242MO - Neoadjuvant nivolumab plus ipilimumab in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) rectal tumors: ECOG-ACRIN EA2201

Background

In MSI-H/dMMR locally advanced rectal adenocarcinoma (LARC), 2 small single-institution studies have demonstrated variable efficacy of anti-programmed cell death protein-1 monotherapy with clinical complete response (cCR) and/or pathologic complete response (pCR) rates of 38%-100% (Ludford, JCO 2023; Cercek, NEJM 2022). EA2201 is a multi-institutional single-arm phase II study evaluating nivolumab (nivo), ipilimumab (ipi) and short course radiation therapy (SCRT) followed by total mesorectal excision (TME) in patients (pts) with MSI-H/dMMR LARC.

Methods

Pts with treatment-naïve MSI-H/dMMR LARC were eligible. Pts received nivo 480 mg and ipi 1 mg/kg every 28 days for 2 cycles, SCRT (5 Gy x 5 fractions) and an additional 2 cycles of nivo + ipi prior to disease reassessment and TME. EA2201 has a two-stage design with a primary endpoint of pCR. Per protocol, in case of a lower than expected TME rate, a combined endpoint of pCR + cCR was allowed. Enrollment of 31 patients over two stages was planned, with a null hypothesis of 25% response rate and alternative hypothesis of 50% response rate, with 90% power and a type I error of 0.09.

Results

In this planned interim analysis, 14 pts were enrolled in the first stage. There was a 57.1% rate of pCR or cCR (95% confidence interval: [31.2%-83.1%]). All 3 patients (100%) who underwent TME had pCR, and 6 pts (including 1 who underwent TME) achieved cCR. Primary reasons for not completing full protocol treatment were achievement of cCR, pt refusal of TME and/or physician decision, and adverse events (AEs: 4/14). Grade 3 AEs included abdominal pain/rectal obstruction, fatigue, urinary tract infection, increase in AST/ALT, decrease in lymphocyte count, acidosis, and arterial thromboembolism; 1 grade 4 event of hypokalemia was noted.

Conclusions

These highly promising data are consistent with an impact of immunotherapy that may obviate more aggressive interventions in MSI-H/dMMR LARC. The proportion of pCR + cCR in this trial is comparable to previously published data. This trial is now being redesigned to give all nivo and ipi upfront prior to consideration of SCRT and TME, with additional nivo monotherapy to be given beyond the four nivo/ipi cycles if warranted.

Clinical trial identification

NCT04751370.

Legal entity responsible for the study

U.S. National Cancer Institute (NCI).

Funding

U.S. National Cancer Institute (NCI).

Disclosure

K.K. Ciombor: Financial Interests, Personal, Advisory Board: Pfizer, Seagen, Personalis, Replimune, Incyte, Exelixis, Bayer, ALX; Financial Interests, Institutional, Principal Investigator: BMS, Array, Incyte, Daiichi Sankyo, Merck, Pfizer, Nucana, Genentech, Seagen. All other authors have declared no conflicts of interest.