Novel mode of action for kidney cancer treatment

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.

Posted on 26 November 201918 March 2021