Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.

107 Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses <1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses <1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]