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Neoadjuvant Immunotherapy Yields Major Response in Colon Cancer Subset


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In a small study of patients with early-stage colon cancer, neoadjuvant ipilimumab (Yervoy) plus nivolumab (Opdivo) produced major pathologic responses in 100% of patients with mismatch repair (MMR)-deficient tumors but in none of the patients with MMR-proficient tumors, researchers reported at the European Society for Medical Oncology (ESMO) 2018 Congress.1

“Short preoperative treatment is safe and led to major pathologic responses in all seven patients with MMR-deficient tumors,” said Myriam Chalabi, MD, of the Netherlands Cancer Institute, Amsterdam, who presented the first results of the study.


Short preoperative treatment [with ipilimumab plus nivolumab] is safe and led to major pathologic responses in all seven patients with MMR-deficient tumors.
— Myriam Chalabi, MD

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Session moderator George Coukos, MD, PhD, Director of the Department of Oncology at the University Hospitals of Canton Vaud and Director of the Lausanne branch of the Ludwig Institute for Cancer Researchat the University of Lausanne in Switzerland, called the study “one of the most important at the meeting” and commented, “These impressive results in the microsatellite instability–high [MSI-H] population are potentially a paradigm shift. This is very good news for the field.”

Rationale for Immunotherapy in Colon Cancer

Trials of immunotherapy in colorectal cancer have focused mainly on patients with metastatic disease and mostly heavily pretreated patients, Dr. Chalabi pointed out. “In that population, we know that MMR-deficient tumors have very high response rates to both monotherapy and combination treatment, and these treatments are also now approved. However, in MMR-proficient tumors, no responses are seen. Even though MMR-deficient tumors account for only about 4% of metastatic colorectal cancers, 15% of early-stage colon tumors are MMR-deficient. So far, we have no data on immune checkpoint inhibition in this patient population.”

In other cancer types, neoadjuvant treatment with immunotherapy has produced response rates that are higher than what is seen in the metastatic setting. Dr. Chalabi and her team hypothesized that immune checkpoint inhibition would be an effective neoadjuvant treatment in primary colorectal cancer, as well.

This could be because primary tumors are more likely to have T-cell infiltration than metastatic tumors. Preexisting T-cell response has been predictive of the response to immune checkpoint inhibition in both nonmetastatic and metastatic colorectal cancers, she said.

NICHE Design

The phase II noncomparative NICHE trial was the first neoadjuvant study to test ipilimumab plus nivolumab in early-stage MMR-deficient and MMR-proficient colon cancers. The study enrolled 19 patients with resectable, early-stage colon cancer, treating them with 1 course of ipilimumab at 1 mg/kg on day 1 and nivolumab at 3 mg/kg on days 1 and 15. The time from colonoscopy to surgery was 6 weeks or less.

For the analysis presented at the ESMO meeting, 14 cases were evaluable, including 7 MMR-deficient tumors and 8 MMR-proficient tumors (1 patient had 2 tumors).

100% Pathologic Response Rate

Immunotherapy was well tolerated, and all patients underwent resection without delays in surgery. Three patients had grade 3 events postoperatively: 1 case each of abdominal infection, anastomotic leak, and pneumonia, none of which was attributed to the immunotherapy.

Major pathologic responses (< 10% residual vital tumor) were observed in 7 (100%) of 7 MMR-deficient tumors, with 4 complete responses (57%). No major pathologic responses were observed in MMR-proficient tumors, and tumor regression was rare, though changes in the tumor microenvironment were observed in MMR-proficient as well as MMR-deficient subgroups, Dr. Chalabi said.

Immune Components

Among thepatients with MMR-deficient tumors, response could not be predicted by pretreatment CD3 infiltration or immune gene signatures. Contrary to what the investigators expected, pretreatment CD3 infiltration was not higher in the MMR-deficient tumors. After treatment, there was a significant increase (P = .031) in CD3 infiltration in the MMR-deficient tumors and a slight increase (P = .461) in the MMR-proficient tumors, she reported.

We believe that our data warrant independent validation of neoadjuvant immunotherapy in MMR-deficient tumors in larger trials—and that they have the potential to be practice-changing.
— Myriam Chalabi, MD

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The MMR-deficient tumors had a significantly (P = .027) higher number of CD8-positive cells at baseline and a median 4.8-fold increase in CD8-positive T cells postoperatively (P = .0009). “What was striking here was when we looked at the posttreatment samples, we saw a significant 2.4-fold increase (P = .018) of CD8-positive T cells also in the MMR-proficient tumors that do not seem to be responding clinically,” said Dr. Chalabi.

NEOADJUVANT IMMUNOTHERAPY IN COLON CANCER

  • The phase II NICHE study evaluated a short course of neoadjuvant therapy with ipilimumab and nivolumab in 14 patients with early-stage colon cancer, with both MMR-deficient and MMR-proficient tumors.
  • All patients with
    MMR-deficient tumors achieved a pathologic response, whereas no patient with MMR-proficient tumors did.
  • The T-cell repertoire was changed in both tumor subsets; the pretreatment T-cell profile did not predict response.

T-cell receptor clonality was not significantly different between MMR-deficient and MMR-proficient tumors before treatment. Both subgroups demonstrated a trend toward a more clonal T-cell repertoire posttreatment.

Pretreatment immune gene signatures were not predictive of response, she continued, but posttreatment interferon-gamma signatures, which increased significantly in the MMR-deficient tumors (P = .036) but not in MMR-proficient tumors (P = .08), improved the ability to distinguish responders from nonresponders.

“We believe that our data warrant independent validation of neoadjuvant immunotherapy in MMR-deficient tumors in larger trials—and that they have the potential to be practice-changing,” Dr. Chalabi concluded. 

DISCLOSURE: Dr. Chalabi has served as an advisor for Bristol--Myers Squibb and has received institutional grants from Bristol-Myers Squibb and Roche. Dr. Coukos has served as an advisor/consultant/speaker for NextCure, Geneos Therapeutics, Roche, Genentech, AstraZeneca, and Bristol-Myers Squibb and has received grants from Celgene, Boehringer Ingelheim, and Bristol-Myers Squibb.

REFERENCE

1. Chalabi M, Fanchi L, van den Berg J, et al: Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. 2018 ESMO Congress. Abstract LBA37_PR. Presented October 22, 2018.


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