How Will ARNT Expression and Novel Combinations Shape RCC Treatment?

At the 2026 Kidney Cancer Research Summit (KCRS26), researchers presented new data characterizing aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β) expression across renal cell carcinoma (RCC) and outlined the design of a phase 1b trial combining a JAK inhibitor with a PD-1 inhibitor for patients who progress on immune checkpoint inhibitor therapy.

CancerNetwork® spoke with Yu-Wei Chen, MD, MS, an assistant professor of medicine at the University of California San Diego, about findings from his group’s real-world analysis of ARNT expression across 4062 RCC tumors profiled, and about the design and rationale for the phase 1b PRISM trial (NCT07219576) combining the anti-PD-1 antibody retifanlimab-dlwr (Zynyz) with the JAK inhibitor ruxolitinib (Jakafi) in patients with clear cell RCC (ccRCC) or non–small cell lung cancer (NSCLC) who progressed on prior checkpoint inhibition, led by Rana McKay, MD.^1,2

He also discussed the risk-benefit calculus of adding belzutifan (Welireg) to adjuvant pembrolizumab (Keytruda) following the phase 3 LITESPARK-022 trial (NCT05239728), how ARNT- and HIF-2α–directed strategies might interact with existing treatment backbones based on results from phase 3 LITESPARK-012 (NCT04736706), which emerging RCC data he believes could reshape practice over the next 3 to 5 years, and ongoing work characterizing KIM-1 as a prognostic biomarker.^3-6

CancerNetwork: At KCRS 2026, you presented research dissecting ARNT expression patterns in RCC and their association with patient outcomes. What are the key translational findings from this analysis, and how ARNT expression might serve as a predictive or prognostic biomarker to refine treatment selection?

Chen: We profiled about 4000 RCC tumors with DNA and RNA sequencing, focusing on ARNT expression. ARNT, also known as HIF-1β, dimerizes with HIF-2α, and the main reason we conducted this analysis is that there is currently a phase 1 study investigating NEO-811, a HIF-1β inhibitor. We wanted to see how ARNT expression looks across RCC tumors in both clear cell and non-clear cell histologies.

We found that ARNT expression was quite consistent across RCC subtypes. We [saw] relatively higher expression in clear cell RCC compared with papillary [disease], followed by medullary RCC and chromophobe. We also saw consistent ARNT expression across primary tumors as well as metastatic tumors, and there were no differences by racial or ethnic subgroup. Overall, the positive finding from this study is that we see consistent, preserved ARNT expression, so if the phase 1 study is able to move forward, we may have the opportunity to investigate ARNT inhibition not only in clear cell RCC but also to see what the efficacy looks like in non–clear cell RCC. In terms of prognostic or predictive value, we did not see ARNT expression serve as a biomarker in our analysis at this point.

Based on your co-authorship of the PRISM trial, what is the mechanistic rationale behind combining a JAK inhibitor with PD-1 blockade to overcome immune checkpoint inhibitor resistance in renal cell carcinoma, and what signal are you hoping to see in early trial readouts?

This is an investigator-initiated study led by Dr. Rana McKay in our group. The rationale behind it is that there is an unmet need once patients with kidney cancer progress after frontline immunotherapy-based combinations. We know that with immunotherapy combinations as first-line treatment, patients can achieve long-term durable responses and even cures in a small subset of patients. The main question is how we can reinvigorate the tumor microenvironment once a patient progresses on frontline therapy. There has been translational and preclinical work investigating ruxolitinib in this setting, and we have seen early success in Hodgkin lymphoma, though not yet in RCC. The reasoning behind this study is that we hope to reinvigorate the tumor microenvironment and reactivate T cells after progression on frontline immunotherapy, and that is the rationale for combining ruxolitinib with a PD-1 inhibitor in this trial. We hope to see clinical responses in this patient subgroup, continued tumor control and shrinkage, and ultimately translate that into long-term durable responses. That is the goal of this study.

Given recent data and debates surrounding perioperative systemic therapy, how do you see the risk-benefit profile evolving for patients with localized disease, especially regarding patient selection for adjuvant immunotherapy?

We know that adjuvant pembrolizumab has been a great success, based on phase 3 KEYNOTE-564 (NCT03142334), showing both a disease-free survival [DFS] and an overall survival benefit. Now we are seeing that move further, with the combination of pembrolizumab plus belzutifan compared with pembrolizumab alone. The key question is still the risk-benefit ratio and how we discuss this data with our patients. We see a DFS HR of 0.72 favoring the combination over pembrolizumab alone; however, we are also seeing more adverse effects [AEs], although most are tolerable, with a generally favorable safety profile for belzutifan, mostly anemia and some hypoxia, and most of these AEs are manageable.

It comes down to how we select patients. If a patient has high-risk features, for example, higher T-stage or grade 4 disease, and is younger, I would be more inclined to be aggressive in offering the combination and discussing the benefit-risk ratio around the AE profile. It comes down to shared decision-making and how the conversation goes with the patient.

HIF pathway dynamics are central to clear cell RCC biology. Based on xyour work with ARNT and broader tumor microenvironment profiling, how might targeting ARNT or downstream HIF pathways interact with existing therapeutic backbones like HIF-2α inhibition or VEGF/immunotherapy [IO] combinations?

This is a nuanced question. At this moment, it is still very early for HIF-1β inhibition. If NEO-811 proves successful, it will be interesting to see whether we can combine HIF-1β inhibition with existing backbone therapies to achieve a higher response rate and more durable tumor control….We do not have the full data yet, so it will be interesting to see the results of the current HIF-1β phase 1 study and learn more about its toxicity profile and efficacy to help move the field forward.

What emerging data or therapeutic strategy from KCRS 2026 do you believe has the potential to most significantly alter clinical practice in RCC over the next 3 to 5 years?

The most exciting agent currently is casdatifan [AB521], another HIF-2α inhibitor, which has demonstrated strong pharmacokinetic/pharmacodynamic data, a favorable safety profile, and early signs of tumor control and response. Casdatifan is currently being evaluated in the phase 3 PEAK-1 trial [NCT07011719], comparing casdatifan plus cabozantinib (Cabometyx) with cabozantinib plus placebo in the treatment-refractory RCC setting, and we are looking forward to the early readout of that data.

Another exciting area is PD-1 and VEGF bispecific antibodies in the RCC space. We have already seen great success with this class in lung cancer, and we are hoping that efficacy translates into RCC as well.

Is there anything else you would like to highlight that we may not have had the opportunity to discuss?

I would like to highlight Wenxin (Vincent) Xu’s, MD, work from the Dana-Farber Cancer Institute group. He presented data on KIM-1 as a prognostic factor based on the [phase 3 COSMIC-313 (NCT03937219)] data. He has been a pioneer in this field, investigating KIM-1 for both its prognostic and predictive value, and he is also designing a phase 3 clinical trial incorporating KIM-1 as a prospective biomarker. We are looking forward to that, and UC San Diego is interested in participating in that trial as well.

References

1. Chen YW, Nazari SS, Elliott A, et al. Dissecting ARNT (HIF-1β) expression patterns in renal cell carcinoma and associations with outcomes. Presented at: Kidney Cancer Research Summit (KCRS26); July 23-24, 2026; Boston, MA.
2. McKay RR, Wei LJ, Chen YW, et al. PRISM: phase 1b of retifanlimab and ruxolitinib in solid malignancies progressing on prior checkpoint inhibition (NCT07219576). Presented at: Kidney Cancer Research Summit (KCRS26); July 23-24, 2026; Boston, MA.
3. Choueiri TK, Motzer RJ, Karam A Jose, et al. Adjuvant pembrolizumab plus belzutifan for renal-cell carcinoma. N Engl J Med. 2026;395(1):32-43. doi:10.1056/NEJMoa2518245
4. Merck and Eisai provide update on phase 3 LITESPARK-012 trial evaluating first-line combination treatments for certain patients with advanced renal cell carcinoma (RCC). News release. Merck & Co, Eisai. April 21, 2026. Accessed August 6, 2026. https://tinyurl.com/mwh9w74v
5. A study of casdatifan in combination with cabozantinib versus cabozantinib alone in participants with metastatic clear cell renal cell carcinoma (PEAK-1). ClinicalTrials.gov. Updated July 31, 2026. Accessed August 6, 2026. https://tinyurl.com/bdbsw5ck
6. Xu W, Choueiri TK, Powles TB, et al. Association of circulating kidney injury molecule-1 (KIM-1) levels with clinical outcomes in advanced renal cell carcinoma (aRCC): retrospective analysis of COSMIC-313. Ann Oncol. 2025;36(suppl 2):S1300-S1301. doi:10.1016/j.annonc.2025.08.3210