Livmoniplimab with or without budigalimab in patients with advanced solid tumors: Results from the combination therapy in the urothelial carcinoma dose expansion cohort.
Authors: Roda Desamparados , Machiels Jean-Pascal H. , Chiu Chang-Fang , Kondo Shunsuke , Adorno Febles Victor Ricardo , Moreno Victor , Lin Chia-Chi , Rha Sun Young Young , David Sarid , Abdul Razak Albiruni Ryan , Kao Steven Chuan-Hao , Patel Maulik , Sahtout Mohammad , Deutsch Jonathan , Ngo Duyen , Ferlini Cristiano , He Kai 
Published: January 2024

617 Background: Checkpoint inhibitors (CPIs) are approved for treating advanced urothelial carcinoma (UC). However, many patients (pts) present with/develop resistance and new therapies are urgently needed. The release of active transforming growth factor beta-1 (TGF-β1) from the glycoprotein-A repetitions predominant (GARP):TGF-β1 complex on regulatory CD4+ T cells suppresses antitumor response. Inhibiting active TGF-β1 release from the GARP:TGF-β1 complex could address CPI resistance in UC. Livmoniplimab (livmo), an antibody targeting the GARP:TGF-β1 complex, is being investigated as monotherapy and in combination with budigalimab (budi), an anti–PD-1 antibody, in a phase 1 study (NCT03821935). We present expanded results from the livmo + budi dose expansion (EXP) in pts with UC. Methods: This is a global, dose escalation (ESC) and EXP study in pts (≥18 yr) with advanced solid tumors; the UC EXP cohort enrolled pts with UC of the bladder and urinary tract that progressed on platinum-based therapy and a CPI in the metastatic setting. The maximum tolerated dose was not reached in the ESC part, and pts in EXP cohorts received the maximum administered dose of 1500 mg livmo (IV, Q2W) and 500 mg budi (IV, Q4W) until disease progression/intolerable toxicity. The primary efficacy endpoint was ORR per RECIST v1.1. Additional efficacy outcomes included DOR and PFS. Safety and PK were also assessed. Results: As of 30 Mar 2023, 200 pts were enrolled, 57 in ESC and 143 in livmo + budi EXP, including 48 pts in the UC EXP cohort. For the UC cohort, median age was 66 yr (49–85), 77% of pts were male, 40%/60% had ECOG PS 0/1, and median prior lines of therapy was 3 (1–9). Livmo PK was not impacted by budi coadministration and no on-treatment anti-drug -antibodies were detected. TEAEs were observed in 100% of pts; most common were pruritus (44%) and decreased appetite (21%). Grade 3/4 TEAEs occurred in 23 pts (48%), with anemia and malignant neoplasm progression (10% each) being the most common; 11 pts (23%) died but no death was related to livmo or budi. TRAEs were observed in 29 pts (60%)/26 pts (54%) for livmo/budi; pruritus (livmo: 33%; budi: 31%) and rash (17% for both) were most common. Among the 45 response evaluable pts, best response rate was 24% (n=11; 95% CI: 12.9, 39.5); confirmed ORR was 18%. Median restricted mean DOR was 7.9 mo (95% CI: 6.0, not reached); median/75th percentile PFS were 1.8 mo (95% CI: 1.6, 4.2)/8.0 mo (95% CI: 2.7, 14.9). Conclusions: Livmo + budi had manageable safety and promising efficacy in pts with advanced UC that progressed on platinum-based therapy and a CPI. ORR in the UC cohort (pts postprogression with platinum + CPI therapy) are comparable with ORR in CPI-naive pts with pembrolizumab (KEYNOTE-045) and nivolumab (CheckMate 275) monotherapy. A subpopulation of pts in the UC cohort had a durable response to livmo + budi. Clinical trial information: NCT03821935 .