Kidney Cancer Research Updates for the Entire Clinical Team: 2025 IKCS North America Edition

• Multi-functional NPs (MINPs) can target both renal cell carcinoma (RCC) tumors, while also enabling adaptive and innate immune response
  • MINPs can activate Tumor Infiltrating Lymphocyte Therapy (TILs) in vivo, without the potential toxicity from conditioning regimens and expense of TILs
• Neoantigen vaccine therapy in RCC
  • Antigen-directed therapies such as neoantigens may be beneficial as it is the most immunogenic, as well as being the most tumor-specific
  • Proof of concept in the melanoma setting, although there are more mutations, the modest mutation burden may still make this an option in RCC
  • Clinical question: can we design an immunologically effective personalized neoantigen vaccine in RCC?
    • Vaccination induces durable T cell expansion and anti-tumor immunity
    • Small sample size: 9 patients; in the adjuvant setting (INTerpath-004 trial – results pending)
  • Future directions: timing of vaccines; before or after use of PD-1/PD-L1 therapy
• Immune Checkpoint Inhibitors (ICI) in metastatic RCC: lessons learned from clinic
  • Current ICI challenges:
    • Primary and adaptive resistance to ICI
    • Lack of predictive biomarkers to enable patient selection
    • Management of immune-related adverse effects
  • Future directions to address these ICI challenges:
    • Utilization of pharmacological EZH2 inhibition with DS3201 to overcome adaptive resistance leading to enhanced anti-CTL4 therapy response (preclinical models)
    • DS3201 plus ipilimumab treatment:
      • Safe and demonstrates clinical anti-tumor responses
    • • Decreases in enrichment of H3K26me3 (epigenetic marker with a role in regulating gene expression, active transcription, and DNA repair)
    • • Enrichment of progenitor T cell gene prior to treatment and expansion of progenitor exhausted T cells seem to suggest treatment response
    • • Type 1 conventional dendritic cells are enriched in responders
• SPOP inhibition with ICI treatment:
  • In RCC, the E3 ligase SPOP is an oncogene in degrading PTEN, which enhances stimulation of interferon genes (STING) activation that triggers an immune response

• Chromophobe RCC
  • Hallmarks:
    • Highest mitochondrial DNA mutation rate
    • Markedly elevated glutathione (GSH)
    • Median survival (metastatic setting): 20 months
  • Potentially new targets:
    • Ferroptosis suppressor protein 1 (FSP1) knockout: FSP1 is upregulated in chromophobe RCC and reduces CoQ10
    • Xenium spatial profiling of sarcomatoid chromophobe RCC
    • New TSC2 mouse (B7H3 knockout) and humanized mouse models
    • P53 mutation; highest mitochondrial DNA mutation rate; elevated GSH – glutathione
• Renal Medullary Carcinoma (RMC) pathogenesis and therapies:
  • Lessons learned in RMC:
    • Extremely aggressive, defined by SMARCB1 tumor suppressor in predominantly young, African American patients with sickle cell trait and other sickle hemoglobinopathies
    • Ineffective therapies: ICI and anti-VEGF tyrosine kinase inhibitors
      • SMARCB1^null tumors are insensitive to angiogenesis inhibition
    • Platinum-based chemotherapy: ORR 29%
    • Bevacizumab/erlotinib regimen: EGFR pathway is upregulated and this combination is clinically active in post-cytotoxic chemotherapy and proteasome inhibition, with erlotinib having more activity given the EGFR inhibition
    • EGFR inhibition is a viable therapeutic strategy for RMC
  • The future is bright:
    • EGFR targeting with panitumumab/nab-paclitaxel combination treatment is the new standard of care for RMC
    • Median survival increased from 13 months to 24+ months; goal for 5 years by 2030
    • Up to 10% of patients are now rendered disease-free
• Birt-Hogg-Dube syndrome associated RCC:
  • FLCN (folliculin gene) – tumor suppressor gene
  • Autosomal dominant mutation
• Translocation RCC (tRCC)
  • tRCC origin likely arises from different nephron cell types as compared to clear cell RCC (ccRCC)
  • Unique pathways in tRCC include EMT, concomitant activation of anabolic (mTORC1) and catabolic (autophagy/lysosome) pathways
  • hASPSCR1-TFE3 expression in nephron progenitor cells and may be why cabozantinib has potential activity in tRCC
  • Driven by oncogenic TFE3 gene fusion
  • Therapeutic targeting:
    • CDH17 – cell-surface cadherin (is expressed in normal GI epithelia, lateral membrane and tight junctions) and is regulated by the TFE3 fusion
    • TFE3 gene fusion:

PET Imaging in RCC:

• Is there a potential prognostic role for both metastatic detection and potential response assessment?
• The new:
  • Theranostics potential:
    • Carbonic anhydrase 9 (CA-IX) targeted PET/CT rapidly evolving as a potential tracer
• ⁸⁹Zr-girentuximab ZIRCON study
• ¹⁷⁷Lu-girentuximab plus (3 ongoing trials)
  • Cabozantinib/nivolumab (STARLITE-1)
  • Nivolumab (STARLITE-2)
  • DNA protein kinase inhibitor (STARSTUCK)
• PSMA PET/CT for RCC?  Expressed in the vasculature in RCC – can improve lesion detection and management
  • PEDASTAL study – oligometastatic RCC – suggesting PSMA PET/CT
  • May be helpful for patients with bone metastasis and/or lymph nodes

Frontline Systemic Therapy in the Era of Adjuvant Therapy:

• Limited role of PD-1 immune checkpoint inhibition (ICI) after adjuvant pembrolizumab from the results of these trials that were testing to see if angiogenesis target therapies would resensitize metastatic RCC to ICI
  • CONTACT trial: cabozantinib vs cabozantinib/atezolizumab
  • TiNIVO2 trial: tivozanib vs tivozanib/nivolumab
• LenCabo Trial: lenvatinib/everolimus vs cabozantinib
  • Patient population: metastatic ccRCC with prior PD-1/PD-L1 ICI with 1-2 prior lines of therapy (n = 90)
    • Randomized 1:1 based on IMDC risk group and prior VEGF therapy
    • Primary Endpoint
      • PFS
    • Secondary Endpoints:
      • ORR by RECIST 1.1
      • Safety
      • OS
  • Results:

• Future Directions:
  • HIF-2 alpha combinations
    • LITESPARK 11: lenvatinib 20 mg/day + belzutifan 120 mg/day vs cabozantinib 60 mg/day
      • Preliminary press release: trial did meet primary endpoint of PFS
    • Casdatifan 100 mg/day + cabozantinib 60 mg/day vs cabozantinib 60 mg/day
  • Novel MOAs and re-sensitizing to ICI
    • GCN2 activators
    • Bispecific t-cell and VEGF-PD-1 engagers
    • Cellular therapies (CD70; CAR-NK studies)

• XmAb819-01: ENPP3 targeted, CD3 bispecific antibody
  • Over 88% of ccRCC patients have membrane ENPP3+ tumor
  • Regimen: parallel subcutaneous and intravenous cohort design
    • Ongoing enrollment
  • Preliminary results (n = 69):
    • Treatment status:
      • Ongoing (17 patients; 25%)
      • Discontinued (52 patients; 75%)
        • Adverse event: 3 patients; 4%
    • Most common ADE:
      • Grade I/II CRS during priming dosing; decline thereafter
      • Grade I/II rash events: responsiveness to antihistamines and steroids (topical/oral)

• Future Directions:
  • Earlier line of therapy; clear evidence of XmAb819 dose response in ongoing dose escalation evaluation

• Concept of Cure for RCC patients by Dena Battle:
  • Discussed the idea of being “cured vs consumed” based on a KCCure (RCC advocacy group) survey of patients and providers in 2024.  It found that 75% of providers are hesitant to use the word “cure,” even in early stage RCC. 
  • Those who feel cured have less distress and spend less time thinking about cancer.  She urged us to consider using the word “cure” as appropriate.
• Nutrition Updates by Dr. Michael Staehler:
  • Take home points:
    • High protein oral nutritional supplements reduce complications and hospital stays
    • Nutritional support improves weight stabilization, lean body mass, QOL and treatment tolerance in advanced cancer patients
  • Although currently there are no large randomized controlled trials looking at clinical endpoints to provide evidence for improved cancer outcomes based on nutrition, the recommendations from this talk are:
    • Encourage unprocessed and high fiber foods (improves gut microbiome and immune function)
    • Identify nutritional risks early and intervene promptly
• Overcoming Cognitive Effects of Treatment Burden by Dr. David Sheppard:
  • Survivorship numbers are growing, making this topic very relevant   
  • Cancer itself is a risk factor for cognitive impairment
  • To address cognitive/treatment burden, focus on mood/distress and fatigue
  • Future interventional trials needed to evaluate stress and fatigue management for cognitive outcomes and QOL
• TKI Toxicity by Dr. Daniel Geynisman:
  • Data has shown that treatment holidays are reasonable to manage side effects and do not worsen cancer outcomes
  • Be mindful as patients tend to under report side effects based on results of KCCure Survey

• KIM-1 is a transmembrane glycoprotein overexpressed in RCC and detectable in urine and plasma with an immune regulatory role; it is a predictive and prognostic biomarker
  • Advantage: Small amount of plasma needed and relatively inexpensive
• KIM-1 has detection, prognostication and treatment evaluation potential in RCC
  • Levels have been able to differentiate between benign versus malignant renal tumors
• Prognostic indicator:
  • High KIM-1 after nephrectomy in the adjuvant setting
    • Higher KIM-1 level associated with worse prognosis
• Treatment response indicator:
  • Decrease in KIM-1 associated with response
  • Decreased KIM-1 after 3 weeks on treatment is associated with better outcomes for immunotherapy

• Future Questions:
  • Can KIM-1 levels be used to decide who should get adjuvant therapy (or not)?
  • Can KIM-1 biochemical progression be “cured” before radiographic progression?
  • Can we “target” KIM-1?
• An exciting future ahead with KIM-1 with hopefully prospective trials needed to validate the benefit of using KIM-1 to improve RCC outcomes

• MK-3475A-D77 Study: treatment-naïve metastatic non-small cell lung cancer (NSCLC)
  • n = 377 patients; randomized 2:1 to receive pembrolizumab subcutaneous (SQ) or intravenous (IV) every 6 weeks with platinum doublet chemotherapy  
  • ORR: 45% (95% CI: 39,52) for SQ pembrolizumab vs 42% (95% CI: 33,51) for IV pembrolizumab
  • No notable differences in PFS or OS
  • Recommended dosage:
    • 395 mg of pembrolizumab SQ and 4,800 units of berahyaluronidase alfa-pmph every 3 weeks
    • 790 mg of pembrolizumab SQ and 9,600 units of berahyaluronidase alfa-pmph every 6 weeks