NEOADJUVANT IMMUNOTHERAPY FOR COLORECTAL CANCER

Neoadjuvant immunotherapy is associated with significant pathological responses in patients with mismatch repair (MMR)-deficient and MMR-proficient early-stage colon cancers, according to first results from the ongoing exploratory NICHE study.

"Most impressive is the 100% response rate in patients with MMR-deficient tumors, and we are still in awe every time we get to share a complete or near-complete response with these patients," Dr. Myriam Chalabi of the Netherlands Cancer Institute, in Amsterdam, told Reuters Health by email.

Neoadjuvant immunotherapy has produced pathological responses in early-stage melanoma, lung cancer and bladder cancer. NICHE is investigating the safety, feasibility, activity and immunological correlates of short-term, preoperative ipilimumab/nivolumab with or without celecoxib in patients with non-metastatic colon cancers.

Dr. Chalabi and colleagues report the pathological responses in the first 40 patients, including 21 MMR-deficient (dMMR) and 20 MMR-proficient (pMMR) tumors (one patient had both). By pretreatment radiological assessment, 81% of patients with dMMR tumors and 40% with pMMR tumors had clinical stage-III disease.

All 20 dMMR tumors had a pathological response, including 12 that showed pathological complete responses, the researchers report in Nature Medicine.

Four (27%) of the 15 patients with evaluable pMMR tumors also showed pathological responses. In the subgroup of seven patients with a pMMR tumor who received celecoxib in addition to immunotherapy, two showed a pathological response and two had tumor regression of 10%-50%, suggesting that celecoxib does not add to the effects of immunotherapy.

During a median follow-up of 8.1 months in the dMMR group and 9.8 months in the pMMR group, all patients with dMMR tumors and all but two with pMMR were alive and disease-free.

Treatment was well tolerated, and all patients underwent radical resections within the predefined six weeks after study inclusion, with primary anastomoses in all patients.

The correlation between radiological assessment of response and histopathological findings was poor, suggesting that CT scans might not be the best way to assess outcomes.

In analyses comparing pMMR responders and nonresponders, the sole biomarker found to predict response was the presence of T cells that co-expressed CD8 and PD-1. Neoadjuvant immunotherapy in early-stage pMMR colon cancers commonly led to immune activation even when this did not result in a pathological response.

"For the pMMR tumors we need to validate CD8+/PD1+ T cells as predictors of response in a prospective study," Dr. Chalabi said. "It will also be interesting to follow up on the long-term survival data in patients who had little or no regression, but clear signs of immune activation, and whether that translates into improved survival."

"Before we can change the current standard of care for early-stage colon cancers, we need to treat more patients with MMR-deficient tumors to show that these responses are seen in a larger cohort," she said. "But we mainly need the 3-year disease-free survival data to convince GI oncologists, and hopefully also regulatory authorities, of a possible new standard of care."

"Additional data from the FOXTROT trial on dMMR tumors will also be an important comparison for this subgroup, considering the lack of pathological response to neoadjuvant chemotherapy in the majority of dMMR tumors," Dr. Chalabi said.

Dr. Cathy Eng of Vanderbilt University's Ingram Cancer Center, in Nashville, Tennessee, who recently reviewed the role of immune-checkpoint inhibitors in the treatment of colorectal cancer, told Reuters Health by email, "This confirms that all physicians should be testing all stages of colorectal cancer for microsatellite instability-high status (MSI-H). If a patient is dMMR, the role of immunotherapy could be considered."

"I find this study groundbreaking because, for a dMMR patient, it suggests we may possibly be able to omit surgery in the future in select patients," said Dr. Eng, who was not involved in the study. "This would be an amazing opportunity for low-lying rectal-cancer patients who are at risk for a permanent colostomy. Could this result in the ability to omit surgery or even radiation therapy in this setting? This may result in sphincter preservation and may result in significant improvement in quality of life."

SOURCE: https://go.nature.com/2XqLuXv Nature Medicine, online April 6, 2020.