Neoadjuvant immunotherapy plus radiation effective in advanced MSI-H rectal cancer

Trial

Phase 2, ECOG-ACRIN EA2201

Doi
https://doi.org/10.55788/acb09b99

The phase 2 ECOG-ACRIN EA2201 trial showed that combination immunotherapy of nivolumab/ipilimumab followed by short-course radiotherapy (SCRT) may prevent more aggressive trimodality interventions in patients with MSI-H/dMMR locally advanced rectal cancer.

The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy and radiation followed by radical surgery. However, this approach can lead to multiple complications. Single institution studies have demonstrated variable efficacy of anti-PD-1 monotherapy with high clinical and/or pathological complete response (cCR and pCR) rates in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) locally advanced rectal cancer of 38–100% [1,2]. In localised MSI-H/dMMR colon cancer, the combination of anti-PD-1 and anti-CTLA4 therapy in the neoadjuvant setting led to a pCR rate of 68% [3].

The phase 2, multicentre ECOG-ACRIN EA2201 trial (NCT04751370) aimed to evaluate the potential of combination immunotherapy (i.e. nivolumab/ipilimumab) followed by SCRT to increase pCR and decrease the need for surgery in patients with MSI-H/dMMR locally advanced rectal cancer. Dr Kristen Ciombor (Vanderbilt University Medical Center, TN, USA) presented the results of the first stage of the trial (n=14) [4].

Patients with MSI-H/dMMR cT3-4Nx or cTxN+ rectal cancer received 2 cycles of nivolumab/ipilimumab followed by SCRT, an additional 2 cycles of nivolumab/ipilimumab, disease reassessment, and total mesorectal excision (TME). The primary endpoint was pCR rate or, in case of a low TME rate, pCR + cCR rate.

Of 14 participants, all received immunotherapy, 12 received SCRT, and 3 received TME. Because of the low TME rate, the primary endpoint assessed was pCR + cCR rate, with a result of 57% (8/14). All participants who underwent TME (3/3) achieved pCR. In 5 participants, TME was deferred due to the achievement of cCR, 2 participants withdrew consent, and 4 did not complete all protocol-specified treatments due to adverse events (AEs). All participants experienced grade 1–2 treatment-related AEs (most commonly fatigue, diarrhoea, and hyperthyroidism); 5 participants had treatment-related AEs of grade 3–4, including 1 grade 4 event of hypokalemia.

“This data shows a promising impact of combination immunotherapy for patients with MSI-H/dMMR locally advanced rectal cancer, that may prevent more aggressive trimodality interventions,” concluded Dr Ciombor. The EA2201 trial is now being redesigned to give all 4 cycles of immunotherapy upfront, followed by 2 cycles of nivolumab monotherapy, SCRT, and TME (with disease reassessment at every step).

Chen G, et al. Lancet Gastroenterol Hepatol. 2023;8:422-431.
Cercek A, et al. N Engl J Med 2022;386:2363-2376.
Chalabi M, et al. N Engl J Med 2024;390:1949-1958.
Ciombor KK, et al. Neoadjuvant nivolumab plus ipilimumab in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) rectal tumors: ECOG-ACRIN EA2201. Abstract 242MO, ESMO Gastrointestinal Cancers Congress 2024, 26–29 June, Munich, Germany.

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