Abstract
The HIF2α antagonist PT2385 achieved responses in 14% of patients with heavily pretreated ccRCC.
Major finding: The HIF2α antagonist PT2385 achieved responses in 14% of patients with heavily pretreated ccRCC.
Clinical relevance: In a phase I trial PT2385 was well tolerated with no dose-limiting toxicities in advanced ccRCC.
Impact: HIF2α antagonism may be an effective strategy for the treatment of patients with ccRCC.
The tumor suppressor gene VHL is inactivated in the majority of patients with clear cell renal cell carcinoma (ccRCC), which results in stabilization of HIF2α and upregulation of HIF2α target genes that promote tumor growth and metastasis, including VEGFA and CCND1, suggesting the potential for therapeutic targeting of HIF2α in patients with ccRCC. In preclinical studies, the first-in-class HIF2α antagonist PT2385 reduced VEGFA expression and induced antitumor activity in VHL-deficient RCC, prompting Courtney and colleagues to investigate its safety and efficacy in heavily pretreated patients with advanced or metastatic ccRCC in a phase I dose-escalation study. A total of 51 patients were enrolled, 26 in the dose-escalation phase and 25 in the dose-expansion phase. The primary objective was to determine the maximum tolerated and/or recommended phase II dose of PT2385, and secondary objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and antitumor activity of PT2385. PT2385 was well tolerated and no dose-limiting toxicities occurred. The most common adverse events were anemia, peripheral edema, and fatigue. The recommended phase II dose was determined to be 800 mg twice daily. Of the 50 evaluable patients, 66% experienced disease control, with one patient (2%) achieving a complete response, 6 patients (12%) having partial responses, and 26 patients (52%) experiencing stable disease. A progression-free survival of more than 14 months occurred in 25% of patients. Taken together, the results of this phase I trial suggest that antagonizing HIF2α with PT2385 produces antitumor activity in patients with advanced ccRCC. Further, the favorable safety profile supports further investigation of PT2385 alone and in combination with other therapeutics.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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