Kidney Cancer Research Updates for the Entire Clinical Team: 2026 ASCO GU

Apr . 08 . 2026

Kidney Cancer Association

The Kidney Cancer Association’s Clinical Advisory Board summarized highlights from the 2026 ASCO Genitourinary Cancers Symposium, held in San Francisco, CA on February 26-28. Emily Wang, PharmD, BCOP, Julia Batten, APRN, MSN, MPH, and Renata Penafiel, MPAS, PA-C reviewed key sessions and provided clinical insights useful for the whole care team. If you learned something new, be sure to share this write up with your colleagues! Don’t forget to request free resources for kidney cancer providers and patients.

Adjuvant Treatment: LITESPARK-022 Trial

Study arms: Pembrolizumab 400 mg IV Q 6 weeks for 9 doses (~1 year) + Belzutifan 120 mg/day or Placebo
- Phase III, double-blind trial in clear cell (cc) renal cell carcinoma (RCC) with M0 and intermediate-high (pT2 grade IV or sarcomatoid or PT3 any Grade, N0) or high (pT4 any grade, N0, or any pT and Grade, N+) risk of recurrence after nephrectomy or ccRCC stage M1 with no evidence of disease (M1 NED) after nephrectomy
- Primary Endpoint:
  - Disease Free Survival (DFS) by investigator
- Secondary Endpoint:
  - Overall Survival (OS)
  - Safety
- Study duration: March 2022 to May 2024
- Median follow up: 28.4 months (range, 15-40.1 months) for this 1^st interim analysis
- Randomization: 1:1

Take home messages:

Pembrolizumab + belzutifan demonstrated statistically significant and clinically meaningful DFS in ccRCC patients with increased risk of recurrence following nephrectomy

Safety profile of pembrolizumab + belzutifan was consistent with the existing ADE profiles of each drug and there was a low rate of ADEs leading to discontinuation of both study drugs

LITESPARK-022 is the first adjuvant phase III trial to show significant benefit for a combination treatment versus immunotherapy comparator and support the use in ccRCC patients with increased risk of recurrence following nephrectomy

Metastatic Treatment: LITESPARK-011 Trial

Study arms: Lenvatinib 20 mg/day plus Belzutifan 120 mg/day versus Cabozantinib 60 mg/day
- Phase III, open-label trial in metastatic RCC patients after receiving anti PD-(L)1 therapy in 1^st or 2^nd line therapy or progressed ≤ 6 months of adjuvant anti-PD-(L)1 therapy
- Primary Endpoints:
  - Progression free survival (PFS)
  - Overall survival (OS)
- Secondary Endpoints:
  - Overall response rate (ORR)
  - Duration of response (DOR)
  - Safety
- Study duration: March 5, 2021 to September 1, 2023
- Median follow up: 19.6 months (range: 9.9-39.8 months) at 1^st interim analysis and 29 months (range: 19.3-49.2 months) at 2^nd interim analysis
- Randomization: 1:1

Exploratory analysis: no difference in time to deterioration in patient reported outcomes as captured by Functional Assessment of Cancer Therapy–Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) and EROTC QLQ-C30 GHS/QOL questionnaires
Take home messages:
- Lenvatinib + belzutifan combination demonstrated superior PFS and ORR as compared to cabozantinib in ccRCC patients following anti-PD-L(1) therapy
- OS favored lenvatinib + belzutifan; however, was not statistically significant and will be further revealed in the final analysis
- Safety profile of lenvatinib + belzutifan was consistent with the existing ADE profiles of each drug
- Time to worsening in disease specific symptoms and QOL were similar between the two treatment arms
- LITESPARK-011 demonstrates that lenvatinib + belzutifan improves outcomes following anti-PD-L(1) therapy and is a possible treatment option in patients that have progressed on anti-PD-L(1) therapy

Potential Future Directions: Up and Coming Trials

Nivolumab + Relatimab + Ipilimumab vs Nivolumab + Ipilimumab Trial

Clinical question: can we build on the benefits of nivolumab and ipilimumab through additional immune manipulation to potentially increase efficacy
Mechanism:
- Lymphocyte-associated gene 3 (LAG3) is normally an inhibitory receptor on activated immune cells involved with T cell exhaustion
- LAG3 is expressed on T cells and co-expression with other inhibitory receptors such as PD-1, that induces the dysfunction of T cells, limiting the anti-tumor T cell response
- Relatlimab is a human LAG3 specific antibody that binds to the LAG3 receptor with high affinity, blocking the interaction of LAG3 interactions with its major histocompatibility complex (MHC) class II ligand, recognized by CD4+ T cells, thus restoring the effector function of exhausted T cells
Phase II trial in treatment naïve metastatic ccRCC patients
Trial design:
- 2 arms:
  - Arm A (n = 40): nivolumab 480 mg / relatlimab 160 mg IV every 4 weeks + ipilimumab 1 mg/kg IV every 8 weeks
  - Arm B (n = 20): nivolumab 480 mg + ipilimumab 1 mg/kg IV every 3 weeks x 4 weeks, followed by nivolumab 480 mg IV every 4 weeks
- Primary Endpoints:
  - Safety
  - Objective response rate (ORR)
- Secondary Endpoints:
  - PFS
  - OS

IVORY Trial

Ivonescimab, first-in-class, tetravalent bispecific antibody targeting PD1 and VEGF signaling
Phase II trial in metastatic RCC after immune checkpoint inhibitor (ICI) therapy
Trial design:
- 2 cohorts:
  - Cohort 1 (n = 20): patients VEGF therapy naïve
  - Cohort 2 (n = 20) patients previously received VEGF therapy
- Treatment:
  - Dosing: Ivonescimab 20 mg/kg IV every 3 weeks until disease progression or unacceptable toxicities
- Primary Endpoints:
  - ORR
  - Disease control rate at 24 weeks
- Secondary Endpoints:
  - Toxicity
  - PFS
  - Duration of response
  - OS

Abstract Spotlight: Belzutifan at High Altitude (Abstract 488)

Background

Belzutifan is an FDA-approved therapy for metastatic renal cell carcinoma (mRCC) that inhibits hypoxia-inducible factor-2 alpha (HIF-2α).

Mechanism of Action

The HIF pathway helps the body adapt to low oxygen. Activation of HIF-2α promotes:

Erythropoietin (EPO) production → stimulates red blood cell formation
Angiogenesis
Tumor survival pathways in renal cell carcinoma

Belzutifan blocks HIF-2α, slowing tumor growth but also interfering with physiologic oxygen-sensing mechanisms.

Why Hypoxia Occurs

Belzutifan-associated hypoxia may result from:

Reduced ventilatory response to low oxygen
Decreased EPO production → anemia
Impaired physiologic adaptation to hypoxia

At high altitude, where oxygen availability is reduced, these effects are amplified.

Key Question

Nearly 1 billion people worldwide live >1000 meters above sea level:
Does altitude affect the safety profile of belzutifan?

Study Purpose

Evaluate the real-world safety of belzutifan in patients living at high altitude, focusing on:

Incidence and severity of hypoxia
Need for oxygen supplementation
Rates of anemia
Comparison with clinical trial populations

Study Overview

This is the first study reporting belzutifan safety in a high-altitude cohort.

Design:

Retrospective chart review (IRB approved)

Population:

Adults with mRCC treated with belzutifan

Patient Population Summary:

Total patients: 34
Average altitude: 1457 m (range 1288–1945 m)
Baseline characteristics:
- Sex: 91% male
- Race: 82% White
- Smoking status: 65% never smokers
- Lung metastases: 65%
- ECOG ≤1 in all patients
- Baseline oxygen use: none

Exclusion Criteria:

Germline Von Hippel–Lindau (VHL) syndrome

Key Definitions:

Hypoxia: SpO₂ <92% (Grade 1, LITESPARK-005 criteria)
Adverse events graded per CTCAE v5

Altitude Assessment:

Estimated via U.S. Geological Survey tools

Treatment Characteristics:

Belzutifan starting dose 200 mg: 17%
Concurrent TKI therapy: 10%

Key Findings

1. Hypoxia

Incidence: 88% (Grade ≥1)
Severe (Grade 3): 47%
Home oxygen required: 82%
Median time to oxygen: 55.5 days

Comparison to LITESPARK-005:

Hypoxia: 14.5%
Oxygen use: 10.2%

Hypoxia Severity Distribution:

Grade 1: 2 patients
Grade 2: 10 patients
Grade 3: 16 patients
Grade 4: 2 patients

Interpretation: High-altitude patients exhibited substantially higher oxygen requirements than clinical trial populations.

2. Anemia

Incidence: 79% developed Grade ≥2 anemia

Mechanism:

Belzutifan inhibits HIF-2α, reducing EPO production → fewer RBCs → lower hemoglobin → reduced oxygen-carrying capacity.
Combined with impaired hypoxic response, this may exacerbate oxygen desaturation at high altitude.

Anemia Severity Distribution:

Grade 1: 7 patients
Grade 2: 14 patients
Grade 3: 13 patients
Grade 4: 0 patient

Why Altitude Matters

LITESPARK-005 trial altitude: ~201 m
Current study altitude: ~1457 m

High-altitude physiology:

Lower atmospheric pressure
Reduced oxygen partial pressure
Lower baseline oxygen saturation

Clinical impact:

Greater oxygen desaturation
Increased need for supplemental oxygen

Key Summary

Among high-altitude patients receiving belzutifan:

88% developed hypoxia
47% had Grade 3 hypoxia
82% required home oxygen
79% developed Grade ≥2 anemia

Conclusion: Altitude significantly influences belzutifan toxicity and oxygen requirements.

Clinical Implications

Monitor for Hypoxia:

Frequent SpO₂ checks (especially first 1–2 months)
Educate patients on symptoms: fatigue, dyspnea, tachycardia, headache

Monitor for Anemia:

Routine CBCs
Assess for fatigue, dizziness, pallor, shortness of breath

Anticipate Oxygen Needs:

82% required home oxygen
Early coordination with DME services recommended

Early Recognition:

Prevent hospitalization
Enable timely dose modification
Maintain therapy continuity

Future Directions

Evaluate belzutifan safety at different altitudes
Determine altitude-specific monitoring strategies
Assess whether dose adjustments reduce hypoxia risk
Develop clinical guidance for oxygen monitoring and management

Reference

McFarland TR, Seidel A, Gebrael G, Ozay ZI, Hooper G, Ostrowski M, Ji R, Nandakumar V, Li H, Maughan BL, Swami U, Batten J, Agarwal N. Incidence of symptomatic hypoxia in a high-altitude cohort of patients with renal cell carcinoma treated with belzutifan. Journal of Clinical Oncology. 2026;44(Suppl 7): Abstract 488. Presented at the 2026 ASCO Genitourinary Cancers Symposium.

Abstract Spotlight: Postoperative surveillance in non clear cell renal cancer: Is current practice best practice? Arighno Das, MD (Abstract 435)

Non clear cell cancer represents 20-25% of RCC cases

Reason for analysis
- Current AUA and NCCN guidelines do not differentiate between clear cell and non clear cell RCC when it comes to post operative surveillance
- Long term recurrence data for these non clear cell RCC remains limited.
Method of analysis
- 712 adults diagnosed with non clear cell RCC
  - These include papillary, chromophobe, translocation, mucinous tubular/spindle cell carcinoma and unclassified RCC
- The analysis recorded recurrence-free survival (RFS) and first recurrence
- Median follow up was 120 months
Findings
- Recurrence was seen in 116 patients (16%) at a median of 26 months
- Patients were evaluated based on AUA/EUA risk groups
  - RFS was significantly different based on risk groups
- Intra-abdominal visceral organs or retroperitoneal lymph noes were most common site of recurrence (38%)
- Next most common site of recurrence was in lungs (19%)
- Chromophobe type RCC was associated with lowest risk of recurrence
Conclusion
- Non clear cell RCC recurrence is uncommon
- Contrary to ccRCC, non clear cell tends to recur in abdomen rather than chest.
- Late recurrences were seen

Take away points

This analysis showed that for non clear cell RCC, recurrences patterns are unique.

Recurrences tend to happen mostly in the abdomen (rather than chest as it does with ccRCC). Clinicians should consider cross sectional abdominal imaging
Recurrences tend to happen later. Clinicians should practice careful long-term surveillance, often over 10 years

Abstract Spotlight: Partial nephrectomy versus ablative therapies for T1a clear cell renal cell carcinoma. Analysis of 2,161 patients. Chang Gon Kim (Abstract 495)

Ablative therapies offer a minimally invasive alternative to small ccRCC, especially in patients with high surgical risk or impaired kidney function

Reason for retrospective analysis
- Comparative data between ablative therapies and partial nephrectomy are limited
Method of analysis
- Study of 2,161 patients who underwent either partial nephrectomy or ablation between 2006 and 2024
- What was studied
  - Survival outcomes
  - Renal function preservation – defined as declines of at least 30% in eGFR baseline
- Challenges
  - Partial nephrectomy group were younger and had higher BMIs
  - Ablation group had lower eGFR levels and were more likely to have other medical conditions.
Findings
- During the 66.3 moths of follow up, locoregional recurrence, distnt recurrence, death, and kidney function decline were superior in the partial nephrectomy group compared to the ablative therapy group
Conclusion
- Partial nephrectomy demonstrated superior oncologic control and kidney function preservation for patients with T1a ccRCC