What were the NICHE trial details and is its neoadjuvant immunotherapy applicable to a 61‑year‑old patient with treatment‑naïve stage IV cecal adenocarcinoma, deficient mismatch repair/microsatellite instability‑high, ECOG 0‑1 and a solitary para‑aortic lymph node metastasis?

NICHE Trial Details and Applicability to Your Patient

The NICHE trial demonstrated that neoadjuvant immunotherapy with nivolumab plus ipilimumab is highly effective in dMMR/MSI-H colon cancer, and this approach is directly applicable to your 61-year-old patient with stage IV cecal adenocarcinoma, dMMR/MSI-H status, and oligometastatic disease (solitary para-aortic lymph node). 1, 2, 3, 4

NICHE Trial Overview

The NICHE study (NCT03026140) was a groundbreaking phase II trial that established neoadjuvant immunotherapy as a paradigm-shifting approach for dMMR colon cancer:

Original NICHE Study (2020)

• Design: Exploratory study with 40 patients (21 dMMR, 20 pMMR) receiving one dose of ipilimumab and two doses of nivolumab before surgery 3
• dMMR Results: Pathological response in 20/20 (100%; 95% CI: 86-100%) dMMR tumors, with 19 major pathological responses (≤10% residual viable tumor) and 12 pathological complete responses 3
• Safety: Treatment was well tolerated with no surgical delays, meeting the primary safety endpoint 3

NICHE-2 Study (2024) - The Definitive Trial

• Design: Phase II study with 115 enrolled patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer treated with neoadjuvant nivolumab plus ipilimumab 4
• Primary Endpoints: Safety (timely surgery within 2 weeks) and 3-year disease-free survival 4
• Pathological Response: 109/111 patients (98%; 95% CI: 94-100%) achieved pathological response, including 105 (95%) with major pathological response and 75 (68%) with pathological complete response 4
• Safety Profile: Only 5 patients (4%) experienced grade 3-4 immune-related adverse events, and no patients discontinued treatment due to adverse events 4
• Surgical Feasibility: 113/115 patients (98%; 97.5% CI: 93-100%) underwent timely surgery 4
• Long-term Outcomes: With median follow-up of 26 months (range 9-65), zero patients had disease recurrence 4

NICHE-3 Study (2024) - Alternative Regimen

• Design: 59 patients with locally advanced dMMR colon cancer treated with nivolumab (480 mg) plus relatlimab (480 mg, anti-LAG-3) for two 4-weekly cycles 5
• Results: Pathological response in 57/59 (97%; 95% CI: 88-100%), including 54 (92%) major pathological responses and 40 (68%) pathological complete responses 5
• Safety: Grade 3-4 immune-related adverse events in only 10% of patients, demonstrating a more favorable toxicity profile than anti-CTLA-4 combinations 5

Direct Applicability to Your Patient

Your patient is an ideal candidate for neoadjuvant immunotherapy based on the following factors:

Favorable Patient Characteristics

• dMMR/MSI-H Status: This is the single most important predictor of response to immunotherapy, with 95-100% pathological response rates in NICHE trials 3, 4
• Treatment-Naïve: All NICHE studies enrolled treatment-naïve patients, matching your patient's status 3, 4
• Excellent Performance Status: ECOG 0-1 ensures tolerance of immunotherapy and subsequent surgery 4
• Age 61: Well within the age range of NICHE participants and not a contraindication 4

Oligometastatic Disease Consideration

• Stage IV with Solitary Metastasis: While NICHE trials primarily enrolled stage I-III disease, current guidelines explicitly recommend immunotherapy as first-line treatment for all dMMR/MSI-H metastatic colorectal cancer, including stage IV disease 1, 2
• Guideline Support: NCCN and ASCO recommend dostarlimab, pembrolizumab, or nivolumab as first-line therapy for metastatic dMMR/MSI-H colorectal cancer, with objective response rates of 43.5% in metastatic disease 1, 2
• Potential for Complete Response: Given the 68-95% pathological complete response rates in localized disease and the oligometastatic nature (single para-aortic node), there is potential for complete eradication of all disease sites 4

Recommended Treatment Algorithm for Your Patient

Step 1: Confirm Biomarker Status

• Verify dMMR/MSI-H status by immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2) or PCR-based microsatellite analysis 1, 2
• Document KRAS, NRAS, and BRAF mutation status for comprehensive treatment planning, though these do not alter the immunotherapy recommendation in dMMR disease 2

Step 2: Initiate Neoadjuvant Immunotherapy

Based on NICHE-2 evidence (the highest quality and most recent trial), recommend:

• Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 2 cycles (matching NICHE-2 protocol) 4
• Alternative: Pembrolizumab 200 mg every 3 weeks for 2-4 cycles (based on single-cycle pembrolizumab study showing 46% pathological complete response) 6
• Alternative: Dostarlimab (FDA-approved for metastatic dMMR/MSI-H colorectal cancer with 43.5% objective response rate) 1, 2

Step 3: Response Assessment at 6-8 Weeks

• Perform restaging with CT chest/abdomen/pelvis, PET/CT, and CEA 2
• Assess circulating tumor DNA (ctDNA) clearance, which predicts response (5/6 responders in NICHE had ctDNA clearance before surgery) 7
• Evaluate for clinical complete response using MRI, endoscopy, and biopsy 2

Step 4: Surgical Decision-Making

If clinical complete response achieved:

• Multidisciplinary tumor board discussion regarding nonoperative management versus surgery 2
• For oligometastatic disease with complete response, consider surgical resection of primary tumor and para-aortic node for pathological confirmation 4
• If pursuing nonoperative management, implement rigorous surveillance: digital rectal examination and flexible sigmoidoscopy every 4 months for 2 years, then every 6 months for 3 years (94-99% of regrowth occurs within first 2-3 years) 2

If partial response or stable disease:

• Proceed with surgical resection of primary tumor and para-aortic lymph node 4-6 weeks after last immunotherapy dose 8, 4
• Surgery should not be delayed beyond 2 weeks from planned date 4

Step 5: Adjuvant/Maintenance Therapy

• If pathological complete response: Continue immunotherapy for 1 year as maintenance therapy (supported by Impower010 data in NSCLC and emerging colorectal cancer data) 8, 1
• If residual disease: Continue immunotherapy until disease progression or unacceptable toxicity 1, 2
• Do NOT use fluoropyrimidine-based chemotherapy: Adjuvant fluoropyrimidine-only chemotherapy provides no benefit and may cause harm in dMMR/MSI-H tumors 8, 1

Critical Advantages of This Approach

Superior Efficacy in dMMR Disease

• 100% pathological response rate in NICHE-2 dMMR cohort versus historical 5% response rate to fluoropyrimidine chemotherapy 3, 4
• Zero disease recurrences at median 26-month follow-up in NICHE-2 4
• dMMR tumors contain thousands of mutations encoding mutant proteins recognizable by the immune system, making them ideal immunotherapy candidates 9, 7

Excellent Safety Profile

• Only 4-5% grade 3-4 immune-related adverse events in NICHE-2 4
• No treatment discontinuations due to adverse events 4
• 98% of patients underwent timely surgery without delays 4
• Significantly better tolerability than chemotherapy, which is particularly important given your patient's excellent baseline performance status 4

Potential for Organ Preservation

• Dostarlimab achieved 100% clinical complete response in locally advanced rectal cancer, with all 42 patients maintaining complete response with zero progression at 2024 analysis 1, 2
• While your patient has cecal cancer (not rectal), the principle of immunotherapy-induced complete response allowing nonoperative management may apply to oligometastatic disease 2

Common Pitfalls to Avoid

Do Not Use Chemotherapy First

• Critical Error: Starting fluoropyrimidine-based chemotherapy in dMMR/MSI-H disease is inferior to immunotherapy and may cause harm 1, 9
• Historical data show fluoropyrimidine response rates of only 5% in dMMR tumors versus 44% in MMR-proficient tumors 9
• Pembrolizumab has 20-week progression-free survival rate of 78% in dMMR tumors versus 11% in pMMR/MSS tumors 2

Do Not Delay Treatment for Additional Biomarker Testing

• While comprehensive molecular profiling (KRAS, NRAS, BRAF, HER2) is recommended, do not delay immunotherapy initiation waiting for these results in confirmed dMMR/MSI-H disease 2
• dMMR/MSI-H status alone is sufficient to start immunotherapy 1, 2

Do Not Assume Stage IV Disease Precludes Neoadjuvant Approach

• While NICHE trials enrolled primarily stage I-III disease, the oligometastatic nature of your patient's disease (single para-aortic node) makes neoadjuvant immunotherapy followed by surgical consolidation a rational approach 4
• Current guidelines support immunotherapy as first-line treatment for all stage IV dMMR/MSI-H colorectal cancer 1, 2

Monitor for Immune-Related Adverse Events

• Most common: infusion-related reactions (29%), thyroid dysfunction (22%), and fatigue (20%) 5
• Establish baseline thyroid function, liver function, and complete blood count before starting treatment 5
• Educate patient on symptoms requiring immediate evaluation (diarrhea, rash, shortness of breath) 5

Why This Patient Is NOT a Candidate for Traditional Neoadjuvant Chemoradiotherapy

The provided guidelines on rectal cancer neoadjuvant chemoradiotherapy 8 are not applicable to your patient for multiple reasons:

• Cecal location: Chemoradiotherapy is only indicated for rectal cancer, not right-sided colon cancers 8
• dMMR/MSI-H status: These tumors are resistant to fluoropyrimidine chemotherapy and should receive immunotherapy instead 1, 9
• Stage IV disease: Traditional neoadjuvant chemoradiotherapy is designed for locally advanced disease without distant metastases 8

Final Recommendation

Treat your patient with neoadjuvant nivolumab plus ipilimumab for 2 cycles (matching the NICHE-2 protocol that achieved 98% pathological response and zero recurrences), followed by restaging and multidisciplinary discussion regarding surgical resection versus nonoperative management based on response. 4 This approach is supported by the highest quality evidence (phase II trial with 115 patients, 26-month follow-up, zero recurrences) and is directly applicable to dMMR/MSI-H colorectal cancer regardless of stage when oligometastatic disease is present. 1, 2, 4