Kidney Cancer Therapeutics

kidney cancer: prevalence

~81,610 new cases in US 2024 - NOT super common
• majority - men (64%)
• 4.2% of ALL new cases

~14,390 deaths in US 2024

median age of diagnosis = 65

5-year relative survival rate
• localized 93%
• regional 74%
• distant 17%

kidney cancer: pathology

renal cell carcinomas (RCC) - majority (>85%) of kidney cancer
• arises from proximal tubular epithelium
• 70% RCC = clear cell histology - exhibits 3p-cytogenetic abnormality which is where Von Hippel-Lindau (VHL) gene located
• other histologic subtypes of RCC (non-clear cell) - papillary, chromophobe, oncocytic, collecting-duct, medullary

other types of cancers - transitional cell, Wilms tumors & renal sarcomas

renal cell carcinomas (RCC) pathogenesis: 6 risk factors

heavy smoking (>21 cigarettes/day)

obesity

HTN

acquired polycystic disease of kidney

age - older

gender - male

renal cell carcinomas (RCC) pathogenesis: sporadic

most clear cell kidney carcinomas; ~90% AND
associated w/ loss of function of Von Hippel-Lindau (VHL) tumor suppressor gene, located on short arm of chromosome 3 - keep things in check

renal cell carcinomas (RCC) pathogenesis: genetic syndromes

2-3% RCC thought to be 2ndary to inherited syndromes, esp. in pts <46yo → genetic counseling

Von Hippel-Lindau (VHL) syndrome - most common
• hereditary, autosomal dominant germline mutation of VHL gene
• pts at high risk to develop RCC & renal cysts & other complications

Birt-Hogg-Dube syndrome - mutations in folliculin gene (FLCN)
• can lead to chromophobe RCC, oncocytomas & clear cell RCC

others - hereditary leiomyomatosis & hereditary papillary renal cancer

kidney cancer: screenings & s/s

currently NO preventative screening for pts w/out hereditary risk
• pts at risk for VHL (family history) SHOULD receive genetic counseling & testing
• pts found to have VHL syndrome MAY receive yearly CT or MRI of abdomen

often asymptomatic but MAY present w/ hematuria, flank pain & mass
• other s/s - fever, weight loss, anemia or pain from metastatic disease

workup - CT of abdomen w/ or w/out pelvic CT & chest X-ray or chest CT

kidney cancer: staging

TNM system

clinical & pathologic stage at time of surgery IF early stage

stage IV - low, intermediate & high-risk stratification (clear cell)

kidney cancer: treatment modalities

surgical resection - effective therapy for clinically localized RCC
• radical nephrectomy
• nephron-sparing surgery

active surveillance - option for low stage pts
• really only utilized in elderly pts & those w/ small renal masses (<2 cm)

systemic therapy

kidney cancer: treatment of localized disease

stage I - NO meds, just surgery
• partial* or radical nephrectomy vs. active surveillance vs. ablative techniques - depend on age
*partial nephrectomy preferred for stage T1a
• followed by surveillance

stage II
• partial or radical nephrectomy then treatment based on histology
• clear cell → surveillance or adjuvant pembrolizumab (category I) x1 year for grade 4 tumors ± sarcomatoid features (high risk)
• non-clear cell → surveillance

stage III
• partial or radical nephrectomy then treatment based on histology
• clear cell → surveillance or adjuvant pembrolizumab (category I) x1 year - regardless of what tumor looks like
• non-clear cell → surveillance or clinical trial

kidney cancer treatment: stage I

curative intent - surgery is ONLY cure
• stage I → partial nephrectomy
• followed by surveillance
• radical nephrectomy in pts w/ T1 or T2 lesions = 80% cure
• however, 20-30% of pts w/ localized disease will have recurrence after nephrectomy

20% of pts present w/ metastatic disease at diagnosis
• lungs, bone, liver & brain

kidney cancer treatment: stage II

partial or radical nephrectomy then treatment based on histology

clear cell → surveillance or adjuvant pembrolizumab (category I) for grade 4 tumors ± sarcomatoid features (high risk)

non-clear cell → surveillance

kidney cancer treatment: stage III

partial or radical nephrectomy then treatment based on histology

clear cell → surveillance or adjuvant pembrolizumab (category I) - regardless of what tumor looks like

non-clear cell → surveillance or clinical trial

kidney cancer treatment: stage IV

cytoreductive nephrectomy - considered in pts who have lung-only metastases, good prognostic risk & performance status; considering immunotherapy or targeted therapies; also considered for pts w/ multiple metastatic sites
• followed by systemic therapy

nephrectomy & removal of metastatic disease (IF solitary site)
• followed by systemic therapy

immunotherapy: anti-PDL-1 agents

atezolizumab

atezolizumab & hyaluronidase

avelumab

durvalumab

immunotherapy: anti-PD-1 agents

nivolumab

pembrolizumab

cemiplimab

dostarlimab

nivolumab & relatlimab

retifanlimab

tislelizumab

toripalimab

immunotherapy toxicities

L - lung (pneumonitis) + liver (hepatitis)

E - endocrine (TSH → levothyroxine, SCr, increase glucose)

G - GI (colitis) - really bad diarrhea

S - skin (rash) - most common

metastatic clear cell: 1st line therapy

favorable risk
• axitinib + pembrolizumab (Cat I)
• cabozantinib + nivolumab (Cat I) - reserved as 2nd line, different receptor targets
• lenvatinib + pembrolizumab (Cat I)
• ipilimumab + nivolumab - NOT significant

poor/intermediate risk
• axitinib + pembrolizumab (Cat I)
• cabozantinib + nivolumab (Cat I) - reserved as 2nd line, different receptor targets
• lenvatinib + pembrolizumab (Cat I)
• ipilimumab + nivolumab (Cat I)
• cabozantinib

*PO TKI + immunotherapy

RCC: tyrosine kinase inhibition - generalized ADEs

GI - diarrhea, nausea

hematologic - neutropenia, thrombocytopenia

cardiac - reduced ejection fraction, prolonged QTc

VEGF side effects - HTN, proteinuria, impaired wound healing, bleeding, thrombosis

endocrine - hypothyroidism, hyper/hypoglycemia

dermatologic - rash (hand-foot syndrome)

hepatic - increased LFTs

RCC: tyrosine kinase inhibition - monitoring

axitinib
• TSH
• CBC
• liver function
• consider protein/urine ratio

cabozantinib
• TSH
• CBC
• liver function
• consider protein/urine ratio

lenvatinib
• TSH
• CBC
• liver function
• consider protein/urine ratio
• LV ejection fraction → ECG monitoring recommended in some pts
• QTc - IF on other meds that increase risk

clear cell renal cancer: stage IV - favorable risk category I recommendations

1st line (metastatic setting) = TKI + immunotherapy
• axitinib + pembrolizumab
• cabozantinib + nivolumab
• lenvatinib + pembrolizumab

clear cell renal cancer: stage IV - poor/intermediate risk category I recommendations

ipilimumab + nivolumab
• ipilimumab MOA - recombinant human monoclonal antibody that binds to cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) → allows for enhanced T-cell activation & proliferation
• nivolumab 3 mg/kg, followed by ipilimumab 1 mg/kg q21days x4 cycles; then nivolumab 480 mg q28 days
• ADEs - immunotherapy SE but can be heightened

axitinib + pembrolizumab
cabozantinib + nivolumab
lenvatinib + pembrolizumab

non-clear cell: 1st line treatment

clinical trial

cabozantinib

cabozantinib + nivolumab

lenvatinib + pembrolizumab

non-clear cell: tyrosine kinase inhibition - monitoring

before each cycle
• CBC w/ differential
• CMP - monthly due to increased LFT

baseline & then periodically → lenvatinib
• ejection fraction/ECHO
• TSH
• urinalysis (proteinuria) → controversial
• BP
• blood glucose levels (NO need for fasting)

non-clear cell: tyrosine kinase inhibition - dose reductions

may initiate based on tolerability of SEs

hepatotoxicity - before & during treatment

renal impairment - NO initial dose adjustments, MAY decrease based on tolerability
• dose MAY need to increase IF pt on hemodialysis

worsening of ejection fraction (EF) - may be required to hold medication

tyrosine kinase inhibition in kidney cancer: pharmacist role

diarrhea - hold TKI to see
• AVOID spicy &/or fatty foods, caffeine & fruit
• drink fluids
• loperamide 4 mg, followed by 2 mg (max 16 mg/24 hrs); caution use IF also on immunotherapy (→ colitis)

nausea
• small, frequent meals
• lenvatinib & cabozantinib - moderate/high risk
➢ schedule antiemetic 60 mins prior to each dose
• all other TKIs - minimal to low emetic risk agent
• PRN agent recommended

hand-foot syndrome
• wear loose cotton clothes
• use sunscreen
• apply creams containing lanolin or urea
• avoid tight-fitting shoes & jewelry

CYP3A substrate
• always check drug-drug interaction w/ home meds
• grapefruit juice

immunotherapy ADEs: pharmacist role

assess pt for ADEs associated w/ immunotherapy “LEGS”

management - high dose steroids, prednisone 1 mg/kg/day
• stop immunotherapy while pt on high dose steroids
• commonly accepted OK to resume IF pt on ≤ prednisone 10 mg/day

hypothyroidism → levothyroxine

rash → topical steroids

metastatic clear cell: subsequent therapy

NO previous immunotherapy
• axitinib + pembrolizumab
• cabozantinib + nivolumab
• lenvatinib + pembrolizumab
• ipilumumab + nivolumab
• cabozantinib
• nivolumab
• everolimus + lenvatinib

prior immunotherapy
• axitinib
• belzutifan - pts who have received PD-1 or PD-L1 inhibitor & VEGF-TKI
• cabozantinib - broad receptors
• everolimus + lenvatinib
• tivozanib - for pts who received 2 or more prior systemic therapies

belzutifan

MOA - inhibit hypoxia-inducible factor 2 alpha (HIF-2α), transcription factor that promotes tumor growth

ADEs - anemia, hypoxia, ocular toxicities, decrease effectiveness hormonal contraceptives

hereditary syndromes: treatment

hereditary leiomyoma-renal cell carcinoma
• erlotinib + bevacizumab (other rec)
• carbozantinib + nivolumab (useful in some circumstances)

tuberous sclerosis
• everolimus (preferred)
• sirolimus (other rec)

Von Hippel-Lindau
• belzutifan (preferred)
• pazopanib (useful in some circumstances)