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Novel mode of action for kidney cancer treatment

Presented by
Prof. Eric Jonasch, MD Anderson Cancer Center, Houston, USA
Conference
ESMO 2019
Prof. Eric Jonasch (MD Anderson Cancer Center, Houston, USA) presented the first-in-human phase 1/2 trial data of investigational drug PT2977 (MK-6482) for the treatment of advanced clear cell renal cell carcinoma (RCC) [1]. PT2977 has a favourable safety profile and at a median follow-up of 13 months, the clinical activity of PT2977 shows promise for the treatment of heavily pre-treated RCC.

Hypoxia-inducible factor (HIF)-2α is a key oncogenic driver in RCC attributed, in 80-90% of patients, to the underlying protein product of von Hippel-Lindau (VHL) tumour suppressor gene deficiency. PT2977 is a potent and selective small molecule HIF-2α inhibitor. The objective of the current study was to evaluate the efficacy and safety of PT2977 (recently renamed MK-6482) for the treatment of advanced clear cell RCC.

In this study, patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended phase 2 dose. Patients with advanced clear cell RCC who had received at least 1 prior therapy were enrolled in an expansion cohort at the recommended phase 2 dose of 120 mg orally once daily. A total of 55 RCC patients were treated with PT2977 120 mg (3 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 (AEs) >25% were anaemia (75%), fatigue (67%), dyspnoea (47%), nausea (33%), peripheral oedema (29%), and cough (31%). Anaemia (26%) and hypoxia (15%) were the most common grade 3 AEs and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related AE was reported in 2 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%. Remarkably, approximately half (49%) of these very heavily pre-treated patients with metastatic RCC were alive and progression-free at 1 year. 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 was 11 months (95% CI 6-17), and the 12-month progression-free survival rate was 49%.

In summary, oral PT2977 demonstrated good tolerability and had a 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.

  1. Jonasch E et al. ESMO Congress 2019. Abstract 911PD.




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