Deficient mismatch repair (dMMR)/microsatellite instability-high (MSIH) colorectal cancer is resistant to conventional chemotherapy but responds to immune checkpoint inhibition (ICI). We review the standard of care in locally advanced dMMR rectal cancer with a focus on ICI. We also present a case report to highlight the treatment complexities and unique challenges of this novel treatment approach. ICI can lead to immune related adverse events (irAEs), resulting in early treatment discontinuation as well as new challenges to surveillance and surgical management. Overall, neoadjuvant ICI can lead to robust treatment responses, but its impact on durable response and organ preservation requires further study.

604 Background: The addition of pembro to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rate and recurrence-free survival in stage II/III TNBC, albeit with substantial chemotherapy-attributed toxicity. We hypothesize that locoregional cytokine therapy could be combined with pembro to optimize immune response and clinical outcome. In a phase Ib early-stage breast cancer trial, we previously demonstrated that peri-lymphatic cytokine injection (IRX-2 regimen, comprised of physiologic doses of IL-2, IFNg, and other cytokines derived from activated donor lymphocytes, given with low-dose cyclophosphamide) is well tolerated and associated with increased intratumoral lymphocytes, T-cell activation, and PD-L1 expression. Here, we report preliminary outcomes of neoIRX, a phase II trial evaluating induction IRX-2 + pembro preceding NACT + pembro. Methods: Subjects with stage II/III TNBC were randomized to receive induction pembrolizumab (all subjects: 200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of NACT + pembro. The primary endpoint was pCR rate following NACT + pembro (n = 15 subjects/arm planned); secondary endpoints were safety and tolerability. We explored post-induction/pre-NACT radiographic (ultrasound) and histologic outcomes (TILs, tumor regression) as a biomarker strategy to predict pCR. Results: The trial terminated after n = 12 subjects due to withdrawal of drug support for IRX-2. The IRX-2 arm achieved 83% pCR (n = 5/6, CI 36-100%) compared to 33% pCR with pembro alone (n = 2/6, CI 4-78%). The regimen was well-tolerated with minimal IRX-2-attributed toxicities (67% grade I skin bruise). Toxicities during NACT + pembro were similar to Keynote-522. 67% (n = 4/6) of IRX-2 subjects experienced week 3 radiographic regression, with evidence of brisk lymphocyte infiltration on week 3 biopsy, and with 100% pCR rate (n = 4/4) following NACT + pembro. n = 2/6 subjects receiving pembro+IRX-2 experienced pCR on week 3 biopsy, versus n = 0/3 evaluable in control arm. Conclusions: Induction IRX-2 + pembro is well tolerated and is associated with encouraging outcomes, supporting further study of peri-lymphatic induction cytokine therapy in stage II/III TBNC. Post-induction radiographic and histologic outcomes may identify patients with immune-responsive tumors, for whom NACT de-escalation may be a promising therapeutic approach to mitigate toxicity. Clinical trial information: NCT04373031 .