Incidence of symptomatic hypoxia in a high-altitude cohort of patients with renal cell carcinoma (RCC) treated with belzutifan.

488 Background: Hypoxia-Inducible Factor (HIF-2α) is a transcription factor that allows for adaptation to environments with decreased oxygen availability. It is also dysregulated in RCC. The FDA has recently approved belzutifan, a HIF-2α inhibitor, for the treatment of metastatic RCC (mRCC) following the results of the LITESPARK-005 trial (NCT04195750). However, oxygen availability decreases with altitude, and it’s estimated that 943 million people worldwide live above 1000 meters in elevation. The effect of altitude on belzutifan treatment has not yet been reported. Here, for the first time, we present detailed safety data on a high-altitude cohort of patients with mRCC treated with belzutifan. Methods: In this IRB approved retrospective study, the inclusion criteria were diagnosis of mRCC and treatment with belzutifan. Patients with germline VHL syndrome were excluded. An SpO 2 of <92% was defined as grade 1 hypoxia (in accordance with LITESPARK-005) and all other adverse events were graded according to CTCAE version 5. Patient residential altitude was estimated using US Geologic Survey (usgs.gov) data. Results: Overall, 34 sequential patients with mRCC met eligibility criteria and were included in the analysis. 31 (91%) were male, 28 (82%) were White, 22 (65%) were never smokers, and 22 (65%) had lung metastases at baseline. 3 (10%) were concomitantly treated with a tyrosine kinase inhibitor, and 5 (17%) started at a dose of 200 mg. All had an ECOG of ≤1 and were not on supplemental O 2 prior to start of therapy. The average residential altitude of this cohort was 1457 m (range: 1288 - 1945). Overall, 30 (88%) experienced grade ≥1 hypoxia, with grade 3 being the most common experienced by 16 (47%) patients. At-home supplemental O 2 was required by 28 (82%) and was prescribed at a median of 55.5 days (IQR: 29.3 - 106.5) after starting belzutifan. Grade ≥2 anemia was seen in 27 (79%) patients. Conclusions: The high incidence of hypoxia and use of supplemental oxygen among our high-altitude patient population is in stark contrast to what was expected based on the LITESPARK-005 trial data. In that trial, the rate of hypoxia of any grade was only 14.5% with 10.2% needing supplemental O 2 . By comparing the LITESPARK-005 patient enrollment numbers to the altitude of their recruiting institutions, we can estimate that the weighted average altitude of the patient’s trial site was 201 m, which is much lower than our institutional cohorts' altitude. Upon external validation, these findings may support future guidelines on closer monitoring and earlier intervention for patients with mRCC receiving belzutifan who reside at high altitudes. Observed adverse events seen in patients with mRCC treated with belzutifan. Hypoxia (n) Anemia (n) Grade 1 2 7 Grade 2 10 14 Grade 3 16 13 Grade 4 2 0