Nivolumab/Ipilimumab/Radiation Combo Produces Responses in Locally Advanced Rectal Cancer

Results from the phase 2 ECOG-ACRIN EA2201 trial (NCT04751370) showed that neoadjuvant treatment with the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and short-course radiation therapy led to responses in patients with microsatellite instability-high (MSI-H)/mismatch repair–deficient (dMMR) locally advanced rectal adenocarcinoma. Data were presented at the 2024 ESMO Gastrointestinal Cancers Congress.

The partial complete response (pCR) plus the clinical CR (cCR) rate was 57.1% (95% CI, 31.2%-83.1%). The pCR for the 3 patients who underwent total mesorectal excision (TME) was 100%. Overall, 11 patients did not complete protocol-specified treatment and included TME deferred due to achievement in cCR (n = 5), withdrawal of consent (n = 2), and adverse effects (n = 4).

“There is a potential role for further personalization of treatment in MSI-H/dMMR locally advanced rectal cancer,” Kristen K. Ciombor, MD, MSCI, associate professor of medicine at Vanderbilt University Medical Center and co-leader of Translational Research and Interventional Oncology Research Program, said during the presentation. “[These include} overcoming potential anti–PD-1 resistance, optimal treatment modality inclusion, duration of therapy, and minimization of toxicity.”

A total of 14 patients were assessed in this trial. Patients received 1 mg/kg of ipilimumab plus 480 mg of nivolumab for 2 cycles plus 5 Gy for 5 fractions of short-course radiotherapy followed by matched combination treatment. Patients then went on to disease reassessment and TME.

Two stages of the trial were planned with 31 patients estimated to enroll. The null hypothesis included 25% pCR. Ciomber noted if 3 or more pCRs were observed during the first stage of the study, the study would continue to the second stage.

Patients were eligible to enroll if they had cT3/4Nx or cTxN+ rectal adenocarcinoma within 15 cm of anal verge, MSI-H/dMMR disease, no active autoimmune disease, and no chronic prolonged systemic steroids.

The primary end point was pCR, and if the TME rate was lower than 85%, pCR could be combined with cCR. The secondary end points were sphincter preservation rate in low-lying tumors, 5-year disease-free survival, overall survival, and safety.

The median patient age was 48.5 years and 35.7% were male. Overall, 85.7% of patients were White, 7.1% were American Indian/Alaskan Native, and 7.1% were unknown. Additionally, 92.9% were non-Hispanic/Latino.

T stage was also assessed and patients had either T2 (14.3%), T3 (57.1%), and T4 stage disease (28.6%). For N stage assessment, patients had N1 (50%), N2 (35.7%), or Nx stage disease (14.3%). Of note, 50% of patients were MSI-H, and 92.9% were dMMR.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 100% of patients. Grade 3/4 TRAEs occurred in 35.7% of patients, and no patients had grade 5 TRAEs. The most common grade 1/2 TRAEs were fatigue (n = 9), diarrhea (n = 8), hypothyroidism (n = 6), anemia (n = 5), and nausea/vomiting, increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, pruritis, and maculopapular rash (n = 4 each).

Grade 3 TRAEs comprised hypokalemia (n = 2), abdominal pain (n = 1), acidosis (n = 1), rectal obstruction (n = 1), increased ALT/AST levels, fatigue, decreased lymphocyte count, and urinary tract infection (n = 1 each). Grade 4 hypokalemia occurred in 1 patient.

At the end of the presentation, Ciomber gave an update on the next steps of the trial. All 4 cycles of combination therapy will be given upfront prior to SCRT or TME. An additional 2 extra cycles of nivolumab monotherapy will be given prior to SCRT and TME if warranted.

Reference

1. Ciomber KK, Hong SC, Eng C, et al. Neoadjuvant nivolumab plus ipilimumab in microsatellite instability-high/deficient mismatch repair rectal tumors: ECOG-ACRING EA201. Presented at the 2024 European Society of Medical Oncology Gastrointestinal Congress; June 26-29, 2024; Munich, Germany. Abstract 242M0.