ESMO 2019: A First-in-Human Phase 1/2 Trial of the Oral HIF-2a Inhibitor PT2977 in Patients with Advanced RCC

Barcelona, Spain (UroToday.com) Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in renal cell carcinoma (RCC) attributed, in 80-90% of patients, to the underlying protein product of von Hippel-Lindau tumor suppressor gene deficiency.1 VHL gene inactivation leads to accumulation of HIF-2α, which heterodimerizes with HIF-1β and activates the transcription of genes associated with tumor progression, such as VEGFA, CCND1, CXCR4, and TGFA2.1 PT2977 is a potent and selective small molecule HIF-2α inhibitor that prevents HIF-2α from heterodimerizing with HIF-1β, blocking the expression of HIF-2α target genes in tumour cells, and inducing regressions in mouse xenograft RCC models. The objective of the current study was to evaluate the efficacy and safety of PT2977 (MK-6482) for the treatment of advanced clear cell RCC, presented at ESMO 2019 by Dr. Eric Jonasch and colleagues.

In this study, patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended phase II dose. Patients with advanced clear cell RCC who had received at least one prior therapy were enrolled in an expansion cohort at the recommended phase II dose of 120 mg orally once daily.

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There were 55 patients treated with PT2977 120 mg (three in dose escalation; 52 in expansion). The median number of prior therapies was 3 (range 1-9), 73% of patients were intermediate risk and 18% were poor risk by IMDC criteria. As of May 15, 2019, the most common all-grade, all-cause adverse events > 25% were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), peripheral edema (29%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common Grade 3 adverse events and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related adverse event (AE) was reported in two patients (4%). There were 13 patients (24%) who experienced a confirmed partial response and 31 patients (56%) had stable disease, with a clinical benefit rate of 80%. The median duration of response was not reached and 81.4% of patients experienced response >= 6 months; 16 (29%) of patients continued treatment beyond 12 months. The median progression-free survival (PFS) was 11 months (95% CI 6-17), and the 12-month PFS rate was 49%.

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Dr. Jonasch’s concluding remarks from this phase I/II trial are as follows:

  • PT2977 is well tolerated and has a favorable safety profile – anemia and hypoxia are on-target toxicities
  • After a median follow-up of 13 months, the clinical activity of PT2977 shows promise for the treatment of heavily pretreated RCC – confirmed response rate of 24%, with 81.4% of patients with response >=6 months
  • A PT2977 monotherapy Phase 3 trial in previously treated advanced RCC patients is planned
Clinical trial identification

NCT02974738.

Presented by: Eric Jonasch, MD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

References:
1. Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear cell renal cell carcinoma. Nat Genet 2013 Aug;45(8):860-867.

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