Activity of Hypoxia-Inducible Factor-2α Antagonist in Advanced Renal Cell Carcinoma

Key Points

  • No dose-limiting toxicities were observed during dose escalation.
  • Response was observed in 14% of patients and stable disease in 52%.

In a phase I trial reported in the Journal of Clinical Oncology, Courtney et al found that a first-in-class hypoxia-inducible factor-2α (HIF-2α) antagonist (PT2385) was active in patients with previously treated advanced clear cell renal cell carcinoma (RCC).

Study Details

In the first-in-human study, 26 patients received PT2385 at doses of 100 to 1,800 mg twice daily during a dose-escalation phase and 25 received the recommended phase II dose of 800 mg twice daily during the dose-expansion phase. Patients had locally advanced or metastatic clear cell RCC that had progressed during one or more prior regimens, including a VEGF inhibitor. Patients had a median of 4 prior therapies (range = 1–7).

Responses

No dose-limiting toxicity was observed at any dose during the dose-escalation phase. Among 50 patients evaluable for efficacy, complete response was observed in 1 (2%), partial response in 6 (12%), and stable disease in 26 (52%).  At data cutoff, 8 patients remained on study, with 13 patients being on study ≥ 1 year. At median follow-up of 17.5 months, 25% of patients had a progression-free survival of > 14 months.

Adverse Events

The most common adverse events were anemia (35% grade 1 or 2, 10% grade 3), peripheral edema (37% grade 1 or 2, 2% grade 3), and fatigue (37% grade 1 or 2). No patients discontinued treatment due to adverse events. Hypoxia occurred in 18% of patients (all receiving ≥ 800 mg twice daily) and was of grade 3 in 10%.

The investigators concluded, “PT2385 has a favorable safety profile and is active in patients with heavily pretreated [clear cell RCC], validating direct HIF-2α antagonism for the treatment of patients with [clear cell RCC].”

The study was supported by Peloton Therapeutics.

Kevin D. Courtney, MD, PhD, of Simmons Comprehensive Cancer Center and Department of Medicine, University of Texas Southwestern Medical Center, is the corresponding author for the Journal of Clinical Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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