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Belzutifan Shows Promise as a Novel Option for Advanced Renal-Cell Carcinoma

2021 Year in Review - Renal-Cell Carcinoma - Renal-Cell Carcinoma

Belzutifan, formerly known as MK-6482, is a hypoxia-inducible factor (HIF)-2α inhibitor. HIF-2α is a transcription factor that is often overexpressed in clear-cell renal-cell carcinoma (RCC), leading to constitutive activation of procarcinogenic genes. Activation of HIF-2α can be mediated by loss of the von Hippel-Lindau gene, which has been reported in approximately 90% of clear-cell RCC cases.1 In August 2021, belzutifan received approval for the treatment of adults with von Hippel-Lindau disease–associated tumors, including RCC.2

In this first-in-human phase 1 study, 43 patients with advanced solid tumors (dose-escalation cohort) and 55 patients with previously treated, advanced clear-cell RCC, including 3 patients from the dose-escalation cohort (dose-expansion cohort), were enrolled. The primary objective of the study was to identify the maximum tolerated dose and the recommended phase 2 dose of belzutifan. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity were secondary end points.1

During the dose-escalation phase of the trial, which used a 3+3 design, no dose-limiting toxicities occurred up to 160 mg once daily. The maximum tolerated dose was not reached, and the recommended phase 2 dose was 120 mg once daily. At all dose levels, reductions in plasma erythropoietin were reported, with similar rates of erythropoietin decrease across belzutifan doses of ≥120 mg.1

Among patients in the clear-cell RCC cohort, the median age was 62 years, and the median number of previous treatments was 3 (range, 0-12). Regimens received by previously treated patients included vascular endothelial growth factor inhibitors (91%), immune checkpoint inhibitors (80%), and mammalian target of rapamycin inhibitors (24%).1

The most common adverse events (AEs) with belzutifan included anemia (76%), fatigue (71%), dyspnea (49%), and nausea (36%). Grade ≥3 AEs included anemia (27%) and hypoxia (16%). Anemia was managed with exogenous erythropoietin and/or blood transfusion. Hypoxia typically improved with supplemental oxygen treatment. A total of 2 patients discontinued treatment as a result of AEs.1

In the dose-expansion RCC cohort, the objective response rate was 25% (all partial responses). An additional 54% of patients had stable disease as their best response, for a disease control rate of 80%. Duration of response was ≥6 months in 71% of responders. The median duration of response was not reached. For patients with favorable-risk and poor-/intermediate-risk RCC, the objective response rate was 31% and 24%, respectively.1

With a median follow-up of 27.7 months, median progression-free survival was 14.5 months (95% confidence interval, 7.3-not reached). In those patients with favorable-risk disease, median progression-free survival was not reached; in those with poor- or intermediate-risk disease, median progression-free survival was 11.0 months.1

The researchers concluded that belzutifan may have potential for advanced clear-cell RCC as a tolerable agent with antitumor activity. Furthermore, the researchers emphasized the unique toxicity profile of belzutifan relative to other agents used for RCC. Combination therapy with belzutifan is currently under investigation for advanced RCC in several phase 3 trials.1,3,4

References

  1. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27:802-805. Erratum in: Nat Med. 2021;27:1849.
  2. US Food and Drug Administration. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. Updated August 13, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease. Accessed November 19, 2021.
  3. ClinicalTrials.gov. A study of belzutifan (MK-6482) in combination with lenvatinib versus cabozantinib for treatment of renal cell carcinoma (MK-6482-011). Updated December 13, 2021. https://clinicaltrials.gov/ct2/show/NCT04586231. Accessed November 19, 2021.
  4. ClinicalTrials.gov. A study of pembrolizumab (MK-3475) in combination with belzutifan (MK-6482) and lenvatinib (MK-7902), or pembrolizumab/quavonlimab (MK-1308A) in combination with lenvatinib, versus pembrolizumab and lenvatinib, for treatment of advanced clear cell renal cell carcinoma (MK-6482-012). Updated December 13, 2021. https://clinicaltrials.gov/ct2/show/NCT04736706. Accessed November 19, 2021.
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