Study Analyzes Welireg Side Effects in Kidney Cancer

While most patients treated with Welireg (belzutifan) experienced at least one side effect, less than 10% of patients had to stop therapy, according to an analysis of four completed studies in patients with advanced clear cell renal cell carcinoma (RCC).

Results, which were presented at the 2024 Kidney Cancer Research Summit, showed that of the 576 patients included in the analysis, 99.3% had at least one all-cause side effect and 61.6% experienced at least one side effect that was grade 3 to 5 (moderate to fatal) in severity. Serious side effects occurred in 41% of patients. Side effects led to dose modifications in exactly half of patients, and this included reductions, interruptions or discontinuations. The treatment discontinuation rate due to side effects was 6.4%. Nineteen patients (3.3%) experienced an any-cause side effect that led to death.

All-grade and grade 3 to 5 treatment-related side effects were reported in 91.3% and 37.7% of patients, respectively. One death, due to multiple organ dysfunction syndrome, was reported to be related to Welireg therapy.

“This is currently the largest pooled safety dataset for a HIF-2α inhibitor we need to be familiar with,” lead study author Dr. Toni K. Choueiri, director, Lank Center for Genitourinary Oncology, co-leader, Kidney Cancer Program, senior physician, Dana-Farber Cancer Institute, Jerome and Nancy Kohlberg Chair and professor of medicine, Harvard Medical School, said in an oral presentation during the meeting. “This is a new drug, with a new mechanism of action.”

Welireg, which targets and inhibits the HIF-2α protein, was first FDA-approved in August 2021 for the treatment of patients with von Hippel-Lindau (VHL) disease-associated RCC, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors that do not immediately require surgery. It was subsequently granted FDA approval in December 2023 for those with advanced RCC who have previously received a PD-1/PD-L1 inhibitor and a VEGF inhibitor.

Because of its unique mechanism of action and a historically distinct side effect profile, Choueiri said that investigators sought to evaluate Welireg’s safety profile across four clinical trials:

• phase 1 LITESPARK-001
• phase 3 LITESPARK-005
• phase 2 LITESPARK-013
• and the VHL-associated RCC cohort in the phase 2 LITESPARK-004 study

Patients eligible to be included in the study had received at least one dose of Welireg at 120 milligrams orally once daily.

The breakdown of the 576 included patients were as follows from each trial: LITESPARK-001 (58 patients, including three patients with advanced solid tumors beyond RCC; 10.1%), LITESPARK-005 (381 patients; 66.1%), LITESPARK-013 (76 patients 13.2%), and LITESPARK-004 (61 patients; 10.6%). LITESPARK-001 and LITESPARK-004 were both open-label, single-arm studies; LITESPARK-005 was a randomized controlled trial and LITESPARK-013 was a randomized two-dose study.

Regarding baseline characteristics, the median age was 61 years (range, 19 to 90 years old) and 35.8% of patients were 65 years and older. Moreover, 76.7% of patients were male. Patients had an ECOG performance status of 0 (meaning that they could perform all their daily tasks with no assistance; 48.3%), 1 (they could independently perform most tasks; 50.0%) or 2 (capable of self-care but not work; 1.7%). Regions comprised Western Europe (39.2%), North America (38.4%) and the rest of the world (22.4%).

The most common all-grade and grade 3 or 4 side effects included anemia, which also comprised patients with decreased hemoglobin (all-grade, 84.2%; grade 3 or 4, 28.8%), fatigue (42.7%; 2.8%, respectively), nausea (24.1%; 0.9%), difficulty breathing (21.4%; 1.7%) and low levels of oxygen (16.3%; 12.2%).

More specifically, anemia led to dose interruptions in 7.1% of patients, dose reductions in 3.8%, and treatment discontinuations in 0.3% of patients. The first time to onset of any-grade anemia was 29 days (range, 1 to 834 days). For hypoxia (low oxygen), these rates were 5.4%, 6.3% and 1.4%; the time to first onset of any-grade hypoxia was 31 days (range, 1-952).

For fatigue, the rates of dose interruptions, reductions and discontinuations were 2.6%, 1.7%, and 0.2%; the time to first onset of any-grade fatigue was 42 days (range, 1-1017).

For nausea, these rates were 2.4%, 0.3% and 0.2%; the time to first onset of nausea was 43 days (range, 1 to 1,346 days). For dyspnea (difficulty breathing), these rates were 1.7%, 0.5% and 0.2%; the time to first onset of dyspnea was 57 days (range, 1 to 911 days).

For dizziness, these rates were 1.6%, 0%, and 0.2%; the median time to first onset of dizziness was 49 days (range, 1 to 974 days). There were no dose interruptions, reductions, or treatment discontinuations due to increased weight; the median time to first onset of increased weight was 111 days (range, 4 to 671 days).

Of the patients who experienced anemia or decreased hemoglobin (485 patients), 22.9% were treated with an erythropoiesis-stimulating agent (ESA; treatment to stimulate bone marrow to produce more red blood cells) alone, blood transfusions (17.5%), or both (12.8%); 31.3% received other treatment. The median time to onset of ESA use and ESA injections per patient was 85 days and five, respectively, and the median duration of ESA use was 196 days. The median time to resolution of anemia was 70 days.

For those with hypoxia (94 patients), 70.2% of patients were treated with oxygen therapy; the median time to onset of supplemental oxygen treatment was 43 days, along with a median of nine days of supplemental oxygen. The median time to resolution of hypoxia was 11 days.

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