Findings Establish PT2385 as a Highly Specific HIF-2 Inhibitor for Patients with Clear Cell RCC

Findings published in Clinical Cancer Research demonstrated a core dependency on hypoxia-inducible factor 2 (HIF-2) in metastatic clear cell renal cell carcinoma (ccRCC) and established PT2385 as a highly specific HIF-2 inhibitor. 

The prospective companion substudy was based on data from a phase I clinical trial of PT2385 in patients with extensively pretreated ccRCC at UT Southwestern and elsewhere. 

“This study exposes the Achilles’ heel of ccRCC tumors,” lead author James Brugarolas, MD, PhD, professor of internal medicine (hematology/oncology) and director of the Kidney Cancer Program at UT Southwestern, said in a press release. 

Patients enrolled in the phase I clinical trial had locally advanced or metastatic ccRCC that had progressed during 1 or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3 10%), peripheral edema (grade 1-2, 37%; grade 3, 2%), and fatigue (grade 1-2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. Further, no patients discontinued the treatment due to adverse events and complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. 

In the companion study, researchers assessed a subset of 10 patients enrolled in the phase I trial at UT Southwestern who were treated at the phase II dose or above, using multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing. PT2385 was found to inhibit HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels, in all but 1 patient, who was treated with the lowest drug concentrations. 

Additionally, PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. Contrastingly, HIF-1 complexes were not affected.

Prolonged PT2385 treatment resulted in the acquisition of resistance, and researchers identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and hindered HIF-2 complex dissociation. Moreover, the researchers identified an acquired TP53 mutation in another location, indicating a potential alternate mechanism of resistance. 

Researchers suggested that their findings indicate that HIF-2α inhibitors such as PT2385 offer a novel and powerful weapon against this disease type.

“Short of a cure, which we’re still struggling to get to patients, we think this drug and other future drugs in this class could offer a durable way to fight this cancer while preserving quality of life,” first author Kevin Courtney, MD, PhD, UT Southwestern associate professor of internal medicine (hematology/oncology), said in a press release. 

Though targeted therapies have noticeably improved the prognosis for patients with ccRCC, only 8% to 11.7% of patients with metastatic disease will survive 5 years, according to the clinical trial authors. Therefore, the advent of more effective therapies is necessary. 

References:

1. Courtney KD, Ma Y, Diaz de Leon A, et al. HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma. Clinical Cancer Research. doi:10.1158/1078-0432.CCR-19-1459.

2. Clinical trial exposes deadly kidney cancer’s Achilles’ heel [news release]. Dallas, Texas. Published February 14, 2020. utsouthwestern.edu/newsroom/articles/year-2020/disabling-kidney-cancer-protein.html. Accessed February 24, 2020. 

3. Courtney KD, Infante JR, Lam ET, et al. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. Journal of Clinical Oncology. doi:10.1200/JCO.2017.74.2627.