Regulatory Decision Summary for Welireg

This Supplement to a New Drug Submission (SNDS) was filed for Welireg (belzutifan) for the expanded indication of Welireg for the treatment of adult patients with advanced renal cell carcinoma following immune checkpoint inhibitors and anti-angiogenic therapies.

Upon review of the submitted data package, Health Canada authorized Welireg with the following modification to the indication: Welireg is approved 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 efficacy of belzutifan was evaluated in the Phase 3 LITESPARK-005 study (MK-6482-005) (herein referred to as Study 005) which included a total of 746 participants with advanced Renal Cell Carcinoma (RCC) who were randomly assigned in a 1:1 ratio to either 120 mg belzutifan (374 participants) or 10 mg everolimus (372 participants), once daily. All participants had received prior PD-1/L1 and VEGF/VEGF receptor-targeted therapies alone or in combination, and could have received up to 3 prior treatment regimens. Everolimus is an acceptable control arm as it was considered standard of care when this study was initiated.

There were two primary outcome measures of Study 005: Progression-free survival (PFS) per blinded independent central review (BICR) using RECIST v1.1; and overall survival (OS). Secondary outcome measures included objective response rate (ORR) and duration of response (DoR) by BICR.

Study 005 met the predefined success criterion for superiority based on PFS at interim analysis 1 (IA1). A statistically significant improvement in PFS per BICR was demonstrated for belzutifan compared to everolimus, with a hazard ratio of 0.75 (95% confidence interval [CI]: 0.63, 0.90); p-Value = 0.00077. The median PFS was 5.6 months (CI: 3.9, 7.0) in the belzutifan arm and 5.6 month (95% CI 4.8, 5.8) in the everolimus arm. At IA2, belzutifan continued to show a clinically meaningful improvement in PFS with a HR of 0.74 (95% CI: 0.63, 0.88). Multiple sensitivity analysis supported the robustness of PFS estimate in IA1 for belzutifan compared to everolimus.

The results of OS at IA1 favored belzutifan over everolimus and continued to demonstrate a benefit over everolimus at IA2, however, the OS data is immature and not statistically significant. The OS HR was 0.88 (95% CI: 0.73, 1.07; 1-sided p = 0.09941). It was noted that there was no OS detriment.

Confirmation of ORR by BICR was a key secondary endpoint. ORR in the belzutifan arm showed a clinically meaningful improvement compared to the everolimus arm at IA2. The ORR was 22.7% (95% CI: 18.6, 27.3) in the belzutifan group and 3.5% (95% CI: 1.9, 5.9) in the everolimus group at IA2.

The majority of adverse reactions associated with belzutifan were managed with supportive care and/or dose modifications and consistent with the known safety profile. Exposure adjusted incidence rates, dose modification and discontinuation rates were lower for belzutifan compared to everolimus, supporting a more favourable safety profile for belzutifan.

The most common (≥10%) treatment-emergent adverse events (TEAEs) more frequently observed in the belzutifan arm compared to everolimus were anemia, fatigue, musculoskeletal pain, nausea, constipation, vomiting, abdominal pain, hypoxia, headache and dizziness. Less common clinically significant AEs associated with belzutifan were vision impairment and weight increased. Grade ≥3 TEAEs (≥2%) observed with belzutifan were anemia (33%), hypoxia (11%), fatigue (3%), musculoskeletal pain (2%), dyspnea (2%), hemorrhage (3%) and COVID-19 (2%).

Serious adverse events were reported in 42% of participants treated with belzutifan. The most common SAEs (≥2% incidence) were hypoxia (8%), anemia (5%) and hemorrhage (3%). Adverse reactions leading to permanent discontinuation were reported in 6% and 15% of participants in the belzutifan and everolimus arm. The most common adverse reactions leading to drug discontinuation in the belzutifan arm was hypoxia (1%). TEAEs leading to dose modifications and dose reductions were reported in 44% vs. 14% of participants in the belzutifan arm vs the everolimus arm. The most common TEAEs leading to dose modifications (≥2%) were anemia, hypoxia, fatigue, diarrhea, hemorrhage, dizziness, dyspnea and pleural effusion.

Differences in the tolerability profile between the geriatric and younger population were labelled in the product monograph (PM). Risks of higher belzutifan exposure due to UGT2B17 or dual UGT2B17 and CYP2C19 poor metaboliser phenotypes, which occurred most commonly in the Asian population, were mitigated by recommending close monitoring in these populations.

Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine and non-routine pharmacovigilance activities, including two safety studies to address the concern of: 1) Anemia due to decreased erythropoietin, Hypoxia and Long-term safety; and 2) Moderate or severe hepatic impairment. The RMP is acceptable.

The effect of food on the pharmacokinetics of belzutifan was not considered clinically significant. Comparative bioavailability data was reviewed and demonstrated that a high-fat, high-calorie meal did not have significant impact on the rate and extent of exposure of belzutifan in the commercial formulation of Welireg.

The final labelling and Product Monograph dated December 05, 2024 were considered acceptable.

The results support the use of Welireg as a second line treatment option for patients who have been previously treated with a VEGF-TKI in combination with immune checkpoint inhibitor (PFD1 or PDL1).

Overall, the benefit-harm-uncertainty profile was favorable for Welireg 40 mg tablet for the recommended indication when used under the conditions of use recommended in the approved Product Monograph. A Notice of Compliance (NOC) is recommended.

For further details about Welireg, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.