Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors

Abstract

Background: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor βγ subunits. Thus, ANV419 preferentially stimulates CD8⁺ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells.

Methods: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023).

Results: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T_1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR).

Conclusions: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors.

Trial registration number: NCT04855929.

Keywords: Immunotherapy; Natural Killer T-Cells; T-Lymphocytes.

Figure 1

Patient disposition. Q2W, once every 2 weeks; RP2D, recommended phase 2 dose.

Figure 2

Cell proliferation over time following ANV419 dosing (Safety Population). The figure depicts mean (±SE), as well as individual results for the proliferation of CD8⁺ T cells, NK cells and T_reg cells on Cycle 1 Day 4. Q3W, once every 3 weeks. *Q3W dosing. CD, cluster of differentiation; NK, natural killer; T-reg, regulatory T cells.

Figure 3

Waterfall plot depicting the best tumor change from baseline (Response Evaluable population). Q2W, once every 2 weeks.*Q3W dosing. All other doses administered Q2W. A single overall response of SD obtained <2 weeks after the first dose of ANV419 is considered NE (due to the minimum criteria for SD not being met). Two response evaluable patients who did not have the sum of target diameters (due to not all lesions being assessed) were not included. CR, complete response; CRC, colorectal cancer; CRVCA, cervical cancer; CUP, cancer of unknown primary; Cut Mel, cutaneous melanoma; HCC, hepatocellular carcinoma; HNC, head and neck cancer; NE, not evaluable; Non Cut Mel, non-cutaneous melanoma; NSCLC, non-small cell lung cancer; OesCa, esophagus carcinoma; PancCA, pancreatic carcinoma; PD, progressive disease; PR, partial response; RCC, renal cell carcinoma; SD, stable disease.