EMITT-1: Clinical and pharmacodynamic activity with the oral ERAP1 inhibitor GRWD5769 and cemiplimab in 6 completed phase 1b expansion cohorts in solid tumors with anti–PD-1 resistance or MSS-CRC.

2500 Background: Resistance to anti-PD-1 therapy remains a major unmet need. GRWD5769 is a first-in-class oral Endoplasmic Reticulum Amino Peptidase 1 inhibitor (ERAP1i) that modulates tumor antigen presentation on MHC-I. Dosing GRWD5769 Q3W on/off generates 2 alternating antigen repertoires (AgR) that could both broaden T cell responses and avoid T cell exhaustion from chronic tumor antigen exposure. We report clinical and translational results from 6 completed stage 1 expansion cohorts of combination GRWD5769 with cemiplimab in patients (pts) with secondary resistance to anti-PD1 and in MSS-CRC (NCT06923761). Methods: Pts with NSCLC, Urothelial (UC), HCC, Cervical & SCCHN with secondary resistance to ≥3 month 1 st line aPD-1 or MSS-CRC without liver mets received 400 mg BD GRWD5769 and cemiplimab. ORR, Durable Clinical Benefit (DCB; defined as CR, PR or SD lasting ≥6 months) and PFS were assessed. T cell repertoire and immune phenotype changes were evaluated longitudinally. Results: All 6 cohorts are fully recruited (n= 81) with median follow up of 6.0 months at this interim analysis. Durable responses were observed in all cohorts (Table 1) with ORR 10-33%; DCB 26-57%. Median PFS ranged from 1.9-7.5 months across evaluable cohorts. Therapy was well tolerated with no observed safety signals. imARs were reported in 12 pts, with only 1 ≥Gr3 event (immune hepatitis) which required drug discontinuation. ≥Gr3 TRAEs occurred in 3% of pts. TCR repertoire diversity increased substantially in pts who achieved clinical benefit, driven by expansion of low-frequency, putative de novo TCR clonotypes. Responders exhibited cyclical Vß gene-usage dynamics indicative of broad T cell clonal expansion and contraction, consistent with AgR shifts resulting from ERAP1i. Dynamic activation of T cell associated genes further supported antigen-driven T-cell remodelling. Conclusions: GRWD5769 with cemiplimab demonstrated broad, durable activity across all 6 phase 1b expansion cohorts in pts with ≥2 prior lines of therapy and secondary anti-PD-1 resistance, or MSS-CRC. Translational analyses suggest that GRWD5769 exerts a dual mechanism of action, both reprogramming antigen-experienced T cells and inducing de novo T cell responses, in keeping with its potential to address both primary and secondary resistance to anti-PD-1 therapy. Based on the efficacy and tolerability of the combination, stage 2 cohort expansions are now ongoing, to inform a randomized Phase 2 study. Clinical trial information: NCT06923761 . Summary of expansion cohort efficacy by iRECIST. Dosed n Evaluable* n ORR%confirmed ORR%unconfirmed DCB % PFS m NSCLC 14 14 14 21 54 7.5 UC 14 12 25 33 44 2.1 HCC 15 14 14 14 32 3.9 MSS-CRC 12 7 29 29 57 2.1 SCCHN 11 7 14 14 26 3.7 Cervix 15 10 10 10 - 1.9 Data snapshot Jan 26, update for presentation. *≥1 scan or PD or death before 1st scan.