Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC): NEST clinical trial update.
Authors: Hissong Erika , Jafari Mehraneh D. , Khan Sahrish , Kasi Pashtoon Murtaza , Guniganti Preethi , Ocean Allyson J. , Siolas Despina , Yeo Heather , Khan Uqba , Pigazzi Alessio , Lutfi Areeb , Chen Zhengming , Shah Manish A. , Hidalgo Manuel 
Published: January 2025

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Background:
Checkpoint inhibitors (CPI) have been transformative for localized dMMR CRC (microsatellite instability-high [MSI-H]), but not for localized pMMR CRC (microsatellite stable [MSS]). The combination of BOT, a novel Fc-enhanced multifunctional CTLA-4 antibody, and BAL, an anti-PD-1 antibody, has demonstrated significant activity in metastatic CRC. We examined this novel dual CPI therapy in patients with MSI-H and MSS localized CRC.
Methods:
This is a single arm trial of neoadjuvant BOT 75 mg/m
2
(day 1) and BAL 240 mg/m
2
every 2 weeks x2 (NEST1) or x4 (NEST2) in patients with localized CRC who were candidates for surgery. The primary endpoint was major pathologic response (MPR), defined as ≥90% pathologic tumor regression. The 95% confidence interval (CI) was computed based on exact method for binomial distribution.
Results:
NEST1 (n=12: 9 MSS / 3 MSI-H) accrued from 3/21/23 to 9/25/23 and NEST2 (n=14: 13 MSS / 1 MSI-H; 2 MSS patients had synchronous CRC) accrued from 2/15/24 to 5/6/24; 2 patients in NEST1 were not evaluable (1 with rectal cancer not resected [ypT0N0 on local excision] and 1 patient with occult lung metastasis). In total, 7 MSS CRC tumors were evaluable from NEST1 and 15 from NEST2; and 3 MSI-H tumors were evaluable from NEST1 and 1 from NEST2, leaving a final evaluable study population of 24 patients (20 MSS / 4 MSI-H) and 26 tumors (22 MSS / 4 MSI-H). The Table provides pathologic response rates across NEST1, NEST2, and MSI-H. With a median follow-up of 13.1 months (NEST1) and 4.8 months (NEST2), no patients have recurred and ctDNA testing remains negative. No grade 4 toxicities were observed and the only treatment-related grade 3 toxicity was diarrhea/colitis in 15% and fever in 4%. Treatment-related grade 2 diarrhea/colitis occurred in 8%, grade 2 fever in 15%, and grade 2 fatigue in 4% of patients. Diarrhea/colitis resolved in all cases with steroids ± anti-TNFα therapy. All patients underwent laparoscopic resection, with 1 conversion to open. No surgeries were delayed due to treatment-related adverse events. Median length of stay was 2 days (range 1-14). Translational data including pathologic evaluation of tumor infiltrate and response will be presented.
Conclusions:
Neoadjuvant BOT/BAL is safe, with no delays to surgery, and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date. The MPR and pCR rate improved with extended time to surgery.
Clinical trial information: NCT05571293
.

Pathologic response to neoadjuvant BOT/BAL in localized CRC.

Pathologic Response
NEST 1n=7 MSS tumors
NEST 2n=15 MSS tumors
MSI-H (3 NEST1, 1 NEST2)

100% (CR%, 95%CI)
1 (14%, 0.4-58%)
6* (40%, 16-68%)
3** (75%, 19-99%)

≥ 90% (MPR%, 95%CI)
2 (29%, 4-71%)
7 (47%, 21-73%)
4^ (100%, 40-100%)

≥ 50%
4 (57%)
9 (60%)
4 (100%)

Median days to Surgery (range)
29 (21-37)
57 (45-104)
46 (34-78)

*2 with carcinoma
in situ
, no tumor bed. ^MPR was in NEST1. **1 was rectal.