Welireg (belzutifan) significantly improved progression-free survival and objective response rates versus everolimus in certain previously treated patients with advanced renal cell carcinoma. - Merck Inc.

In the study, Welireg demonstrated a statistically significant improvement in one of the trial’s dual primary endpoints of progression-free survival (PFS) and in a key secondary endpoint of objective response rate (ORR) compared to everolimus. These late-breaking data are being presented for the first time during a proffered paper session at the European Society for Medical Oncology (ESMO) Congress 2023 (abstract #LBA88) and are also being discussed with regulatory authorities worldwide.

At the first pre-specified interim analysis (IA1) at a median follow-up of 18.4 months (range, 9.4-31.7), Welireg significantly reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p<0.001) versus everolimus in these patients. results at the second pre-specified interim analysis (ia2) were consistent with ia1. at a median follow-up of 25.7 months (range, 16.8-39.1), welireg reduced the risk of disease progression or death by 26% (hr="0.74" [95% ci, 0.63-0.88]) versus everolimus.></0.001)>

Treatment with Welireg was also associated with a statistically significant improvement in ORR at IA1; the ORR was 21.9% (95% CI, 17.8-26.5), with a complete response (CR) rate of 2.7%, for patients who received Welireg versus an ORR of 3.5% (95% CI, 1.9-5.9), with no patients achieving a CR rate, for patients who received everolimus (p<0.00001). at ia2, the orr was 22.7% (95% ci, 18.6-27.3), with a cr rate of 3.5% for patients who received welireg versus a 3.5% orr (95% ci, 1.9-5.9), with no patients achieving a cr rate, for patients who received everolimus.></0.00001).>

Additionally, overall survival (OS), the trial’s dual primary endpoint, favored Welireg versus everolimus (HR=0.87 [95% CI, 0.71-1.07]; p=0.096) and (HR=0.88 [95% CI, 0.73-1.07]; p=0.099) at IA1 and IA2, respectively; however, this result did not reach statistical significance.

“There are limited treatment options for patients with advanced RCC whose cancer progresses after both immune checkpoint and anti-angiogenic therapies,” said Professor Laurence Albiges, chair, Gustave Roussy Cancer Medicine Department and study investigator for LITESPARK-005. “Therefore, it is an important step forward to see that in this study, belzutifan demonstrated a statistically significant reduction in the risk of disease progression or death, and an improvement in overall response rate compared to everolimus for these patients who urgently need additional treatment options after their disease progresses.”

“These are the first positive Phase III data in patients with advanced RCC following both immune checkpoint and anti-angiogenic therapies, and the first Phase III data to readout from the Welireg clinical program,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “This latest research demonstrates that Welireg has the potential to improve outcomes for these patients and reinforces Merck’s commitment to advance research for patients with difficult-to-treat cancers through our robust clinical development program evaluating multiple novel mechanisms, including Welireg.”

Additional data from the LITESPARK clinical development program being presented at the ESMO Congress 2023 include Phase II results from the LITESPARK-003 (#LBA87) and LITESPARK-013 (#1881O) trials evaluating Welireg in advanced RCC. As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2023, in addition to a Merck-sponsored study evaluating the impact of Von-Hippel Lindau (VHL) disease-associated tumor treatment on mental health (#83P).

“Belzutifan is a HIF-2alfa inhibitor, a first-in-class anti-cancer therapy that has shown strong early clinical results in renal cell carcinoma,” 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. “For patients with advanced RCC, these results from LITESPARK-005 marks a first step in helping to address the unmet medical need for additional treatment options for adult patients with advanced RCC following both prior VEGFR and PD-1/L1 targeted therapies, and we look forward to further findings across the first-line, second-line and adjuvant settings of RCC, as part of the broader LITESPARK clinical development program.”

Welireg is a first-in-class, HIF-2alfa inhibitor therapy approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery based on data from the Phase II LITESPARK-004 trial. Additional applications are currently under regulatory agency review worldwide based on LITESPARK-004.

LITESPARK-005 is part of a comprehensive development program for Welireg, comprised of four Phase III trials in RCC, including LITESPARK-011 and LITESPARK-012, evaluating WELIREG in the second-line and treatment-naïve advanced disease settings, and LITESPARK-022, evaluating WELIREG in the adjuvant setting.

Merck previously announced that based on these positive results from LITESPARK-005, the FDA has granted priority review for a supplemental new drug application (sNDA) for Welireg for the treatment of adult patients with advanced RCC following immune checkpoint and anti-angiogenic therapies. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of January 17, 2024.

Study design and additional data from LITESPARK-005 :LITESPARK-005 is a randomized, open-label Phase III trial (ClinicalTrials.gov, NCT04195750) evaluating Welireg compared to everolimus for the treatment of patients with advanced clear cell RCC that has progressed after prior treatment with PD-1/L1 and VEGF-TKI therapies, in sequence or in combination. The dual primary endpoints are PFS and OS. Secondary endpoints include ORR, duration of response and safety. The trial enrolled 746 patients who were randomized to receive WELIREG (120 mg orally once daily) or everolimus (10 mg orally once daily). Results at IA1 showed that among patients who received Welireg, median PFS was 5.6 months (95% CI, 3.9-7.0) versus 5.6 months (95% CI, 4.8-5.8) among patients who received everolimus. At IA2, for patients who received Welireg, median PFS was 5.6 months (95% CI, 3.8-6.5) versus 5.6 months (95% CI, 4.8-5.8) for patients who received everolimus. The estimated 12-month PFS rate was 33.7% for patients who received Welireg versus 17.6% for patients who received everolimus, and the estimated 18-month PFS rate was 22.5% for patients who received Welireg versus 9.0% for patients who received everolimus. At IA1, median OS was 21.0 months (95% CI, 17.2-24.3) for patients who received Welireg versus 17.2 months (95% CI, 15.3-19.0) for patients who received everolimus. At IA2 median OS was 21.4 months (95% CI, 18.2-24.3) for patients who received WElireg versus 18.1 months (95% CI, 15.8-21.8) for patients who received everolimus. Overall survival will be tested at a subsequent analysis.

The safety profile of Welireg in this study was consistent with previously reported studies; no new safety concerns were identified. Treatment-related adverse events (TRAEs) occurred in 89% of patients who received Welireg (n=331) versus 89.4% of patients who received everolimus (n=322). Grade greater than 3 TRAEs occurred in 38.7% of patients who received Welireg versus 39.4% of patients who received everolimus. Adverse events led to discontinuation of study treatment in 5.9% of patients who received Welireg and 14.7% who received everolimus. Treatment-related adverse events led to death in 0.3% of patients who received Welireg (n=1) and 0.6% of patients who received everolimus (n=2).

The most common all-cause adverse events (occurring in greater than 10% of patients) in the Welireg arm were anemia (82.8%), fatigue (31.5%), nausea (18.0%), constipation (16.7%), peripheral edema (16.1%), dyspnea (15.1%), back pain (14.8%), asthenia, decreased appetite, arthralgia and hypoxia (14.5% each), vomiting (12.9%), dizziness (12.4%), headache and increased alanine aminotransferase (12.1% each), diarrhea (11.8%) and increased aspartate aminotransferase (11.6%).