Welireg (belzutifan) / Merck (MSD) - LARVOL DELTA

Network meta-analysis of second- and later-line therapies in advanced renal cell carcinoma: A comparative effectiveness approach. (ASCO-GU 2026) - "Lenvatinib + everolimus (HR 0.49 vs placebo) and atezolizumab + cabozantinib (HR 0.56 vs placebo) demonstrated the greatest OS benefit. Compared with other active regimens, lenvatinib + everolimus significantly improved OS versus everolimus and temsirolimus monotherapy, ranking highest for OS (P-score = 0.88)...Lenvatinib + everolimus also ranked first for ORR (P-score = 0.94), followed by belzutifan (P-score = 0.86)... In this NMA, lenvatinib + everolimus demonstrated the greatest overall efficacy across OS, PFS, and ORR, outperforming all other therapies except telaglenastat + cabozantinib in PFS. These findings suggest lenvatinib + everolimus as the leading option for second- or later-line therapy in advanced RCC. However, results should be interpreted with caution and warrant confirmation in future large, head-to-head randomized trials."

HEOR • Metastases • Retrospective data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Application Submitted for LENVIMA (lenvatinib) in Japan Seeking Approval of Additional Dosage and Administration for Combination with WELIREG (belzutifan) for Renal Cell Carcinoma that has Progressed After Chemotherapy (Eisai Press Release) - "This application is based on the results of the Phase 3 LITESPARK-011 trial evaluating the dual regimen of LENVIMA plus WELIREG for the treatment of patients with advanced renal cell carcinoma (RCC) whose disease progressed on or after treatment with anti-programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy."

Japan filing • Renal Cell Carcinoma

SARS-CoV-2 spike S1-mediated HIF-2α activation in retinal endothelial cells suggests a mechanism contributing to post-COVID endothelial dysfunction. (PubMed, Front Immunol) - "Belzutifan was used as a pharmacologic probe to assess the role of HIF-2α signaling in S1- and plasma-associated endothelial responses...These findings identify a spike-responsive, HIF-2α-associated ED pathway in retinal endothelial cells. Modulation of this pathway altered endothelial barrier responses to both recombinant S1 and plasma from patients with PCS, highlighting a candidate mechanism that may contribute to PCS-associated vascular dysfunction."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Fatigue • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • EPAS1 • HIF1A • KDR

Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer. (PubMed, J Clin Invest) - "Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC)...Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1-STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • JAK1 • SOCS3

Ascending dose escalation of belzutifan plus palbociclib for previously treated advanced clear cell renal cell carcinoma (ccRCC): Phase 1/2 LITESPARK-024 study part 1. (ASCO-GU 2026) - P1/2 | "Bel + palbo had a manageable safety profile. Gr ≥3 TRAEs were frequent. No new safety signals occurred."

Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1

A Clinical Study of Belzutifan (MK-6482) and Zanzalintinib in People With Renal Cell Carcinoma (RCC) (LITESPARK-034/LS-034/MK-6482-034) (clinicaltrials.gov) - P3 | N=758 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. (ASCO-GU 2026) - P3 | "Adjuvant pembrolizumab plus belzutifan demonstrated a statistically significant and clinically meaningful improvement in DFS vs pembrolizumab plus placebo in pts with ccRCC at increased risk of recurrence post nephrectomy, with a safety profile consistent with the known profiles of each drug. These results support adjuvant pembrolizumab plus belzutifan as a potential new standard of care in RCC at increased risk of recurrence."

Clinical • Late-breaking abstract • P3 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. (ASCO-GU 2026) - P3 | "Bel + lenva demonstrated superior PFS and ORR vs cabo in pts with advanced ccRCC following anti–PD-(L)1 therapy. OS favored bel + lenva but did not reach statistical significance and will be tested further at final analysis. The safety profile of bel + lenva was consistent with the profiles of the individual drugs."

Clinical • Late-breaking abstract • Metastases • P3 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

Pembrolizumab plus belzutifan improves disease-free survival in high-risk kidney cancer after surgery (ecancer) - "The combination significantly improved disease-free survival compared with pembrolizumab alone, with higher two-year disease-free survival rates. Overall survival data are still maturing, but early trends favour the combination."

Video • Renal Cell Carcinoma

Hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan in von Hippel-Lindau (VHL) disease–associated neoplasms: 5-year follow-up of the phase 2 LITESPARK-004 study. (ASCO 2025) - P2 | "After 5 years of follow-up, belzutifan continues to demonstrate durable antitumor activity and a manageable safety profile, consistent with prior reports. Most pts remain on treatment after this period. Results continue to support the use of belzutifan in pts with VHL disease–related RCC, CNS HB, and pNETs who do not require immediate surgery."

P2 data • Anemia • Cerebral Hemorrhage • CNS Disorders • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Ophthalmology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

Belzutifan for advanced pancreatic neuroendocrine tumors (panNETs): Results from cohort A2 of the phase II LITESPARK-015 study (ESMO 2025) - P2 | "c Kaplan-Meier method for censored data. Conclusions Belzutifan demonstrated limited antitumor activity with manageable safety in pts with advanced panNETs."

Metastases • P2 data • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • EPAS1

LITESPARK-015: Belzutifan in advanced pheochromocytoma and paraganglioma (ESMO 2025) - P2 | "Table: 1705O PPGL N = 72 ORR, n (%) [95% CI] 19 (26.4) [16.7, 38.1] CR 0 PR 19 (26.4) SD 42 (58.3) DCR, n (%) [95% CI] 61 (84.7) [74.3, 92.1] Median DOR mo (range) NR (2.7+to 24+) 12-mo DOR rate, % 65.7 Median PFS mo (95% CI) 22 (13.8- NR) 12-mo PFS rate, % 66.2 Median OS mo (95% CI) NR (NR- NR) 24-mo OS rate, % 75.5 CR, complete response; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease Conclusions Belzutifan provided clinically meaningful antitumor activity and durable responses in pts with advanced PPGL, with manageable safety and no new safety signals. These results support the use of belzutifan for the treatment of advanced PPGL."

Metastases • Neuroendocrine Tumor • Oncology • Solid Tumor • EPAS1 • SDHB

Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. (PubMed, Ann Oncol) - P1/2 | "Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase 3 LITESPARK-012 study."

Journal • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Updated results from the phase 2 LITESPARK-003 study of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). (ASCO-GU 2025) - P2 | "With updated follow-up, belzutifan plus cabozantinib showed durable antitumor activity in both frontline and subsequent-line treatment of patients with RCC and a safety profile consistent with prior reports. These results support further investigation of a HIF-2α inhibitor in combination with a VEGFR-TKI as a treatment option for advanced ccRCC in both settings. aBased on the sum of diameter of the target lesions at baseline."

Clinical • Metastases • P2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1

Adjuvant pembrolizumab (pembro) plus belzutifan (bel) for clear cell renal cell carcinoma (ccRCC): primary and exploratory efficacy outcomes from the phase 3 LITESPARK-022 study (EAU 2026) - No abstract available

Clinical • P3 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

Phase 1b/2 KEYMAKER-U03 substudy 03C of belzutifan plus zanzalintinib or belzutifan monotherapy for recurrent clear cell renal cell carcinoma during or after anti–PD-(L)1 therapy. (ASCO-GU 2026) - P1/2 | "Background: Adjuvant pembrolizumab is a standard of care for patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence post-surgery. No hypothesis testing and no formal comparisons are planned. This study is currently enrolling."

Monotherapy • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

LITESPARK-033: A Clinical Study of Belzutifan and Zanzalintinib in People With Recurrent Kidney Cancer Following Adjuvant Therapy (MK-6482-033) (clinicaltrials.gov) - P3 | N=904 | Recruiting | Sponsor: Merck Sharp & Dohme LLC

Trial initiation date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043) (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma (ccRCC). (ASCO-GU 2025) - P1/2 | "Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Clinical Trial Registration Number: NCT04626518 Background: The phase 1/2 KEYMAKER-U03 Substudy 03B (NCT04626518) is being conducted to evaluate combination treatments for previously treated advanced ccRCC. Lenvatinib + belzutifan (arm B5) exhibited durable antitumor activity and a safety profile consistent with the individual profiles of the drugs. Results from Substudy-03B support further investigation of lenvatinib + belzutifan combination for pts with advanced RCC, as in LITESPARK-011."

Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) (clinicaltrials.gov) - P1 | N=210 | Recruiting | Sponsor: Merck Sharp & Dohme Corp. | Trial primary completion date: Apr 2020 ➔ Apr 2018

Trial primary completion date • Castration-Resistant Prostate Cancer • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

HIF-2α Inhibitor Combinations Knock Back Kidney Cancer in Two Trials. (PubMed, Cancer Discov) - "When combined with the PD-1 inhibitor pembrolizumab as an adjuvant treatment, it reduced the risk of disease recurrence by 28% and prolonged disease-free survival over pembrolizumab alone. For patients whose disease returned following immunotherapy, belzutifan and the VEGFR inhibitor lenvatinib bested the VEGFR inhibitor cabozantinib in overall response, progression-free survival, and duration of response."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: Merck Sharp & Dohme Corp. | Trial primary completion date: Apr 2018 ➔ Mar 2020

Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) (clinicaltrials.gov) - P1 | N=400 | Recruiting | Sponsor: Merck Sharp & Dohme Corp. | Active, not recruiting ➔ Recruiting | Trial completion date: Apr 2020 ➔ May 2022

Enrollment open • Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) (clinicaltrials.gov) - P1 | N=1000 | Recruiting | Sponsor: Merck Sharp & Dohme Corp. | Trial completion date: Dec 2023 ➔ May 2025 | Trial primary completion date: Jun 2021 ➔ May 2025

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) (clinicaltrials.gov) - P1 | N=210 | Recruiting | Sponsor: Merck Sharp & Dohme Corp. | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor