Remarkable Success with Dual Immunotherapy Before Surgery in Colon Cancer

Colorectal cancer is the third most common cancer worldwide, accounting for approximately 10% of all cancer cases, and the second leading cause of cancer-related death worldwide. Tumors with a particular genetic characteristic, mismatch repair–deficient (dMMR) tumors, account for 10% to 15% of colon cancer cases and are often resistant to standard chemotherapy. In recent years, immunotherapy has been investigated for its potential effects in these patients, with promising results. This article examines in detail the efficacy and safety of neoadjuvant nivolumab combined with ipilimumab in patients with locally advanced dMMR colon cancer, based on the NICHE-2 study findings.

NICHE-2 was presented at the ASCO 2024 Annual Meeting by medical oncologist Dr. Myriam Chalabi and, on June 5, 2024, in NEJM , it was published.

Neoadjuvant immunotherapy has shown promising results in several cancers, but study data on this approach in colon cancer are limited. A phase 2 study therefore evaluated the safety and efficacy of neoadjuvant nivolumab plus ipilimumab in patients with locally advanced dMMR colon cancer.

Study Details and Success Stories

NICHE-2 was conducted by the Netherlands Cancer Institute. According to principal investigator Dr. Myriam Chalabi, "This particular type of colon cancer contains many DNA errors, making tumor cells easier for the immune system to detect. The immune system needs only a small boost to target the tumor cells successfully," she says.

Two years earlier, Chalabi had presented preliminary results at a major international congress. She received a standing ovation for her work, and the #Chalabiplot phenomenon, referring to a graph illustrating the striking results in her presentation, resonated on X (formerly Twitter). "I still get goosebumps when I think back to that moment. The positive emotions in the room were palpable. These results could significantly improve outcomes for future patients," she says.

The first signs of success appeared soon after Chalabi launched the NICHE trial. "We wanted to explore what neoadjuvant immunotherapy could do for people with nonmetastatic colon cancer. We saw that every patient in the study responded well to the new treatment," Chalabi says.

Design of the Current Study

Patients with previously untreated, nonmetastatic, locally advanced dMMR colon cancer received neoadjuvant nivolumab and ipilimumab. The two primary endpoints were safety (a delay of ≤2 weeks in planned surgery because of treatment-related toxic effects) and 3-year disease-free survival. Secondary endpoints included pathological response and genomic analysis results.

Findings

• Timely Surgery: Of 115 patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent planned surgery on time. Surgery was delayed by more than 2 weeks in only 2 patients.

• Adverse Events: In 5 patients (4%), grade 3 or 4 immune-related adverse events occurred. No patient had to discontinue treatment because of treatment-related adverse events.

• Pathological Responses:

  • The efficacy analysis included 111 patients.
  • A pathological response was observed in 109 patients (98%; 95% CI, 94 to 100).
  • A major pathological response (≤10% residual viable tumor) was found in 105 patients (95%).
  • A pathological complete response (0% residual viable tumor) was observed in 75 patients (68%).

• Follow-Up and Recurrence Rate: Median follow-up was 26 months (range, 9 to 65 months). No patient experienced disease recurrence.

• Overall Treatment Efficacy: Neoadjuvant nivolumab plus ipilimumab was effective in patients with locally advanced dMMR colon cancer, producing a high pathological response rate with an acceptable safety profile.

Why This Study Matters

Neoadjuvant immunotherapy is immunotherapy given before surgery to help prevent cancer from spreading or returning. For larger tumors, it is used to make surgery easier. The main rationale for treatment before surgery is that the immune system can interact with more tumor cells, the DNA errors within those tumors and more immune cells. This enables it to target cancer cells more effectively.

Clinical Use and Next Steps

The treatment studied is not yet available to patients in the Netherlands. "This trial was conducted to make the treatment accessible to patients with this type of colorectal cancer. By the end of this year, we will have followed these patients for three years. If most are still cancer-free, we should work to make this a standard treatment option," Chalabi says.

"For patients with colorectal cancer who respond well to neoadjuvant immunotherapy, this and similar studies have brought us to the point of omitting chemotherapy before surgery. The next critical step is to make this treatment available as standard care. We are working toward that now. Eventually, we hope to offer patients who respond well the option of avoiding surgery altogether."

Conclusion

This study highlights the potential of neoadjuvant immunotherapy for dMMR colon cancer and offers new hope for patients in whom chemotherapy has limited effects. The high pathological response rates and disease-free survival observed suggest that this treatment approach should be evaluated in a broader patient population.