Background: High-dose interleukin-2 (IL-2) has been approved in metastatic renal cell carcinoma (RCC) and metastatic melanoma, and can result in durable complete responses, including cures. Its use has been limited by life-threatening treatment-related multisystem toxicities, consisting mainly of vascular leak syndrome. XTX202 is a masked, tumor-selective IL-2 that is designed to be pharmacologically inactive in non-tumor tissue when circulating systemically and unmasked by matrix metalloproteases (MMPs) found preferentially in the tumor microenvironment (TME). XTX202 is expected, therefore, to achieve a wider therapeutic index resulting in increased efficacy and lower toxicity compared to existing non-tumor selective IL-2 based-therapies. The IL-2 domain of the XTX202 molecule is modified to reduce binding to the high-affinity IL-2 receptor while maintaining binding to the intermediate-affinity IL-2 receptor, thereby decreasing activation of regulatory T-cells relative to wild-type IL-2, while still activating effector T cells. A masking domain is designed to pharmacologically inactivate IL-2 until it is activated by MMPs that are enriched in the TME. Cleavage at a protease cleavage site in the XTX202 linker by MMPs results in an active IL-2 moiety when the masking domain is released. XTX202 is designed with the goal of producing a localized anti-tumor immune response and limiting exposure of the active form of XTX202 in non-tumor tissue. Preclinically, XTX202 exhibited tumor-selective activity in mice without peripheral toxicities in non-human primates [O’Neil et al. ASCO 2021]. Methods: XTX202-01 trial (NCT05052268) is a first-in-human Phase 1/2 study to determine a recommended Phase 2 dose of XTX202 (Phase 1) and to evaluate the efficacy of XTX202 monotherapy in patients with metastatic RCC and unresectable or metastatic melanoma (Phase 2). Patients with advanced solid tumors are eligible for Phase 1 and will receive XTX202 monotherapy administered every 21 days in an accelerated and standard 3+3 dose escalation design. Phase 2 will consist of 2 parts: Part 2a will enroll patients with metastatic RCC who have received a prior tyrosine kinase inhibitor therapy and have been treated and progressed on an anti-PD-1 therapy. Part 2b will enroll patients with unresectable or metastatic melanoma who have received immune-checkpoint therapy with an anti-PD-1 therapy and an anti-CTLA-4 therapy to determine the efficacy of XTX202 monotherapy in this population. Enrollment to the study began in January 2022. Clinical trial information: NCT05052268.