GI cancer

Neoadjuvant immunotherapy may allow organ sparing approach in CRC: NICHE2

The first results from the landmark NICHE-2 trial have shown ”spectacular” efficacy for neoadjuvant immunotherapy in patients with mismatch repair-deficient (dMMR) colon cancer.

Presented at the ESMO Congress 2022, the findings were described as setting the scene for immunotherapy to be the new standard of care in patients with dMMR early colon cancer rather than chemotherapy, and also the potential for an ‘organ sparing’ non-operative surveillance approach to be the new standard of care.

Study investigator Professor Miriam Chalabi, a medical oncologist at the Netherlands Cancer Institute, said the NICHE 2 trial was designed to confirm promising results of the exploratory NICHE trial, which in 2020 showed pathological responses were achieved in 100% of dMMR tumours with neoadjuvant immune checkpoint inhibitors.

In the NICHE-2 trial, 112 patients with untreated non-metastatic dMMR colon cancer received one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) ≤6 weeks prior to surgery.

The co-primary endpoint of safety was met, with 4% of patients experiencing grade 3–4 immune-related adverse events and all but two patients (98%) having timely surgery.

While the co-primary endpoint of disease free survival has yet to be reported, the preliminary results for pathological responses were “unprecedented” said Prof Chalabi. With a median 5.4 weeks from first dose to surgery, major pathological response (MPR) was seen in 95% of patients and 67% had a complete pathological complete response (pCR).

No patients had disease recurrence after a median follow-up of 13.1 months.

“This stands in stark contrast to data from neoadjuvant chemotherapy in the same patient population, with only 7% pathological responses,” said Prof Chalabi.

She said the DFS data was due to be reported in 2023, and the current results suggested the next step should be studies into ‘watch and wait’ organ sparing approaches in dMMR colon cancer.

In an ESMO discussion session Professor James Larkin, consultant medical oncologist at the Royal Marsden Hospital, London, described the data as “striking” and bringing the organ-sparing paradigm closer to reality.

“You don’t see many waterfall plots like this. Striking data: very brief treatment and obviously a very major effect,” he said.

According to Prof Larkin, the findings were consistent with recent positive results achieved with neo-adjuvant immunotherapy in locally advanced dMMR renal cancer, which had also raised the possibility of patients avoiding life-altering organ surgery.

“Clearly neoadjuvant checkpoint inhibition can have a major impact in sensitive populations, leading to greater benefit and potentially less treatment,” he said.

He also postulated that future neoadjuvant immunotherapy regimens could be monotherapy and may not require anti CTLA4 therapy.

Also commenting on the findings, Dr Jenny Seligmann from the University of Leeds, UK, said NICHE-2 suggested that for patients with dMMR early colon cancer, future treatment schedules will almost certainly be with immunotherapy rather than chemotherapy.

However caution was warranted on whether these data support the use of neoadjuvant immunotherapy as standard of care in early colon cancer.

“Before clinical practice can change, we need clarification on several aspects. Firstly, the trial was conducted in a single centre where there is great expertise in patient selection and treatment delivery and committed multidisciplinary teams, so confirmation of these results in other settings is urgently needed. Also, as we await data for the co-primary endpoint of 3-year DFS, longer term follow-up data are needed to confirm the initial results,” she said.

Patient selection was another major consideration for use of neoadjuvant immunotherapy, Dr Seligmann said.

“In the adjuvant setting, patient selection is made according to post-operative pathology, whereas in the neoadjuvant setting, decisions are based on CT assessment of the tumour as well as the biopsy, and we know radiological assessment of lymph nodes is particularly difficult in dMMR cancers. This is an area that needs development while we wait for the final results of the NICHE-2 trial.”

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