Kidney Cancer Research Updates for the Entire Clinical Team

Results

• Study design: Phase 3, randomized, double-blinded trial
• Patient population: previously untreated, IMDC intermediate or poor risk advanced renal cell carcinoma (RCC)
• Endpoints:
  • Primary: Progression Free Survival (PFS; first 550 randomized patients)
  • Secondary: Overall Survival (OS; all patients)
• Treatment arms:
  • Cabozantinib 40 mg/day with nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenous (IV) every 3 weeks for 4 cycles, followed by nivolumab 480 mg IV every 4 weeks for up to 2 years
  • Placebo with nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenous (IV) every 3 weeks for 4 cycles, followed by nivolumab 480 mg IV every 4 weeks for up to 2 years
• Results:
  • Median follow-up time: 45 months

• Abbreviations: AE = adverse events, CI = confidence interval, ORR = overall response rate

• Important Takeaways:
  • First-line treatment with triple therapy continues to demonstrate PFS and ORR benefit in patients with intermediate or poor risk with comparable OS between the 2 arms
  • Higher grade 3/4 treatment-emergent AEs with triple therapy

What is KIM-1?

• A type 1 transmembrane protein that is primarily expressed in the proximal tubules of the kidneys in response to injuryPlays a critical role in the repair of renal tubular cells following damageElevated levels in the bloodstream or urine are often associated with kidney injury, including conditions like acute kidney injury (AKI) and RCCThe KIM-1 ectodomain is detectable in plasma and serumKIM-1 has been shown to be overexpressed in RCCSignificant findings:
  • Evaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC)
    • Key Question: Are KIM-1 levels at baseline and after 1 cycle of nivolumab + ipilimumab or sunitinib associated with treatment outcomes?Key Findings: 
      • Higher levels of KIM-1 at baseline were associated with shorter overall survival (OS) independent of International Metastatic RCC Database Consortium (IMDC) risk group, nephrectomy status and tumor burden, in both the nivolumab + ipilimumab and sunitinib armsDecrease in KIM-1 from baseline to Cycle 2, day 1 (3 weeks after Cycle 1, day 1) was strongly associated with progression free survival (PFS) and OS among patients treated with nivolumab + ipilimumab, but not in patients treated with sunitinibPatients with a >30% decrease in KIM-1 had a median PFS of 70.8 months versus 4.2 months for those with a >30% increase in KIM-1Median OS was 85.4 months versus 26.6 monthsOverall response rate (ORR) was 69.3% versus 13.9%
      Key Summary:
      • Circulating KIM-1 may be a useful minimally invasive biomarker for monitoring patients on RCC immunotherapy
    Circulating kidney injury molecule-1 (KIM-1) in association with kidney injury biomarkers and outcomes in metastatic renal cell carcinoma
    • Key Question: Does kidney disease, a common co-morbidity among RCC patients, impact the association of KIM-1 with RCC outcomes?Key Findings:
      • Higher baseline levels of KIM-1 were associated with worse progression-free survival and overall survival in patients with metastatic renal cell carcinoma.Plasma KIM-1 remained a significant prognostic marker for PFS and OS even after adjusting for other kidney injury biomarkers (cystatin C, TNFR1, TNFR2) and estimated glomerular filtration rate (eGFR).The prognostic value of KIM-1 was consistent across clear cell and papillary RCC.KIM-1 proved more prognostic for OS outcomes than the IMDC risk groups.
      Key Summary:
      • The prognostic value holds true even in patients who have coexisting acute kidney injury (AKI) or chronic kidney disease (CKD).The addition of KIM-1 improves IMDC model performance and may be useful for risk prognostication in RCC

• Important Takeaway:
  • Promising findings, but additional studies needed to prospectively validate the utility of KIM-1 as a biomarker for RCC
• Learn More

Updated Results

• 651 patients, median follow up of 67.6 months (5.5 years)
• Tx arms: nivolumab + cabozantinib (NC) vs sunitnib (S)
• Updated results:
  • Median PFS: 16.4 months (NC) vs 8.3 months (S)
    • 42% reduction in the risk of disease progression of death (HR 0.58, 95% CI [0.49, 0.7])
  • Median OS: 46 months (NC) vs 35.5 months (S)
    • 21% reduction in the risk of death (HR 0.79, 95% CI [0.65, 0.96])
  • ORR: 55.7% (NC) vs 27.4% (S)
  • Median duration of response: 22 months (NC) vs 15.2 months (S)

• Important Takeaways:
  • Long-term efficacy observed with combination nivolumab plus cabozantinib vs sunitinib
  • Safety and tolerability were management and consistent with previously reported results
  • Continued support for utilization of combination nivolumab plus cabozantinib as standard of care

Results

• Study Population:
  • 1167 respondents to online survey with 492 receiving systemic therapy for mRCC
  • Therapy line: 42% first, 30% second, 13% third and 15% fourth or higher  
• Findings:
  • Hospitalizations and visits to the emergency room were significantly correlated with lower quality of life (QOL) and higher NCCN distress score (p<.001)
  • 89% of patients think about cancer every day; 44% spend a few to several hours per day thinking about cancer
  • mRCC affects activities of daily living (eating and sleeping) and ability to socialize

• Important Takeaways:
  • Patients with mRCC need streamlined care (clinic, lab, ER visits) to minimize burden of cancer and improve QOL 
  • Important to assess both physical and mental impact of cancer for patients (and caregivers) and promote programs to improve support and QOL 

Results

• HC-7366 is a novel, highly selective and potent activator of general control nondepressible 2 (GCN2) kinase
• Novel mechanism of action:
  • GCN2 kinase is a core regulator of metabolic stress through activation of the integrated stress response, where prolonged activation suppresses protein synthesis and induced cell cycle arrest, ultimately leading to apoptosis
  • HC-7366 decreases HIF expression in tumor and immunosuppressive myeloid cells, inhibiting glycolysis, oxidative phosphorylation, and TCA cycle function in tumor cells
• Trial design:
  • Treatment arms include HC-7366 60 mg daily monotherapy or HC-7366 (20 mg, 40 mg, 60 mg daily) in combination with belzutifan 120 mg daily
  • Secondary endpoints include ORR, duration of response (DOR), time to response (TTR), disease control rate (DCR), PFS, and OS
  • Key inclusion criteria include prior therapies, >/= 1 measurable lesion, and willingness to provide biopsy or archival tumor samples at two timepoints

• Important Takeaway:
  • Future directions to follow up on the results of this novel mechanism of action for potential use in RCC  

Results

• Data regarding the use of treatment among 70-year-old or older patients are scarce
• CABOLD study seeks to address these gaps by addressing the real-life use of combinations in older patients
• Trial design:
  • Patients will receive standard of care treatment consisting of cabozantinib 20 mg or 40 mg daily and nivolumab on a 28-day cycle (240 mg on Days 1 and 15 for the first 2 cycles, followed by 480 mg on Day 1 for subsequent cycles)
  • Patients will benefit of a multi-modal follow-up including medical oncologists, geriatricians, and trained nurses to monitor safety closely
  • Primary endpoint is to describe real-life treatment patterns of cabozantinib and nivolumab including dose modifications and interruptions due to toxicity
  • Secondary endpoints include efficacy, survival, tolerance, and quality of life

• Important Takeaway:
  • Future directions to follow up on the results of combination of cabozantinib and nivolumab among older patients with RCC  

Results

• Background:
  • A benign solid tumor of the kidney
  • Patients do not experience noticeable symptoms that prompts a workup
    • Symptomatic tumors may cause flank pain, hematuria, or retroperitoneal bleeding
  • Usually found incidentally through imaging that patients may undergo for other clinical reasons
  • Due to the benign nature, usually monitored without any acute intervention or treatment until they reach 4-6 centimeters; they then may be treated based on clinical judgement and symptom presentation
• Study Population:
  • 839 patients, about 82% were female with a median age of 59 years
• Findings:
  • Patients with bleeding were noted to have larger tumors (6.5cm) on initial imaging compared to patients that did not report bleeding were noted to have smaller tumors (1.2cm or less)
  • There are significant differences in characteristics and growth patterns between patients that experienced bleeding and those that did not

• Important Takeaway:
  • Patients with larger tumor growth experienced greater bleeding and change in tumor size compared to patients that did not report bleeding, which was a significant factor in determining course of intervention  

Results

• Advanced or metastatic RCC patients were randomized 1:1 to receive nivolumab 1200 mg SQ + recombinant human hyaluronidase PH20 every 4 weeks or nivolumab 3 mg/kg IV every 2 weeks until disease progression
  • SQ administration given over 2-8 minutes in the thigh or abdomen
• After 8 months of minimum follow-up, ORR was 24.2% with nivolumab SQ (95% CI 19-30%) vs 18.2% with IV nivolumab [95% CI 13.6%-23.6%; relative risk 1.33 (95% CI 0.94-1.87)]
• Nivolumab SQ was noninferior to nivolumab IV based on PK and ORR without any new safety signals being observed

• Important Takeaway:
  • SQ nivolumab may be coming to your clinic soon! 

• Background:
  • Clear cell renal cell carcinomas are associated with VHL gene inactivation, like what is found in von-Hippel-Lindau disease, a genetic disorder
  • This causes the activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α), leading to a hypoxic state that drives angiogenesis and tumor growth and proliferation
• Belzutifan specifics:
  • A pill that is used in the treatment of advanced kidney cancer
  • Approved by the FDA in 2021 for the treatment of VHL and in 2023 for clear cell RCC based on the Litespark-005 clinical trial
  • Blocks HIF-2α from interaction with other regulators in the cellular hypoxic state and diminishes the availability of targets for tumor growth
  • Standard dose is 120 mg (40 mg tablets) taken by mouth daily
  • Generally well tolerated:
    • Side effects are anemia, shortness of breath, fatigue, mild nausea, and/or muscle aches
  • It can be administered with or without food

• Important Takeaway:
  • It continues to be studied with other medications as part of clinical trials to assess its effectiveness in treating renal cell carcinoma