(UroToday.com) The 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 13th and 15th 2025, was host to the Poster Session C: Renal Cell Cancer; Adrenal, Penile, Testicular and Urethral Cancers. Dr. Marston Linehan presented Abstract 469: Exploring the efficacy of belzutifan in the treatment of renal cell carcinoma associated with von Hippel-Lindau disease: A comparative analysis with external control arm.
Dr. Linehan began his poster presentation by highlighting that LITESPARK-004 (LS-004) is a phase 2, single-arm trial evaluating the first-in-class hypoxia-inducible factor 2α (HIF-2α) inhibitor, belzutifan, in patients with von Hippel-Lindau (VHL) disease (NCT03401788). This trial demonstrated an objective response rate (ORR) of 64.0% (95% CI, 50.6-75.8) in patients with VHL disease-associated renal cell carcinoma (VHL-RCC) after a median follow-up of 37.8 months. Among the 61 enrolled patients, 7 (12%) underwent renal surgery, including 4 patients while on treatment. Median time to surgery (TTS) was not reached in LS-004. (1) Notably, belzutifan has been granted FDA approval for VHL-RCC based on the results of the LS-005 trial. (2)
The investigators performed A VHL RCC natural history study to benchmark LS-004 using comparable study end points. In the absence of randomization, an external control arm (ECA) analysis using natural history study data to provide a comparator for the evaluation of drug effectiveness.
The objectives of the study were to develop an external control arm using real-world clinical outcomes from patients with von Hippel-Lindau renal cell carcinoma (VHL-RCC) and to compare key clinical outcomes, including the overall response rate (ORR) and time to surgery (TTS), between the natural history study cohort and the LS-004 trial.
The external comparator arm was derived from a natural history study of von Hippel-Lindau renal cell carcinoma (VHL-RCC) patients evaluated at the U.S. National Cancer Institute from 2004 to 2020, including those with renal tumors ≥10 mm. RECIST-based outcomes were assessed in patients with a baseline and at least two follow-up scans to confirm response, while surgery was evaluated using electronic medical records. The natural history cohort included up to five years of follow-up. LS-004 (LITESPARK-004; NCT03401788) was a phase 2, single-arm clinical trial that enrolled 61 patients with VHL-RCC and other tumors, with a median follow-up of 37.8 months used for analysis.
Natural history study participants meeting key inclusion and exclusion criteria were selected to closely match those in LS-004. Propensity scores (PS) were developed using a logistic regression model incorporating baseline prognostic factors such as age, sex, VHL disease mutation/deletion, number of target tumors, largest tumor size, prior renal surgery, and days before the index date. Inverse probability of treatment weighting (IPTW) with the average treatment effect among the treated (ATT) was the primary method for PS adjustment, with PS matching as a supplemental approach. Baseline balance was assessed using the absolute standardized mean difference (SMD), with a threshold of ≤0.1 indicating good balance
After applying key LS-004 eligibility criteria, 244 patients were included in the external comparator arm, with 178 having three or more scans for the objective response rate (ORR) analysis. Prognostic factors and baseline characteristics were well balanced between the external comparator arm and LS-004 after propensity score weighting. For the ORR analysis, absolute standardized mean differences (SMD) were ≤0.06 across all baseline covariates, while for the time to surgery (TTS) analysis, all covariates had an SMD <0.1. The propensity score-adjusted absolute SMD was ≤0.03 across all covariates.
A large difference in treatment effect was observed for the propensity score (PS)-weighted objective response rate (ORR). In the LS-004 cohort, the ORR was 63.9% (95% CI 51.9-76), compared to just 1.5% (95% CI 0-3.3) in the natural history cohort, highlighting a significant treatment benefit.
In terms of TTS, the Median (95% CI) TTS was 51.3 (43.8, NR) months in the natural history cohort and not yet reached in LS-004.
One limitation of this study is that imaging intervals in the natural history study (NHS) cohort were likely longer than those in LS-004, potentially delaying the assessment of clinical need, such as surgery. However, this would bias the results toward the null of no treatment effect.
Dr. Linehan wrapped up his poster with the following conclusions:
- The magnitude of the treatment effect with belzutifan is large in LS-004 compared with the external comparator arm.
- Despite the possibility of residual confounding, including effects of unmeasured confounders, observing such a large effect is unlikely due to chance.
- The results support the demonstrated antitumor activity and efficacy of belzutifan in the treatment of VHL-RCC seen in LS-004.
Presented by: Marston Linehan, MD, Chief of the Urologic Oncology Branch at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.
Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
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- Choueiri TK, Powles T, Peltola K, de Velasco G, Burotto M, Suarez C, Ghatalia P, Iacovelli R, Lam ET, Verzoni E, Gümüş M, Stadler WM, Kollmannsberger C, Melichar B, Venugopal B, Gross-Goupil M, Poprach A, De Santis M, Schutz FA, Park SH, Nosov DA, Porta C, Lee JL, Garcia-Del-Muro X, Biscaldi E, Manneh Kopp R, Oya M, He L, Wang A, Perini RF, Vickery D, Albiges L, Rini B; LITESPARK-005 Investigators. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024 Aug 22;391(8):710-721. doi: 10.1056/NEJMoa2313906. PMID: 39167807.