Phase 1/2 study of ARV-806, a PROTAC KRAS G12D degrader, in <i>KRAS</i> G12D–mutated advanced solid tumors, including pancreatic cancer.

Abstract

TPS792 Background: Mutated KRAS is a common oncogenic driver of pancreatic, colorectal, and lung cancer. There are no approved therapies that target the KRAS G12D mutation, the most common KRAS alteration in cancer cells. ARV-806, a PROteolysis TArgeting Chimera (PROTAC) KRAS G12D degrader, is a bifunctional small molecule consisting of a KRAS G12D–binding domain joined by a linker to an E3 ubiquitin ligase–binding domain. ARV-806 creates a trimer complex with KRAS G12D and an E3 ubiquitin ligase, which induces ubiquitination of KRAS G12D and its subsequent degradation by the proteasome. ARV-806 binds both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS G12D. In preclinical studies, ARV-806 demonstrated robust KRAS G12D degradation and antiproliferative activity; in pancreatic and colorectal cancer cell lines, ARV-806 showed &gt;25-fold increased potency in inhibition of cell proliferation compared with clinical KRAS inhibitors or another KRAS G12D degrader. Low intravenous doses of ARV-806 administered weekly or every 2 weeks induced robust tumor growth inhibition (including tumor regressions) in cell line–derived xenograft models of pancreatic and colorectal cancer and in a patient-derived xenograft model of lung cancer, supporting clinical investigation in these patient populations. Here, we describe a multicenter, first-in-human study (NCT07023731) to evaluate ARV-806 in patients with KRAS G12D–mutated advanced solid tumors. Methods: Patients eligible for phase 1 have an advanced solid tumor, prior standard-of-care therapy for their disease, and KRAS G12D mutation detected in tumor tissue or by circulating tumor DNA. Patients eligible for phase 2 have advanced pancreatic ductal adenocarcinoma, ≥1 prior line of systemic therapy, and KRAS G12D mutation confirmed by molecular or next-generation sequencing of tumor tissue. In both phases, patients must have Eastern Cooperative Oncology Group performance status 0/1, ≥1 measurable lesion, and no prior treatment with a KRAS G12D– or a KRAS G12C–targeting therapy, including pan-KRAS inhibitors or degraders. In phase 1, patients will receive escalating intravenous doses of ARV-806 weekly or every 2 weeks in 28-day cycles to evaluate its safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Primary endpoints of phase 1 are dose-limiting toxicities during the first cycle and adverse events to determine the maximum tolerated dose (MTD; or maximum administered dose if MTD not reached) and to select recommended phase 2 dose(s) (RP2Ds) for cohort expansion. In phase 2, patients will receive ARV-806 at one or more doses selected from phase 1 to evaluate its antitumor activity and support further RP2D optimization. Clinical trial information: NCT07023731 .