Tossicità renale da Immune checkpoint inhibitors - Patrizia Giannatempo - Aiom

Tossicità renale
    da Immune
    checkpoint
     inhibitors
  Patrizia Giannatempo
Fondazione IRCCS Istituto Nazionale
     dei Tumori, Milano, Italy

Disclosures

 Co‐Investigator in IMvigor210, IMvigor211,
  CA209‐275, MK‐3475‐045, DANUBE trials

Typical patient with   Typical clinical trial
  bladder cancer           participant

Renal dysfunction is common in
patients with urothelial cancer
Proportion of patients deemed ineligible (i.e. creatine clarance
   < 60 min/ml) by the Cockroft‐Gault formula by age group

                                                     Dash et al, Cancer, 2006

The burden of cancer is shifting to the
   elderly
                 3.0

                 2.5                                                         85

                 2.0
                                                                             75–84

                 1.5
                                                                             65–74

                 0.5                                                         50–64

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
                                                            Keizer RJ et al., Clin Pharma 2010
  to 4 weeks).                                                    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

Quanto riportato in RCP

            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

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

Case Report
• 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

Immuno‐related nephritis: symptoms
 • 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

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

Immuno checkpoint inhibitors and
                     Renal Failure
                 How many patients?
                     Ipilimumab              Tremelimumab                 Nivolumab              Pembro                   Atezo                   Durvalumab

Mechanism
                         CTLA‐4                     CTLA‐4                     PD‐1                   PD‐L1                    PD‐L1                   PD‐L1
                        inhibitor                  inhibitor                 inhibitor               inhibitor                inhibitor               inhibitor

Status                                                                      FDA HL,
                                                                             H&N,                  FDA H&N,               FDA NSCLC,
                         FDA                      FDA
                                                                          lung cancer,              NSCLC,                 urothelial               Under trial
                       melanoma               mesothelioma
                                                                             RCC,                  melanoma                carcinoma
                                                                           melanoma
Renal
failure
                              1                      None                        1‐3

Patients (N = 350)
      • Advanced urothelial
        cancer                                                                            Primary Endpoints
      • No prior chemotherapy
                                             Pembrolizumab
        for metastatic disease                200 mg Q3W                                • ORR in all patients
      • ECOG PS 0‐2                                                                     • ORR in patients with
      • Ineligible for cisplatin                                                          PD‐L1–positive
        based on ≥ 1 of the                                                               tumors
        following:
       – CrCl

• 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%)

Immune checkpoint inhibitors and Renal
               Failure
         How many patients?
• 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.

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

Thank you

patrizia.giannatempo@istitutotumori.mi.it

                               AIOM incontra SIN