Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort.

2054 Background: Patients with progressive/recurrent glioblastoma (GBM) have very poor prognosis, and novel treatments are urgently needed. Hypoxia is a prominent feature of the tumor microenvironment in GBM and has been implicated as a potential mechanism of resistance to radiation therapy, which is a key part of standard-of-care treatment for GBM. HIF-2α has been suggested as a key therapeutic target because it plays a role in stabilizing the hypoxic environment in GBM tumors. Belzutifan, a first-in-class HIF-2α, has shown efficacy in advanced renal cell carcinoma and in von Hippel-Lindau disease–related renal cell carcinoma, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas. The phase 1 LITESPARK-001 trial (NCT02974738) was designed to evaluate belzutifan across solid tumors. Here, we report results from the GBM expansion cohort of LITESPARK-001. Methods: Patients enrolled in the GBM cohort had histologically confirmed, IDH wild type GBM that is first recurrent following radiation therapy and temozolomide according to the Response Assessment in Neuro-Oncology (RANO) criteria and had a measurable contrast-enhancing lesion by MRI imaging and a Karnofsky performance scale score ≥60%. Patients received belzutifan 120 mg by mouth twice daily. End points for this cohort included objective response rate (ORR), clinical benefit rate (CBR, CR + PR + SD of any duration), and progression-free survival (PFS) per RANO criteria by investigator assessment and safety. Results: Overall, 25 patients were enrolled in the GBM cohort. Median age was 63 years (range, 35-75), and most patients were male (n = 15; 60%). Median follow-up was of 1.9 months (range, 0.7-5.1). ORR was 0% (95% CI, 0.0-13.7) and CBR was 8% (95% CI, 1.0-26.0). Median PFS was 1.4 months (95% CI, 1.1-1.8). All patients (100%) experienced ≥1 adverse event and 15 (60%) experienced a grade 3-5 adverse event. The most common adverse events were anemia (n = 16 [64%]), fatigue (n = 13 [52%]), headache (n = 8 [32%]), muscular weakness (n = 8 [32%]). Two patients (8%) died from adverse events (both disease progression). No deaths were considered related to treatment. Conclusions: Antitumor activity was not observed with belzutifan for patients with GBM who received prior radiation therapy and temozolomide. The safety profile was similar to previous studies with belzutifan. Further efforts are warranted to identify therapies for patients with glioblastoma to improve outcomes. Clinical trial information: NCT02974738 .