NICHE-2: ‘Unprecedented’ Waterfall Plot Achieved With Neoadjuvant Immunotherapy in dMMR Colon Cancer

Get Permission

Treatment with neoadjuvant immunotherapy in colon cancer resulted in major pathologic responses in 95% of patients, NICHE-2 investigators reported at the European Society for Medical Oncology (ESMO) Congress 2022.1 Additionally, after 4 weeks of nivolumab plus ipilimumab, 67% of patients with mismatch repair–deficient (dMMR) colon cancer achieved pathologic complete responses and as yet no disease recurrence, according to Myriam Chalabi, MD, PhD, a medical oncologist at the Netherlands Cancer Institute.

“After 4 weeks of nivolumab plus ipilimumab, 67% of patients with dMMR colon cancer achieved pathologic complete responses and as yet no disease recurrence.”
— Myriam Chalabi, MD, PhD

Tweet this quote

In a study in dMMR rectal cancer reported at the 2022 ASCO Annual Meeting,2 6 months of neoadjuvant treatment with the anti–PD-1 agent dostarlimab-gxly led to clinical complete responses in 100% of the first 14 patients and spared all of them from chemotherapy, radiation therapy, and surgery.

Now, according to Dr. Chalabi, NICHE-2 has demonstrated a similar outcome in colon cancer, with an “unprecedented” response, given that most patients had stage III, high-risk disease. “This stands in stark contrast to data from neoadjuvant chemotherapy in this same patient population,” she said. She noted that with traditional treatment, 5% to 7% of patients achieve pathologic responses.

“Of note, this treatment was very well tolerated,” she said. A total of 4% of patients receiving this immunotherapy doublet experienced a grade 3 or 4 immune-related adverse event.

The results of this trial and another neoadjuvant immunotherapy study in resectable melanoma led session moderator Florian Lordick MD, PhD, a gastrointestinal cancer specialist, to offer this comment: “This has been one of the most exciting scientific sessions of any scientific congress in oncology—ever.” Dr. Lordick is Professor of Medicine at the University of Leipzig, Germany.

Florian Lordick MD, PhD

Florian Lordick MD, PhD

The nonrandomized multicenter NICHE-2 trial enrolled 112 patients with nonmetastatic, previously untreated dMMR colon adenocarcinoma, cT3 and/or node-positive disease based on radiologic staging, no clinical symptoms or radiologic suspicion of perforation, and no clinical signs of obstruction. The study was initiated by investigators after 32 patients with nonmetastatic dMMR colon cancer in the NICHE-1 trial had a 100% rate of pathologic responses, with 60% achieving a pathologic complete response to dual checkpoint blockade.3

A Pathologic Response Rate of 99%

In 107 patients evaluated for efficacy, 106 patients (99%) had a pathologic response, 102 (95%) had a major pathologic response, 72 (67%) had a complete pathologic response, and 4 (4%) had a partial pathologic response. The one patient lacking a pathologic response had 60% residual visual tumor upon evaluation, Dr. Chalabi revealed.

For the 97 patients in the per-protocol population who had Lynch status available, 65 had a sporadic dMMR tumor, and 32 had Lynch syndrome. For patients with sporadic tumor, the pathologic complete response rate was 58%; for those with Lynch syndrome, it was 78% (P = .056).

Response was characterized by the amount of residual viable tumor, as follows: pathologic response, ≤ 50%; major pathologic response, ≤ 10% (this includes tumors with a pathologic complete response in the primary but residual tumor in the lymph nodes); and pathologic complete response, 0% residual viable tumor in the primary tumors and nodes.

Elaborating on the residual tumor picture during the discussion, Dr. Chalabi said the researchers found some dMMR tumors were less “inflamed” than expected, though all patients responded. “However, after treatment, all tumor beds are inflamed. No tumor is left. It’s all taken up, mostly by CD8 T cells and other phenotypes of immune cells,” she said. “We are working on studying this more…. It will be interesting to see, for the patients who do have remaining cells in the tumor bed, whether this might be a dynamic event and, if we’d waited longer, whether they might have disappeared as well.”

Of the 14 patients with positive lymph nodes after treatment, 3 received adjuvant chemotherapy. Five patients were aged 70 or older and did not receive adjuvant chemotherapy, and six patients refused chemotherapy.

There has been no disease recurrence at a median follow-up of 13.1 months (range = 1.4–57.4 months). The 3-year disease-free survival data are expected in 2023.

Safety Profile

In total, 61% of patients experienced an immune-related adverse event of any grade, but they were grade 3 or 4 in only four patients. Two patients had an immune-related adverse event leading to a delay in surgery of at least 2 weeks. Infusion reactions, dry mouth, hyper- or hypothyroidism, fatigue, and flu-like symptoms were the most common grade 1 or 2 toxicities. A surgery-related adverse event was observed in 21% of patients; 13% of these events were grade ≥ 3, and 5% were anastomotic leakage or wound infections.

About NICHE-2

In NICHE-2, the 112 patients in the intention-to-treat population received 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the first cycle, then nivolumab alone in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. The primary endpoints of this study were 3-year disease-free survival and safety; secondary endpoints included major pathologic response and complete pathologic response. Safety and feasibility would be reached if surgery was performed on time, with ≤ 2 weeks’ delay in 95% of patients. A 3-year disease-free survival of 93% would also be deemed successful.


  • The nonrandomized phase II NICHE-2 trial evaluated a 4-week course of neoadjuvant nivolumab plus ipilimumab in early-stage resectable colon cancer.
  • All patients responded, 95% had a major pathologic response, and 67% achieved a complete pathologic response.
  • A complete tumor response, which mirrors recent findings for single-agent neoadjuvant immunotherapy in rectal cancer, is unprecedented in this malignancy.

Patients could not have active autoimmune disease or other medical conditions requiring systemic steroid or immunosuppressive medications. At baseline, median patient age was 60, 58% were female, 87% had an Eastern Cooperative Oncology Group performance status of 0, 68% had primary tumors in the right colon, 74% had radiologic high-risk stage III disease, and 48% had radiologic high-risk disease with both T4 and N2 features.

All patients underwent surgery and achieved tumor-free (R0) resection margins, with 98% of patients undergoing timely surgery and meeting the safety endpoint of the trial. The median time from the first dose with the combination to surgery was 5.4 weeks.

Looking Ahead

Organ-sparing approaches will be evaluated in future studies of dMMR colon cancer. And since response assessment is more difficult in colon cancer than in rectal cancer, circulating tumor DNA dynamics and novel imaging techniques could help with evaluation and may aid in achieving organ preservation.

“I believe neoadjuvant immunotherapy has a very strong potential to become standard of care for patients with dMMR colon cancer. The future has never been brighter for this patient population, and for that, I urge the pharmaceutical companies to strive for registration of neoadjuvant immunotherapy,” Dr. Chalabi concluded. 

DISCLOSURE: Dr. Chalabi reported no conflicts of interest. Dr. Lordick has served as a consultant or advisor to Amgen, Astellas, AstraZeneca, Bayer, BioNtech, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Roche, and Servier; has received honoraria from BMS, Eli Lilly, Falk Foundation, Incyte, Medscape, MedUpdate, MSD, Novartis, Roche, Servier, Springer-Nature, and StreamedUp!; and has received research support from Astellas, BMS, and MSD.


1. Chalabi M, Verschoor Y, Van den Berg J, et al: ESMO Congress 2022. Abstract LBA7. Presented September 11, 2022.

2. Cercek A, Lumish MA, Sinopoli JC, et al: 2022 ASCO Annual Meeting. Abstract LBA5. Presented June 5, 2022.

3. Chalabi M, Fanchi LF, Dijkstra KK, et al: Nat Med 26:566-576, 2020.

Related Articles

Expert Point of View: James Larkin, PhD and Andrea Cercek, MD

Invited discussant James Larkin, PhD, a clinical researcher at the Royal Marsden Hospital, London, commented on the findings from NICHE-2.1 “These striking data are consistent with the recent report in locally advanced mismatch repair–deficient [dMMR] rectal cancer from Memorial Sloan Kettering.2...