ESMO West 2024: Dr Lentz Discusses Findings From the NICHE-2 Trial in Advanced Colorectal Cancer
Presenter:
Robert Lentz, MD, University of Colorado School of Medicine
Conference:
2024 ESMO West
The Bottom Line
The NICHE-2 trial demonstrated that neoadjuvant (pre-surgery) immunotherapy using ipilimumab (IPI) and nivolumab (NIVO) resulted in a 100% three-year disease-free survival (DFS) for a specific population of patients with mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI-H) locally advanced colon cancer. These findings suggest a potential shift in pre-surgical treatment paradigms, pending further research and regulatory approvals.
Background
Patients with mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI-H) colon cancers represent about 10–15% of all non-metastatic colon cancers. These cancers are characterized by defects in the DNA repair process, which result in a high mutational burden and increased vulnerability to immunotherapy, a type of anti-cancer treatment that helps the immune system better recognize and attack cancer cells. Treatment of localized dMMR/MSI-H rectal cancer has recently changed, as we now use initial immunotherapy, with many patients not requiring chemotherapy, radiation, or surgery. Despite their responsiveness to immunotherapy with immune checkpoint inhibitors (ICIs) in the advanced setting, however, the standard treatment for localized dMMR/MSI-H colon cancer remains surgery followed by adjuvant (post-surgery) chemotherapy. Recurrence rates for this group of patients ranges between 20 and 40%, which underscores the need for an improved therapeutic approach.
Previous studies such as the FOxTROT study highlight the limitations of chemotherapy in this setting. For example in FOxTROT, patients with dMMR/MSI-H colon cancer who received neoadjuvant chemotherapy showed only a 7% pathologic response, with no clear impact on recurrence rates. This lack of benefit prompted researchers to explore immunotherapy as an alternative. The NICHE-2 trial was designed upon earlier findings showing the efficacy of immune checkpoint inhibitors in the metastatic setting, to assess whether these agents could provide similar benefits in the neoadjuvant (pre-surgery) setting for patients with locally advanced disease.
Patients and Study Design
The NICHE-2 trial was a multicenter study that enrolled 111 patients with previously untreated, non-metastatic dMMR/MSI-H colon cancer. To qualify for the trial, patients needed to have locally advanced tumors (stage cT3/4 and/or node-positive), that were deemed surgically treatable (resectable), and who showed no clinical signs of bowel obstruction or perforation. The treatment involved two doses of nivolumab, immunotherapy, a PD-1 inhibitor, and one dose of ipilimumab (IPI), a CTLA-4 inhibitor. The second dose of nivolumab was administered two weeks after the first, with surgery scheduled two to four weeks after the second dose. All patients then underwent surgery. Primary endpoints in the study were safety and three-year disease-free survival (DFS), with secondary endpoints including pathologic response rates and an exploratory analyses of circulating tumor DNA (ctDNA) dynamics, a marker to assess residual disease burden.
Main Results
Results from NICHE-2 previously reported in the New England Journal of Medicine in June of 2024 showed that pathologic responses, assessed after surgery, were observed in 98% of patients, with 68% achieving a pathologic complete response (pCR)—meaning that no residual tumor was detected in the resected tissue. These findings are in alignment with results reported at this year’s European Society for Medical Oncology (ESMO) Congress which showed a three-year DFS rate of 100%, indicating that no patients experienced disease recurrence during the study period. The outcomes were quite remarkable considering the poor response of dMMR/MSI-H tumors to neoadjuvant chemotherapy that have been observed in previous studies.
In addition, the study demonstrated the ability of circulating tumor DNA (ctDNA) to provide a meaningful assessment of treatment response. At baseline, ctDNA (a marker of microscopic residual disease) was detected in the vast majority (92%) of patients. However, after just one cycle of immunotherapy, 45% of patients had clearance of their ctDNA, and this increased to 83% of patients after the second cycle of immunotherapy. Notably, by three weeks post-surgery, all patients were ctDNA-negative.
Safety and Adverse Events
The immunotherapy regimen used in NICHE-2 was overall well-tolerated. All patients completed both cycles of immunotherapy and underwent their surgery as planned, with no compromise in surgical outcomes. Only 2% of patients experienced a delay in surgery due to adverse events, and severe to life threatening (grade 3–4) toxicities were reported in 4% of participants. Long-term hormone replacement therapy was required in 11% of patients, mainly due to thyroid or adrenal insufficiency, which Dr Lentz emphasized as an important consideration for long-term survivorship care. Overall, the safety profile was consistent with expectations for immune checkpoint inhibitors, and the low incidence of severe events supported the feasibility of this approach.
Clinical Insights
Dr Lentz described the NICHE-2 trial as a potential "game-changer" for the treatment of locally advanced dMMR/MSI-H colon cancer. He emphasized the unprecedented nature of the trial’s outcomes, particularly the 100% DFS at three years, which he stated was “remarkable across oncology.” While the regimen, neoadjuvant immunotherapy followed by surgery, is not yet approved or included in major treatment guidelines, Dr Lentz highlighted its promise as a treatment option to be considered on a case-by-case basis, particularly in the setting of a multidisciplinary care team. Commenting on the role of ctDNA as a biomarker for predicting and monitoring treatment response, he noted that, while ctDNA offered significant insights, its use for guiding non-operative management of patients remains challenging. "Future research," he noted, "is essential to determine how best to integrate these tools into standard care, particularly for patients who might benefit from organ-preserving approaches." He cautioned, however, that surgery should remain a cornerstone of treatment until further evidence supports non-operative strategies.
Conclusion
The NICHE-2 trial represents a significant advance in the treatment of dMMR/MSI-H colon cancer. With the exceptional pathologic response rates and DFS outcomes observed, the findings underscore the potential of neoadjuvant immunotherapy to reshape the standard of care in colorectal cancer. As Dr Lentz noted, however, further research is needed to help refine patient selection, optimize treatment protocols, and explore the possibility of avoiding surgery in certain cases. At present NICHE-2 provides a compelling foundation for discussion with a select group of patients with dMMR/MSI-H colon cancer optimally in a multidisciplinary setting.
“We need a better treatment option in this setting, and NICHE-2 demonstrates that neoadjuvant ipi/nivo can provide exceptional outcomes, including 100% three-year DFS. This is remarkable in oncology, and offers a path forward for dMMR/MSI-H colon cancer.”
Speaker Disclosure Information: Dr Lentz reported the following disclosures for this presentation: Institutional Research Funding: ALX Oncology, Merck, Lilly, Guardant, EDDC, Boehringer Ingelheim, AstraZeneca; Consulting/Advisory Fees: Boehringer Ingelheim, Agenus, Merck, Natera.