ASCO 2023 Kidney Cancer Roundup

Cedars Cinai Cancer Center, Los Angeles, CA

Correspondence to: Email:

Dear Colleagues,

Dear Colleagues,

The journey of Belzutifan towards the goal of getting its FDA approval for patients with refractory renal cell carcinoma has reached another milestone1. The FDA has granted priority review to the supplemental new drug application (sNDA) for belzutifan. The sNDA seeks approval for the indication of patients with previously treated advanced renal cell carcinoma following immune checkpoint and anti-angiogenic therapies. The interim findings from LITESPARK-005(NCT04195750) demonstrates that the treatment with belzutifan led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with everolimus in adult patients with advanced renal cell carcinoma whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor (TKI) treatments2.

The current study results add to a growing body of early phase trial results that suggest meaningful clinical benefits from HIF2 pathway inhibition in patients with RCC. “This is not only the first new mechanism to demonstrate potential in advanced RCC in recent years but also the first phase III trial to show positive results in advanced RCC following these therapies", says Marjorie Green, MD, senior vice president at Merck Research Laboratories, in a press release1. “Patients with advanced RCC face low survival rates, and for those whose cancer progresses following PD-1/L1 and VEGF-TKI therapies, there is a need for new treatment options that can reduce their risk of disease progression or death.”

This registrational study where patients with treatment-refractory clear cell RCC were randomized between belzutifan and everolimus was conducted with the goal of obtaining approval for belzutifan in the refractory disease setting. "Based on the data on the phase 1b/2 study we conducted in patients with previously treated advanced RCC, it became clear belzutifan is an active drug3,4,” Eric Jonasch, MD, professor in the department of genitourinary medical oncology, division of cancer medicine, at The University of Texas MD Anderson Cancer Center in Houston, TX. The safety portion of the analysis showed that belzutifan’s profile was consistent with that shown in prior studies as there were no new safety signals with either treatment compared with previously reported safety outcomes with the treatments. However, the shortcoming of this study is improvement in overall survival (OS) did not reach statistical significance despite statistically significant improvement demonstrated in another secondary end point, objective response rate (ORR). OS will be tested again at a subsequent analysis.

The impact of recent LITESPARK-005 findings on securing the belzutifan's niche including how far up in the treatment algorithm it could move, remains to be seen. As expected, the investigators are already exploring whether survival outcomes with longer follow-up will confirm the promising initial clinical activity of the combination in this setting. Advanced phase trials are testing belzutifan plus lenvatinib versus cabozantinib in the treatment refractory setting [NCT04586231], and the addition of belzutifan to lenvatinib and pembrolizumab as frontline therapy [NCT04736706] are ongoing. LITESPARK-005 is 1 of 4 late-stage trials evaluating belzutifan in RCC. Similarly, we are keeping a close eye on belzutifan’s prospects as part of second-line (LITESPARK-011), treatment-naïve (LITESPARK-012) and adjuvant therapy (LITESPARK-022; belzutifan plus pembrolizumab; NCT05239728) in advanced RCC setting. Currently, there is a lot of excitement around belzutifan. It is going to be interesting to see where that agent ends up panning out in RCC. In this issue, Shapiro and colleagues critically evaluate the efficacy of cytoreductive nephrectomy and explore options for integrating CN within the contemporary systemic therapy landscape. Gessner and colleagues summarizes the biology of hERVs, their identified role in ccRCC, and and how hERVs may impact response to immunotherapy in ccRCC. In other review piece, Patel et al proposes that early integration of palliative care into routine RCC care can help improved decision making and patient outcomes.

Happy fall season 2023!


  • 1. FDA accepts for priority review Merck’s supplemental new drug application for Welireg (belzutifan) in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. September 19, 2023. Accessed September 19, 2023. news/fda-accepts-for-priority-review-merckssupplemental- new-drug-application-for-weliregbelzutifan- in-certain-previously-treated-patientswith- advanced-renal-cell-carcinoma-rcc/
  • 2. Merck announces WELIREG (belzutifan) phase-3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. August 18, 2023. Accessed September 19, 2023. welireg-belzutifan-phase-3-litespark- 005-trial-met-primary-endpoint-of-progressionfree- survival-in-certain-previously-treated-patientswith- advanced-renal-cell-carcinoma/
  • 3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials. gov. Updated August 1, 2022. Accessed August 18, 2023. NCT04195750
  • 4. Jonasch E et al. Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease N Engl J Med 2021; 385:2036-2046. DOI: 10.1056/ NEJMoa2103425.
  • 5. Choueiri T.K. et al., Phase 2 study of the oral hypoxia-inducible factor 2a (HIF-2a) inhibitor MK- 6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). J. Clin. Oncol. 2021;39:272. doi: 10.1200/ JCO.2021.39.6_suppl.272.
  • 6. A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022). Accessed Sep 17, 2023. https://classic.clinicaltrials. gov/ct2/show/NCT05239728