Welireg (belzutifan)

Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

P2, N=730, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Aug 2026 --> Mar 2027 | Trial primary completion date: Aug 2026 --> Mar 2027

P1, N=14, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=1800, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

P1/2, N=400, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting programed cell death protein 1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.

P1, N=14, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=30 --> 0 | Not yet recruiting --> Withdrawn

P3, N=249, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1, N=80, Recruiting, HiberCell, Inc. | Not yet recruiting --> Recruiting

P3, N=1653, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs...MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.

In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.

P1, N=80, Not yet recruiting, HiberCell, Inc.

P1, N=17, Completed, Merck Sharp & Dohme LLC | Recruiting --> Completed

P1, N=40, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=370, Active, not recruiting, Merck Sharp & Dohme LLC | Phase classification: P1b/2 --> P1/2

In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788.

Enrollment for this study is currently ongoing. Clinical trial information: NCT02861573.

Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required.

Surgical removal is considered the first line of therapy, although belzutifan, a HIF-2α inhibitor, is currently being tested as a potential therapy. Early screening with plasma metanephrines may assist in identifying PPGLs in patients with CCHD.

After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety.

P1/2, N=400, Recruiting, Merck Sharp & Dohme LLC | Phase classification: P1b/2 --> P1/2

Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting.

4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months).

P1b/2, N=370, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

In the LITESPARK-005 and -003 trials, the HIF-2α inhibitor looks effective in advanced clear-cell renal cell carcinoma, both as monotherapy and in combination with VEGFR tyrosine kinase inhibitors. The results favor expanding belzutifan's use beyond von Hippel-Lindau disease-associated cancers, its only current indication.

Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.

Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2α inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC.

Currently, widespread in-vitro and in-vivo research is focusing on targeting HIF with drugs that have already been approved for use by the FDA, such as belzutifan, in renal cell carcinoma...Although HIF-targeting agents have been investigated for over a decade, their use in therapy-resistant cancers remains relevant and should be explored further. In addition, the use of naturally occurring HIF inhibitors should be considered as an add-on therapy for the currently used regimens.

In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.

Promising results with the HIF-2α transcription factor inhibitor, belzutifan, alone or in combination with other agents, have been reported. Antibody drug conjugates, including enfortumab vedotin and sacituzumab govitecan, have continued to show activity in urothelial cancer with promising clinical outcomes...The combination of androgen-signaling inhibitors, docetaxel, and androgen deprivation therapy (PEACE-1, ARASENS), as well as the use of abiraterone acetate for adjuvant therapy in high-risk disease (STAMPEDE), is included. There is also growing evidence for the use of the radioligand therapy Lu-PSMA-617 in metastatic castrate resistant disease, with an established overall survival benefit in this patient population (VISION, TheraP)...Several studies using new therapies or new combinations of therapies have improved the chances of patients living longer with these cancers, especially those with advanced disease. Here, we discuss a selection of the most compelling recently published data that have changed the way these cancers are treated, as well as those that are expected to change treatment in the near future.

Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

These results further support the combination of an HIF-2α inhibitor and VEGFR-TKI as a potential treatment option for advanced ccRCC in both the first- and subsequent-line settings. Table: LBA87 Cohort 1 Cohort 2 Total (n = 50) IMDC favorable (n = 28) IMDC intermediate/poor (n =22) Total (n = 52) IMDC favorable (n = 11) IMDC intermediate/poor (n = 41) ORR, % (95% CI) 70 (55-82) 79 (59-92) 59 (36-79) 31 (19-45) 27 (6-61) 32 (18-48) Best overall response, n (%) CR 4 (8) 3 (11) 1 (5) 2 (4) 0 2 (5) PR 31 (62) 19 (68) 12 (55) 14 (27) 3 (27) 11 (27) SD 14 (28) 6 (21) 8 (36) 32 (62) 8 (73) 24 (59) PD 1 (2) 0 1 (5) 3 (6) 0 3.(7) NA 0 0 0 1 (2) 0 1 (2)

Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg QD as the preferred dose for belzutifan.

Conclusions Belzutifan was associated with a statistically significant improvement in PFS and ORR vs everolimus for pts with advanced ccRCC after immune checkpoint and anti-angiogenic therapies. The safety profile of belzutifan was consistent with prior reports with no new safety signals.