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.
Year: 2026
Type: conference-abstract
Abstract: 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.
Source: Journal of Clinical Oncology
Authors: Fiona Thistlethwaite, Desamparados Roda, Eduardo Castanon Alvarez, Victor Moreno, Tatiana Hernandez Guerrero, Javier García-Corbacho, Jia Liu, Vikram Kumar Jain, Emiliano Calvo, Iphigenie Korakis, Kaïssa Ouali, Thibault De La Motte Rouge, Ruth Plummer, Christian H.H. Ottensmeier, Philippe Alexandre Cassier, Stefan N. Symeonides, Natalie Hyland, Cheryl McAlpine, Tanya Palmer, Thomas Lillie
Institutions: University of Manchester, The Christie NHS Foundation Trust, Universitat de València, Instituto de Salud Carlos III, INCLIVA Health Research Institute, Centro de Investigación Biomédica en Red de Cáncer, Clinica Universidad de Navarra, Hospital Universitario Fundación Jiménez Díaz, Delfos Hospital, Hospital Clínico Universitario Virgen de la Victoria, St Vincent's Hospital Sydney, The Kinghorn Cancer Centre, Mater Adult Hospital, Hospital Universitario HM Sanchinarro, Institut universitaire du cancer de Toulouse Oncopole, Institut Claudius Regaud, Institut Gustave Roussy, Centre Eugène Marquis, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Sir Bobby Robson Foundation, Newcastle University, Clatterbridge Cancer Centre NHS Foundation Trust, Centre Léon Bérard, Edinburgh Cancer Research, University of Edinburgh, Grey Wolf Therapeutics Limited (United Kingdom)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7162508407