Preoperative botensilimab (BOT) with or without balstilimab (BAL) for patients with resectable locally advanced pMMR or dMMR colon cancer: Results from the UNICORN trial by GONO.
Authors: Ghelardi Filippo , Ambrosini Margherita , Raimondi Alessandra , Sabella Giovanna , Cerantola Riccardo , Palermo Federica , Di Donato Samantha , Spada Daniele , Tamberi Stefano , Perissinotto Eleonora , Bergamo Francesca , Passardi Alessandro , Tamburini Emiliano , Rosati Riccardo , Sartore-Bianchi Andrea , Guaglio Marcello , Cremolini Chiara , Montroni Isacco , Lonardi Sara , Pietrantonio Filippo 
Published: January 2025

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Background:
Standard treatment for patients (pts) with localized colon cancer (CC) is surgery and adjuvant chemotherapy where indicated. Neoadjuvant strategies allow for earlier exposure to systemic therapy, potentially leading to tumor downstaging, micro-metastases eradication, improved survival, and may pave the way for non-operative management (NOM). BOT, a novel Fc-enhanced multifunctional anti-CTLA-4 antibody plus BAL, an anti-PD-1 antibody, have demonstrated activity in proficient mismatch repair (pMMR) CC pts with durable responses in metastatic CC and unprecedented rates of pathological complete response (pCR) in the localized setting.
Methods:
UNICORN is a window-of-opportunity, multicohort, umbrella platform phase II trial enrolling non-metastatic, radiologically staged rT3-4 N0-2, resectable CC pts to be treated with a short course preoperative targeted treatment according to a prespecified molecular profile assessed by immunohistochemistry and next-generation sequencing on tumor biopsy. Pts with pMMR or deficient (dMMR) tumors received intravenous (IV) BOT at 1 mg/kg on day 1 (cohorts 4 or 6) or IV BOT 1 mg/kg on day 1 and BAL 3 mg/kg on days 1 and 15 (cohorts 5 or 7, enrolled after 4 and 6) and underwent radical surgery on day 35 ± 5. Pathological response (pR), major response (pMR) and pCR rates were defined as ≤ 50%, ≤10% and 0% residual viable tumor. The primary endpoint was centrally assessed pMR rate in each cohort. According to a Fleming 1-stage design, choosing β=80% and α=5%, 14 pts were enrolled in each cohort and the treatment was judged promising if ≥5/14 pMRs were observed.
Results:
All 56 enrolled pts completed preoperative treatment and underwent surgery. Timely surgery was performed in most pts (98%), except 1 who underwent surgery with a delay < 4 weeks due to treatment-related hyperthyroidism. Among pts with pMMR disease, activity was limited for BOT monotherapy (pMR 0%, pR 43%). With BOT + BAL, pCR was 29%, pMR 36% and pR 71%. Among those with dMMR status, BOT led to pCR, pMR and pR in 29%, 36% and 64% pts, respectively. Notably, BOT + BAL led to pCR and pMR in 93% and 100% pts. Adverse events (AEs) of any grade occurred in 28/56 pts (50%), and 22 (39%) were deemed immune-related. Serious AEs occurred in 9 pts (16%) and were treatment-related in 3 pts (5%).
Conclusions:
The primary endpoint was met in all cohorts except for BOT monotherapy in pts with pMMR status. Despite limited sample size, the activity of 1 neoadjuvant cycle with BOT + BAL favorably compares to ipilimumab/nivolumab in both pMMR and dMMR subgroups. pCR rate was remarkable in pMMR and the highest ever reported in dMMR pts, paving the way to NOM studies irrespective of MMR status.
Clinical trial information: EU-CT 2022-501308-90-00
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Molecular status
n°
Treatment
pCR, n (%)
pMR, n (%)
pR, n (%)

pMMR
14
BOT
0 (0)
0 (0)
6 (43)

14
BOT/BAL
4 (29)
5 (36)
10 (71)

dMMR
14
BOT
4 (29)
5 (36)
9 (64)

14
BOT/BAL
13 (93)
14 (100)
14 (100)