HIF-2α Inhibitor Combinations Keep Active in Second-Line RCC

Ongoing research in renal cell carcinoma (RCC) suggests that hypoxia-inducible factor 2-α (HIF-2α) inhibitors are poised to move into expanded second-line settings, according to a presentation by Wenxin (Vincent) Xu, MD, during the 43rd Annual CFS®: Innovative Cancer Therapy for Tomorrow™ conference in New York, New York.¹

With the approval of belzutifan (Welireg) for patients with advanced RCC,² ongoing trials evaluating the class of drug in combination with immunotherapy look promising. Based on findings from the phase 3 LITESPARK-005 trial (NCT04195750), which evaluated 746 patients with unresectable locally advanced or metastatic clear cell RCC who had progressed following both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF tyrosine kinase inhibitor (TKI). Patients were randomly assigned to receive 120 mg belzutifan or 10 mg everolimus once daily.

Investigators reported an improvement in PFS for the belzutifan arm compared with the everolimus arm (HR, 0.75; 95% CI, 0.63-0.90; 1-sided P = .0008). Kaplan-Meier curves reflected nonproportional hazards with similar median PFS estimates of 5.6 months (95% CI, 3.9-7.0) in the belzutifan arm and 5.6 months (95% CI, 4.8-5.8) in the everolimus arm. While OS results were immature at the current analysis, with 59% of deaths reported, no trend toward a detriment was observed.

Two recent LITESPARK trials evaluating belzutifan combination regimens met their respective end points of PFS and disease-free survival (DFS) in patients with different RCC stages.

In LITESPARK-011 (NCT04586231), belzutifan plus lenvatinib was evaluated in patients with advanced RCC whose disease had progressed on or after prior anti–PD-1/L1 therapy.³

At the prespecified interim analysis, the combination demonstrated a statistically significant and clinically meaningful improvement in PFS compared with cabozantinib (Cabometyx). The secondary end point of OS was also improved, but it did not reach statistical significance.³

The other belzutifan-based trial evaluated the combination of belzutifan and pembrolizumab (Keytruda) in patients with clear cell RCC following nephrectomy in the phase 3 LITESPARK-022 trial (NCT05239728).⁴

In the adjuvant setting, the combination demonstrated a statistically significant and clinically meaningful improvement in DFS, the study’s primary end point, compared with pembrolizumab in combination with placebo. The trial will continue to evaluate OS, a key secondary end point.⁴

“Hopefully, these findings will lead to more active combination therapies in patients who are not doing well in the first line,” Xu said.

Current Treatment Toolbox

The current treatment toolbox focuses on 4 classes of agents: VEGF/VEGFR, mTOR, immunotherapy, and HIF-2α.

“If you review overall survival rates from randomized first-line phase 3 trials in the last 20 years, you’ll see a steady improvement,” said Xu, an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts. “Hopefully, this trend will continue,” he added.

For new patients, the first step is to determine their International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, which helps inform their prognosis based on factors such as the time from diagnosis to treatment, laboratory results, and performance status. Anemia status, hypercalcemia, neutrophil count levels, and signs of thrombocytosis are often considered.

“Some oncologists use this model as a way to predict who should get which first-line therapy, but I would argue that that’s going to be less and less useful over time,” Xu said. “As we learn more about kidney cancer biology, it’s clear that underlying biology doesn’t correlate entirely with IMDC risk score,” Xu continued.

In summary, for patients with metastatic disease in the first line, approaches include surveillance, TKI monotherapy, or a TKI plus a PD-1 inhibitor. For those with intermediate or poor risk, treatment options include ipilimumab (Yervoy) plus nivolumab (Opdivo).

“Even though this is a fatal disease, we now have more and more patients who are experiencing durable remissions, and it’s not uncommon to see survival of 5 years or longer,” Xu said.

In the second-line setting, a few trials have offered OS benefit, including METEOR (NCT01865747) and Motzer RJ, et al (NCT01136733).^5,6 But the subject of rechallenging patients with immunotherapy after progression on first-line immunotherapy or adjuvant chemotherapy has been broached.

“Two randomized phase 3 trials have shown that the answer is no,” Xu said.

The CONTACT 03 trial (NCT04338269) showed that the median PFS with the use of atezolizumab (Tecentriq) plus cabozantinib was 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) with cabozantinib alone (HR, 1.03; 95% CI, 0.83-1.28; P = .784).⁷ In the phase 3 TiNivo-2 study (NCT04987203), median PFS was 5.7 months (95% CI, 4.0-7.4) with tivozanib-nivolumab and 7.4 months (95% CI, 5.6-9.2) with tivozanib monotherapy (HR, 1.10; 95% CI, 0.84-1·43; P =.49).⁸

“PD-1–based doublets are appropriate in the first-line setting. Second-line approaches should focus on nonoverlapping mechanisms that have not already been used in prior treatment,” Xu said. “Ongoing trials may continue to progress the standard of care, leading to new FDA approvals on the horizon,” Xu concluded.

REFERENCES

1. Xu W. Novel approaches to Combination Therapy in RCC. Presented at: 43rd Annual CFS®: Innovative Cancer Therapy for Tomorrow™. November 12-14, 2025. New York, NY. https://tinyurl.com/ms4k4nxu

2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. Accessed November 16, 2025. https://tinyurl.com/3ascvetk

3. Merck and Eisai announce Welireg (belzutifan) plus Lenvima (lenvatinib) met primary endpoint of progression-free survival (PFS) in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. October 28, 2025. Accessed November 16, 2025. https://tinyurl.com/3rav9afd

4. Merck announces Keytruda (pembrolizumab) plus Welireg (belzutifan) met primary endpoint of disease-free survival (DFS) in certain patients with clear cell renal cell carcinoma (RCC) following nephrectomy. News release. October 28, 2025. Accessed November 16, 2025. https://tinyurl.com/35re9rm9

5. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016

6. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

7. Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500

8. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6