This approval of WELIREG marks the first time a new treatment has been approved in a novel therapeutic class in advanced RCC since 2015
Reno, Nevada (UroToday.com) Merck, known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved WELIREG, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).
The approval is based on statistically significant and clinically meaningful results from LITESPARK-005, which is the only trial in advanced RCC to specifically evaluate patients who have progressed following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. In the trial, WELIREG demonstrated superior progression-free survival (PFS) (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in advanced RCC following treatment with both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF receptor targeted therapy, given in sequence or in combination. Also, WELIREG showed an objective response rate (ORR) of 22% (n=82) (95% CI, 18-27) versus 4% (n=13) (95% CI, 2-6) for everolimus.
“Despite recent progress in the treatment of advanced RCC, there is yet to be an option specifically approved for patients whose disease progresses following a PD-1 or PD-L1 inhibitor and a TKI therapy,” said Dr. Toni K. Choueiri, LITESPARK-005 study chair, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg professor of medicine, Harvard Medical School. “This approval of belzutifan introduces a meaningful new treatment option for certain patients, as belzutifan reduced the risk of disease progression or death compared to everolimus.”The WELIREG label contains a boxed warning that exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective. WELIREG can cause severe anemia that can require a blood transfusion. Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of and periodically throughout treatment with WELIREG. For more information, see “Selected Safety Information” below.
“In 2021, WELIREG became the first HIF-2α inhibitor therapy approved in the U.S. for the treatment of adult patients with certain VHL disease-associated tumors and is now approved for eligible patients with advanced RCC,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “This approval of WELIREG marks the first new therapeutic class available for eligible patients with advanced RCC in nearly a decade, and was based on the statistically significant progression-free survival benefit observed in patients following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI when compared to everolimus.”Study design and additional data supporting the approval
The approval was based on data from LITESPARK-005, an open-label, randomized, active-controlled clinical trial (ClinicalTrials.gov, NCT04195750) in 746 patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. Patients could have received up to three prior treatment regimens and were required to have measurable disease per RECIST v1.1. Patients were randomized 1:1 to receive WELIREG (120 mg) (n=374) or everolimus (10 mg) (n=372) orally once daily. Randomization was stratified by the International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and the number of prior VEGF receptor targeted therapies (1 versus 2-3). Patients were evaluated radiologically at Week 9 from the date of randomization, then every 8 weeks through Week 49, and every 12 weeks thereafter.
The major efficacy endpoints were PFS as assessed by blinded independent central review (BICR) according to RECIST v1.1 and overall survival. Additional efficacy endpoints included ORR as assessed by BICR according to RECIST v1.1.
The trial demonstrated a statistically significant improvement in PFS for patients randomized to WELIREG compared with everolimus.
Among the 82 patients treated with WELIREG who achieved a confirmed response based on BICR per RECIST 1.1, 25 (30%) patients had a duration of response ≥12 months. Overall survival results were immature. At the time of the subsequent pre-specified analysis, 59% of the patients had died in the randomized population.
In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in these patients. Median PFS was 5.6 months (95% CI, 3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27), with a complete response (CR) rate of 3% (n=10) and a partial response (PR) rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13).
The median duration of exposure was 7.6 months (range, 0.1 to 28.5 months) for WELIREG. Serious adverse reactions occurred in 38% of patients who received WELIREG. Serious adverse reactions in ≥2% of patients who received WELIREG were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%) and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis and hemorrhage (0.5% each). Permanent discontinuation of WELIREG due to adverse reactions occurred in 6% of patients. Adverse reactions that resulted in permanent discontinuation of WELIREG (≥0.5%) were hypoxia (1.1%), anemia and hemorrhage (0.5% each). Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions that required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%) and hemorrhage (2.2%). Dose reductions of WELIREG due to an adverse reaction occurred in 13% of patients. Adverse reactions that required dose reduction in ≥1% of patients were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase. Clinically relevant adverse reactions in <10% of patients who received WELIREG in LITESPARK-005 included hemorrhage (9%) [including intracranial/cerebral hemorrhage (0.8%)], rash (8%), hypertension (6%), visual impairment [including vision blurred (4%), visual acuity decreased (1.1%), visual impairment (0.5%), and retinal detachment (0.3%)] (6%), and increased weight (5%).
Source: Merck, MSD. (2023 December, 15) FDA Approves Merck’s WELIREG® (Belzutifan) for the Treatment of Patients With Advanced Renal Cell Carcinoma Following a PD-1 or PD-L1 Inhibitor and a VEGF-TKI [Press Release]. https://www.merck.com/news/fda-approves-mercks-welireg-belzutifan-for-the-treatment-of-patients-with-advanced-renal-cell-carcinoma-rcc-following-a-pd-1-or-pd-l1-inhibitor-and-a-vegf-tki/