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

Barcelona, Spain ( The Von Hippel Lindau – Hypoxia Inducible Factor signaling axis is dysregulated in renal cell carcinoma. PT2977 is a small molecular inhibitor of HIF-2alpha, a key oncogenic driver within the VHL-HIF signaling pathway. Pre-clinical data indicates that this inhibitor blocks the association of HIF-2alpha with HIF-1beta, thus blocking the expression of genes important for cell growth and inhibiting the growth of mouse models of renal cell carcinoma.

This poster presents RCC data from a dose-escalation study designed to determine the recommended phase 2 dose of PT2977 (NCT02974738). Data from 55 patients metastatic renal cell carcinoma (RCC) treated with drug at a 120 mg dose was presented. By IMDC criteria, 3/4 of patients were an intermediate risk, and 18% were poor risk. The patients were heavily pre-treated, with a median of 3 prior treatments, most commonly VEGF/VEGFR axis targeting agents or checkpoint inhibitor immunotherapy.

ESMO 2019 prior treatments

Median progression-free survival at the time of analysis was 11 months, and the overall response rate was 24% (all partial responses). 69% of patients experienced some form of tumor shrinkage on therapy. Treatment is ongoing in a total of 29% of the original cohort. While most responses were noted by 20 weeks, at least two patients experienced marked tumor shrinkage at the 40-week timepoint.  

ESMO 2019 best response RECIST

ESMO 2019 max change from baseline

Therapy was tolerated reasonably well, and common side effects included anemia, fatigue, and dyspnea. Anemia was managed with erythropoietin supplementation. Of note, 26% of patients experienced hypoxia, which like other common side effects listed is thought to be related to on target HIF-2alpha inhibition. This resolved with oxygen supplementation and was reversible with drug cessation.  

ESMO 2019 all cause adv events

In summary, PT2977 was reasonably tolerated and resulted in partial and durable responses in a heavily treated cohort of mRCC patients. Further study of this compound in mRCC is planned in a phase 3 monotherapy trial.  

Presented by: Eric Jonasch, MD, Professor, University of Texas MD Anderson Cancer Center, Houston, Texas

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain