Non-operative management in mismatch repair deficient (dMMR) esophagogastric cancer (EGC) following immune checkpoint inhibition (ICI).

4078 Background: ICI achieves deep and durable responses in patients with dMMR and microsatellite instability-high (MSI-H) EGC, creating an opportunity for non-operative management (NOM) of localized disease. However, limited data exists regarding long-term outcomes with NOM and factors associated with ICI failure, which we evaluated in this retrospective cohort study. Methods: We identified patients with EGC managed at MSK from 2007-2025 whose tumors were dMMR by IHC or MSI-H by next generation sequencing and analyzed patient/tumor characteristics and clinical outcomes in those who received curative-intent therapy (systemic therapy and/or surgery; ICI was first introduced in 2018). Clinical complete response (cCR) was defined as the absence of disease by available clinical, radiographic, and endoscopic assessment. Results: A total of 211 patients with localized dMMR/MSI-H EGC were identified, with median follow-up of 48 months (IQR 24-77). Primary tumor sites were stomach (71%), GE junction (17%), and esophagus (12%). Among 122 patients who underwent germline testing, 15 (12%) had Lynch syndrome. Initial treatment was upfront surgery in 85 patients (40%), chemotherapy (chemo) in 68 (32%), ICI alone in 44 (21%), and chemo/ICI in 14 (7%). Among 58 patients treated with ICI +/- chemo, 27 (47%) achieved a cCR. 6 patients underwent surgery despite cCR, with pathologic complete response (pCR) rate of 4/6 (67%); pCR rate in those without cCR was 3/16 (19%), yielding an overall pCR rate of 32%, higher than the pCR rate observed with chemo alone (5/48 [10%]). 21 patients elected for NOM after cCR; among those with ≥1 year of follow-up, 16 of 17 (94%) remain alive and surgery-free at 1 year. cCR rates were similar between those receiving ICI alone (45%) and chemo/ICI (50%). Notably, 2/2 (100%) patients treated with dual ICI therapy achieved cCR. Lower cCR rates were observed in patients with shorter time on ICI therapy (5/17 [29%] with ≤3 months of ICI vs 14/30 [47%] with > 3 and < 6 months vs 8/11 [73%] with ≥6 months) and in those with clinical nodal involvement (6/17 [35%] vs 14/19 [74%] in N0); 3 patients who underwent surgery had pCR at tumor but residual nodal disease. cCR rate was also numerically lower in the 19% of patients with MMR heterogeneity, defined by focal loss of MMR proteins on IHC or discordant MMR status between tissue specimens (4/11 [36%] vs 23/47 [49%] in non-heterogeneous cases). Conclusions: In this MSK cohort, ICI induced deep responses in nearly half of patients with localized dMMR/MSI-H EGC. Patients achieving cCR who pursued NOM demonstrated excellent outcomes, with most remaining surgery-free at 1 year, supporting the viability of NOM after careful multidisciplinary review.