EA2201 – A Phase II Study of Neoadjuvant Nivolumab plus Ipilimumab and Short-Course Radiation in MSI-H/dMMR Locally Advanced Rectal Adenocarcinoma

The study chair for this trial is Kristen Ciombor, MD (Vanderbilt-Ingram Cancer Center). The study co-chairs are Cathy Eng, MD (Vanderbilt University/Ingram Cancer Center) and Xin Yao, MD (ThedaCare Regional Cancer Center).

The standard of care for patients with stage 2 and 3 rectal cancer is a multimodality approach consisting of concurrent chemoradiotherapy, total mesorectal excision (TME), and adjuvant chemotherapy. However, a pathologic complete response (pCR) only occurs in 15% of patients. The remaining 85% have residual tumor cells in their surgical specimens, signaling a higher risk of disease recurrence and suboptimal patient outcomes. Furthermore, even if multimodality therapy cures patients, they can experience chronic toxicities, as well as temporary or permanent colostomies, which can significantly lower their quality of life. Patients with rectal cancer need new treatments to improve cure rates, minimize long-term toxicities, and reduce surgical morbidity.

Recent research has demonstrated that patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer have high response rates to immunotherapy with durable, prolonged responses. In fact, MSI-H/dMMR tumors are highly sensitive to immune checkpoint inhibitors across cancer types. For example, pembrolizumab is approved by the Food and Drug Administration (FDA) to treat this subgroup of cancers, irrespective of the primary tumor site.

The FDA also approved nivolumab plus or minus ipilimumab for metastatic colorectal cancer. Early research suggests these two drugs may be effective in localized colorectal cancer as well. Therefore, the phase II EA2201 study will test the effect of nivolumab plus ipilimumab, with short-course radiation, for the neoadjuvant treatment of patients with low-lying, locally advanced MSI-H/dMMR rectal cancer. Investigators believe this approach may yield increased pCR rates prior to TME, and thus, may result in increased sphincter preservation. The goal is to accrue 31 patients. If successful, EA2201 will provide data for larger/additional studies.

This trial has a single-arm design. All patients in the study will be treated initially with nivolumab plus ipilimumab for two 28-day cycles. Patients will then receive short-course radiotherapy (one week) followed by two additional 28-day cycles of nivolumab plus ipilimumab. Physicians will then reassess the patients with digital rectal exam and imaging (MRI and sigmoidoscopy) and then proceed to surgery. Finally, patients will be considered for either adjuvant chemotherapy or observation per physician and patient discretion. After the completion of therapy, patients will be followed for at least five years.

Patients are eligible for the trial if they have confirmed stage 2 or 3 MSI-H/dMMR locally advanced, low-lying rectal adenocarcinoma. They must not have had previous chemotherapy or immunotherapy for rectal cancer, or previous radiotherapy to the pelvis.

Learn more about EA2201 at ecog-acrin.org.