populations and translated into fewer recurrences and improved survival. Randomized studies will also need to compare neoadjuvant immunotherapy with current treatment strategies, including surgery followed by adjuvant chemotherapy and the neoadjuvant chemotherapy approach investigated in FOxTROT.
Identifying which MSS tumors are most likely to respond will be equally important. A treatment that benefits only a subgroup of patients must be supported by biomarkers capable of selecting that subgroup before therapy begins.
A New Direction for the Majority of Patients
Neoadjuvant immunotherapy has already changed expectations for MSI colon cancer. The emerging findings in MSS disease suggest that its reach could eventually extend further.
A 26% pathological response rate after only a few weeks of nivolumab and ipilimumab does not yet establish a new standard of care. It does, however, demonstrate that meaningful immune responses are possible in a tumor population long considered resistant to checkpoint inhibition.
Professor Chalabi’s presentation was followed by Dr. Pashtoon Kasi’s discussion of NEST-1, which is evaluating the next-generation CTLA-4 antibody botensilimab in combination with balstilimab as neoadjuvant treatment for resectable colorectal cancer.
Together, these studies represent an important shift in how researchers are approaching MSS colon cancer: moving treatment earlier, strengthening immune activation and investigating whether a short preoperative intervention can produce durable clinical benefit.
Written by Nare Hovhannisyan, MD
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