529 Phase 1 study of INCB086550, an oral PD-L1 inhibitor, in immune-checkpoint naive patients with advanced solid tumors

Abstract

<h3>Background</h3> INCB086550 is an orally administered small molecule that binds PD-L1 and inhibits PD-1/PD-L1 interaction. Translational data demonstrating markers of immune activation in patients following INCB086550 were previously reported.¹ Preliminary clinical data from this phase 1 study are presented below. <h3>Methods</h3> Adult patients (≥18 years) with advanced solid tumors were enrolled into this open-label study. Patients had disease progression after standard available therapy or were intolerant of or ineligible for standard treatment. Measurable disease was required. A modified 3+3 dose-escalation design was employed, followed by dose expansions. The primary endpoints were safety and tolerability of INCB086550, identification of a pharmacologically active dose and/or MTD, and confirmation of the RP2D. Secondary endpoints included PK, pharmacodynamics, and efficacy as assessed by investigator-determined ORR and DCR (CR, PR, or SD ≥12 weeks). <h3>Results</h3> As of 9Apr2021, 79 patients received treatment (<b>Table 1</b>); 57.0% were female, 62.0% had ≥2 prior lines of therapy, and 16% received prior IO treatment. Forty-six (58.2%) patients had treatment-related TEAEs; those occurring in ≥5% of patients are presented in <b>Table 2</b>. Ten patients (12.7%) had grade ≥3 treatment-related TEAEs. Immune-related TEAEs occurred in 15 patients (19.0%); the most common (&gt;1 patient) included peripheral sensory neuropathy (n=5), pruritus (n=3), immune-mediated neuropathy (n=2), and peripheral motor neuropathy (n=2). In total, 10 (12.7%) patients had TEAEs of peripheral neuropathy; all were grade ≤3. All grade 2 or 3 TEAEs of peripheral neuropathy resolved or improved with either study drug continuation without dose modification, dose reduction, or drug interruption/discontinuation. Patients with TEAEs leading to treatment interruption were 21 (26.6%), dose reduction 5 (6.3%), and discontinuation 13 (16.5%). Five patients (6.3%) died of a TEAE (cerebrovascular accident, dyspnea, general physical health deterioration, intestinal obstruction, intracranial hemorrhage [each n=1]); all fatal TEAEs were considered unrelated to study drug. The efficacy-evaluable population included 68 patients; ORR was 11.8% (95%CI, 5.2%–21.9%; CR, 1.5%; PR, 10.3%), and DCR was 19.1% (95%CI, 10.6%–30.5%; <b>Table 3</b>). Eight objective responses were observed at doses ≥400 mg BID (<b>Table 4</b>); 3 of these were noted among the 5 IO treatment-naive patients with MSI-H tumors who received 400 mg BID. <h3>Conclusions</h3> Immune-related AEs observed in this ongoing phase 1 study are consistent with those seen with antibody immune checkpoint inhibitors, with the exception of peripheral neuropathy. Preliminary efficacy of INCB086550 in tumor types known to be responsive to anti-PD-(L)1 therapy is encouraging and warrants further investigation. <h3>Trial Registration</h3> Clinicaltrials. gov identifier NCT03762447 <h3>References</h3> Piha-Paul S, et al. J Immunother Cancer. 2020;8(suppl 3):A255. <h3>Ethics Approval</h3> The study protocol was approved by institutional review boards (IRB) or independent ethics committees at participating centers. All study participants gave informed consent before taking part. The approval numbers were: Integ Review IRB (Austin, TX), RM 598; MD Anderson Cancer Center Office of Human Subject Protection (Houston, TX), IRB ID 2018-0765; ADVARRA (Columbia, MD), IRB# 00000971; Ethisch Comité/Comité d’ Ethique Hospital (Brussels, Belgium), A2021/085; Hôpital Saint-Louis (Paris, France), Prof Le Tourneau – 2020-118/Ref. of the Promoter 0.09.22.72214; NHS Health Research Authority London - City &amp; East Research Ethics Committee (Bristol, UK), IRAS project ID:282291/REC reference: 20/LO/1001; Comitato Etico IRCCS Pascale (Milan, Italy), ISS Validation Protocol Number 29111(2020)-PRE21-1835; Comitato Etico Della Fondazione IRCCS ”Istituto Nazionale Dei Tumori”- Milano CE150053 (Milan, Italy), INT 230/20; Comitato Etico Regione Toscana - Area Vasta Sud Est CE150047, 18064; Comitato Etico Indipendente Istituto Clinico Humanitas CE150081, 940/20; Regulatory Pharma Net (Pisa, Italy), IEC 1393.