Peloton Therapeutics, Inc. announced that results from a Phase 1 study evaluating PT2385 in patients with advanced kidney cancer were published online in the Journal of Clinical Oncology (JCO).These data demonstrated PT2385, the first clinical stage antagonist of hypoxia inducible factor-2a (HIF-2a), has a favorable safety profile and is active in patients with heavily pretreated clear cell renal cell carcinoma (ccRCC), validating HIF-2a antagonism for the treatment of patients with ccRCC. HIF-2a is a transcription factor implicated in the development and progression of kidney and other cancers. The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of kidney cancer cases, leading to stabilization of HIF-2a and upregulation of the expression of genes that are important to tumor growth and metastasis. While many currently available therapies for ccRCC inhibit a single pathway, inhibition of the transcriptional activity of HIF-2a has the potential to inhibit a number of pathways that contribute to tumor growth in this disease. Peloton has succeeded in creating a series of orally-available small molecules that bind to HIF-2a and inhibit its transcription of disease-promoting genes. These include a second HIF-2a antagonist PT2977, a structurally-related compound that is more potent and affords enhanced exposure relative to PT2385. PT2977 is currently being investigated in Phase 1 clinical trials for the treatment of solid tumors and ccRCC, and in a Phase 2 clinical trial for the treatment of patients with VHL disease. This Phase 1 open-label, multi-center, dose-escalation study was designed to determine the recommended Phase 2 dose, evaluate the safety, pharmacokinetics (PK), pharmacodynamic (PD) profiles, and to assess the anti-tumor activity of PT2385. Twenty-six heavily pretreated patients with locally advanced or metastatic ccRCC and at least one prior therapy with vascular endothelial growth factor (VEGF) inhibitor were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Based on safety, PK, and PD data, 800 mg twice per day was selected as the recommended Phase 2 dose and subsequently administered to an additional 25 patients enrolled in an expansion cohort. PT2385 was well tolerated, with anemia (grade 1-2, 35%; grade 3, 10%), peripheral edema (grade 1-2, 37%; grade 3, 2%), and fatigue (grade 1-2, 37%; no grade 3), being the most common treatment-emergent adverse events. No treatment-emergent cardiovascular toxicities were reported. No patients discontinued treatment due to AEs. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, 13 patients had remained on study for at least one year. At a median follow-up of 17.5 months, 25% of patients had progression-free survival of greater than 14 months.