Patrizia Giannatempo
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Tossicità renale da Immune
checkpoint
inhibitors
Co‐Investigator in IMvigor210, IMvigor211, CA209‐275, MK‐3475‐045, DANUBE trials
Disclosures
Typical patient with bladder cancer
Typical clinical trial participant
Renal dysfunction is common in patients with urothelial cancer
Dash et al, Cancer, 2006
Proportion of patients deemed ineligible (i.e. creatine clarance
< 60 min/ml) by the Cockroft‐Gault formula by age group
The burden of cancer is shifting to the elderly
Edwards BK et al. Cancer. 2002
Slide used with courtesy of T. Cerny
3.0
2.5
2.0
1.5
0.5
0
85
75–84
65–74
50–64
<50
2030 2040 2050
2020
2000 2010
Year
Immunotherapy and
kidney failure
Metabolism and Elimination of
Therapeutic Monoclonal Antibodies
• mAbs are metabolized to peptides and amino acids in several tissues, by circulating reticuloendothelial system (RES=macrophages and monocytes)
• Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc‐receptor [FcRn]), which explains their long elimination half‐lives (up
to 4 weeks). Keizer RJ et al., Clin Pharma 2010 Tabrizi MA et al., DDT 2006 Lammerts van Bueren JJ et a., Cancer Res 2006 Duconge J et al., Drug Metab Pharmacokinet 2002
Pharmacokinetics of Therapeutic Monoclonal Antibodies
• intracellular metabolism and be reduced to small endogenous amino acids
• GFR 15 mL / min / 1.73 m (2) or higher has no effect on the clearance compared to normal renal function
Keizer RJ et al., Clin Pharma 2010 Tabrizi MA et al., DDT 2006 Lammerts van Bueren JJ et a., Cancer Res 2006 Duconge J et al., Drug Metab Pharmacokinet 2002
Quanto riportato in RCP Nivolumab:
• Non sono state riscontrate differenze clinicamente importanti nella clearance di nivolumab tra pazienti con compromissione renale lieve(GFR < 90 e ≥ 60 mL/min/1,73 m2; n = 379) moderata (GFR < 60 e ≥ 30 mL/min/1,73 m2; n = 179) e pazienti con funzionalità renale normale.
• I dati su pazienti con compromissione renale severa (GFR < 30 e ≥ 15 mL/min/1,73 m2; n = 2) sono troppo limitati per poter trarre delle conclusioni in questa popolazione
Pembrolizumab
“Non è necessario alcun aggiustamento della dose nei pazienti con danno renale lieve o
moderato. KEYTRUDA non è stato studiato in pazienti con danno renale grave
Quanto riportato in RCP
Immunotherapy and renal impairment
• Ipilimumab/Nivolumab/Pembrolizumab :
– Currently approved ICBs have not been evaluated in patients with severe renal impairment
– No dose adjustment is recommended for patients with mild or moderate renal impairment (i.e. ≥30 ml/min creatinine clearance)
• Clinical and pharmacokinetic data with pre‐
existing severe renal impairment are limited
Uso compassionevole Atezolizumab inel carcinoma uroteliale (II linea)
• …..
• …..
• …..
• Pazienti con adeguata funzionalità renale
• …..GFR>15 mL/min/1,73 m2
Immune checkpoint antibodies:
Renal toxicity
Case Report
• 78‐year‐old man was hospitalized for acute kidney injury
• Metastatic (bone, lung and lymph nodes) melanoma was diagnosed on February 2012
• Ipilimumab 10 mg/Kg every 3 weeks RT (6 Gys in 3 fractions on one axillarymetastatic lymph node)
• 5 days after the 2nd injection, the patient experienced fatigue, anorexia, mild diarrhea and a grade 3 rashes.
Ipilimumab was discontinued.
• Body temperature = 38.5 °C
• blood pressure = 120/80 mm Hg
Izzedine H. et al.,Invest New Drugs 2014
• Progressive renal failure was observed 1 week
• Blood examination:
– leucocytes 11,450/mm3 with eosinophils 2,300/mm3 – urine proteins (0.3 g in a 24 h collection)
– 35.5 leucocytes per high‐power field – negative urinary cultures
• Serum creatinine from 0.68 to 2.33 mg/dl (creatinine clearance 28 ml/min versus 84 ml/min at baseline)
• Hepatitis B and C serology, anti‐nuclear antibody, antineutrophil cytplasmic antibodies (ANCAs) and antiglomerular basement antibodies were negative
Case Report
• Septic screening was negative, no volume depletion, hemodynamic stress, nor administration of nephrotoxic medications neither radio contrast, urinary Bence Jones protein was negative.
• Renal ultrasound showed enlarged, swollen kidneys without dilated pyelocaliceal cavities.
• A percutaneous renal biopsy was performed.
– Severe interstitial inflammation + edema + polynuclear infiltration in glomerular
Case Report
• Oral prednisone at a dose of 1 mg/kg for 4 weeks, followed by fast tapering.
• Serum creatinine level fell to 1.0 mg/dl over the next 2 weeks without dialysis and urinary
leucocytes disappeared.
• His rash had completely resolved and the rest of medical examination was within normal limits.
• Staging showed a 40 % tumor reduction
Case Report
• Mainly asymptomatic laboratory findings
– Elevated creatinine and blood urea nitrogen (BUN) levels
• Change in urine output, proteinuria, flank pain, and edema may be symptoms of renal failure
• Fever may occur
• In some case + other immune‐related AE
• Appears much later, after 14–42 weeks on
immunotherapy Naidoo J,et al. Ann Oncol.2015 Kodner CM el al. Am Fam Physician 2003 Izzedine H et al. Invest New Drugs. 2014 Voskens CJ et al. Plos One 2013
Immuno‐related nephritis: symptoms
Differential diagnosis of immuno‐
related nephritis
• Acute deydration from fluid loss (eg. Diarrhea, CT‐
induced)
• Infection
• Physical obstruction
• Tumor progression in kidney and/or metastatic disease
• Autoimmune disease (e.g LES, sarcoidosis)
• Vascular etiologies
• Metabolic abnormalities (e.g. diabetes)
Kodner CM et al.Am Fam Physician. 2003 Rahman M, et al. Am Fam Physician. 2012
Differential diagnosis of immuno‐
related nephritis
• Infectious etiologies
– fever, chilling, nausea, vomiting, pos urine cultures or viral serology
• Obstruction Hydronephrosis
• PD in kidney CT scan
• Autoimmune disease Ab (ANAs …)
• Vascular etiologies
– livedo reticularis, abdominal bruits, funduscopic abnormalities
• Immuno‐related asymptomatic, mild proteinuria, gradually increasing creatinine, rash
Diagnosis of immuno‐related nephritis:
• Clinical assessment (vital signs, hydratation status, hypotension …)
• Laboratory finding:
– GFR
– Urinalysis
– Complete blood count
– Urine colture and viral serology (e.g.CMV, EBV)
• Radiologic finding:
– US and/or CT scans
Ipilimumab Tremelimumab Nivolumab Pembro Atezo Durvalumab
Mechanism CTLA‐4 inhibitor
CTLA‐4 inhibitor
PD‐1 inhibitor
PD‐L1 inhibitor
PD‐L1 inhibitor
PD‐L1 inhibitor Status
FDA melanoma
FDA mesothelioma
FDA HL, H&N, lung cancer,
RCC, melanoma
FDA H&N, NSCLC, melanoma
FDA NSCLC, urothelial carcinoma
Under trial
Renal failure All Grade (%)
1 None 1‐3 <1 None 1‐2
Kumar V. et al. Pharmac 2017, Hodi et al., 2010; Wolchok et al., 2010; Ibrahim et al., 2011; Eggermont et al., 2015, 2016; Horvat et al., 2015; Larkin et al., 2015; Postow et al., 2015; Robert et al., 2015, Tarhini et al., 2012; Ribas et al., 2013b; Calabro et al., 2015; Kindler et al., 2016, Topalian et al., 2012, 2014; Weber J. S. et al., 2013; Borghaei et al., 2015; Brahmer et al., 2015; Larkin et al., 2015; Rizvi et al., 2015; Robert et al., 2015a; Ferris et al., 2016, Berger et al., 2008; Armand et al., 2013; Westin et al., 2014, Berger et al., 2008; Armand et al., 2013; Westin et al., 2014, Fehrenbacher et al., 2016;
Rosenberg et al., 2016; Rittmeyer et al., 2017, Massard et al., 2016
Immuno checkpoint inhibitors and Renal Failure
How many patients?
CPS = combined positive score of tumor and immune cell PD‐L1 expression.
Pembrolizumab 200 mg Q3W Pembrolizumab
200 mg Q3W
Primary Endpoints
• ORR in all patients
• ORR in patients with PD‐L1–positive
tumors
Patients (N = 350)
• Advanced urothelial cancer
• No prior chemotherapy for metastatic disease
• ECOG PS 0‐2
• Ineligible for cisplatin based on ≥ 1 of the following:
– CrCl <60 mL/min – ECOG PS 2
– ≥ grade 2 neuropathy or hearing loss
– NYHA class III CHF
• Secondary Endpoints: DOR, PFS, OS, and ORR in all patients, PD‐L1 positive and PD‐L1–high expressing patients; safety and tolerability; establish an assay cut point for high PD‐L1 expression
Balar AV et al., Lancet 2016
CDDP UNFIT: KEYNOTE‐052
• Baseline characteristics:
– 70% (n= 83) pts with renal impairment
• GFR less than 60 mL/min and more than 30 mL/min
– 7%(n=8) pts with renal impairment + ECOG PS2
Treatment‐related adverse events:
Renal failure 2 (2%)
• Durvalumab + Tremelimumab 2%
• Ipilumumab (lupus nephrititis or granulomatous nephritis
• Nivolumab + platinum‐doublet chemo in NSCLC phase I
Segal NH, et al. ESMO 2014.
Antonia S, et al. Lancet Oncol 2016.
Izzedine H, et al. Invest New Drugs 2014.
Thajudeen B, et al. AM J Ther 2015 Di Giacomo AM, et al. Cancer Immunol Immunother 2009.
Immune checkpoint inhibitors and Renal Failure
How many patients?
Treatment of immuno‐related nephritis
• Steroids even for low‐grade events (Grade 2) in order to prevent potential progression to higher‐grade event
• Monitor:
– Routine urinalysis
– Elevated serum BUN and creatinine, GFR,
electrolyte imbalance, decrease in urine output, proteinuria
Immuno‐related Nephritis Take home message
• Most cases asymptomatically
• Gradual increases in serum creatinine levels
• Rule out other causes of elevated creatinine or acute failure
• An early intervention can prevent worse or irreversible renal injury ‐‐ Steroids
• Routine laboratory monitoring of kidney function at baseline, prior to each treatment, after treatment cessation
AIOM incontra SIN
patrizia.giannatempo@istitutotumori.mi.it
