1498 Safety, tolerability and preliminary efficacy of QLP2117, a novel CCR8 antibody, in patients with advanced solid tumors: results from a dose-escalation phase 1a clinical trial

<h3>Background</h3> CCR8 is an important chemokine receptor expressed on intratumoral regulatory T cell (Tregs). Selective depletion of intratumoral Tregs by targeting CCR8 may be a promising therapeutic approach. QLP 2117 is a highly selective IgG1 antibody against CCR8 with enhanced antibody-dependent cell-mediated cytotoxicity by glycoengineering. Here we present the results of an ongoing phase 1a trial of QLP2117 in advanced solid tumors. <h3>Methods</h3> The phase 1 trial recruited patients with locally advanced, recurrent or metastatic solid tumors who have failed standard treatment. During the dose-escalation stage (1a), patients were recruited regardless of CCR8 expression level following a Bayesian optimal interval design. QLP2117 was administered via intravenous injection Q3W in eight cohorts (3 mg, 10 mg, 30 mg, 90 mg, 270 mg, 540 mg, 800 mg, 1200 mg). During the dose-expansion stage (1b) only CCR8-positive patients are recruited. The primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in dose-escalation stage, and was objective response rate in dose-expansion stage. <h3>Results</h3> As of August 18, 2024, 18 patients with solid tumors were recruited from 3 mg to 540 mg cohorts. The trial is still ongoing. DLT occurred in one patient at 540 mg dose level, which was grade 3 platelet count decreased with bleeding tendency. MTD was not reached yet. Treatment-related adverse events (TRAEs) occurred in 16 (88.9%) patients, of whom two (11.1%) were grade ≥3. TRAEs with incidence of ≥20% were aspartate aminotransferase increased (5[27.8%]), alanine aminotransferase increased (4[22.2%]), lymphocyte count decreased (4[22.2%]), hyperuricemia (4[22.2%]), and anemia (4[22.2%]). Two (11.1%) patients discontinued treatment due to TRAEs of liver dysfunction (270 mg) and platelet count decreased (540 mg), respectively. One (5.6%) patient died of hemophagocytic syndrome and platelet count decreased along with progressive disease. QLP2117 exhibited linear pharmacokinetics. CCR8+Treg in circulation decreased after QLP2117 treatment in all patients. Tumor biopsy on cycle 3 from a patient with nasopharyngeal carcinoma showed decreased CCR8 levels. As of data cut-off, six patients had stable disease (SD) per RECIST v1.1, among whom three patients showed tumor shrinkage. In five patients with at least one tumor assessment in the 540 mg cohort, disease control rate was 60%. Three patients were still receiving treatment. One patient with metastatic colorectal cancer showed SD and was still on treatment after 11 months. <h3>Conclusions</h3> QLP2117 showed manageable safety and tolerability in patients with solid tumor. The efficacy of QLP2117 warranted further exploration, particularly in combination with anti-PD-1 agents.