Renal insufficiency and TKI ? Myth or Reality Vincent LAUNAY-VACHER Service ICAR, CHU Pitié-Salpêtrière, Paris Friday September 2, 2016 Paris

COI Vincent Launay-Vacher 3 years Indirect links (Research grants, eJournals, Educational grants, …) Amgen, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Gilead, Hospira, Ipsen, Leo Pharma, Pierre Fabre, Roche, Teva, Vifor Pharma Direct links (Consulting, Talks, …) Amgen, Leo Pharma, Pierre Fabre Oncology, Roche, Sanofi, Takeda, Teva Service ICAR SiteGPR Cancer & the Kidney International Network

Renal insufficiency is highly frequent in cancer France1,2 : IRMA studies (IRMA-1 and IRMA-2) 4’684 et 4’945 patients (all types of solid tumors) DFG<60 : 12.0% et 11.8% (MDRD) Belgium3 : B-IRMA study 1’218 patients (all types of solid tumors) DFG<60 : 16.1% (MDRD) United-States4 : 1’114 patients (kidney cancer) DFG<60 : 22,0% (MDRD) Japan5 : 231 patients (all types of solid tumors) DFG<60 : 25.0% (MDRD) Austria6 : 1’100 patients (all types of solid tumors) DFG<60 : 14.7% (MDRD) et 16.1% (CKD-EPI) Prevalence varies from 12 to 25% 1Launay-Vacher V et al. Cancer 2007; 2Launay-Vacher V et al. Semin Nephrol 2010; 3Janus N et al. Br J Cancer 2010; 4Canter D et al. Urology. 2011; 5Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011; 6Königsbrügge O et al. Thromb Res 2014

Renal insufficiency is highly frequent in cancer Whatever the type of tumor, only a MINORITY of patients present with NORMAL renal function 1Launay-Vacher V et al. Breast Cancer Res Treat 2010; 2Launay-Vacher V et al. Lung 2009; 3Launay-Vacher V et al. Clinical Genit Cancer 2009; 4Personal data IRMA-1

Renal insufficiency in kidney cancer 23% 21% 22% 12,5% 22% 22% Canter D et al. Urology. 2011

Renal insufficiency impacts survival France1 : DFG<60 => Decreased Overall Survival HR 1.27 (p=0.0002) Japan2 : DFG<60 = independent risk factor for increased 1-year mortality Korea3 : 30<DFG<60 => HR 1.12 (p=0.04) for increased cancer-related mortality DFG<30 => HR 1.75 (p<0.001) for increased cancer-related mortality Australia4 : DFG<60 => increased cancer-related mortality HR 1.27 Each decrease in GFR of 10 ml/min/1.73m2 = 18% increase in cancer-related mortality (p<0.001) 1Launay-Vacher V et al. Semin Nephrol 2010; 2Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011; 3Na SY, et al. Am J Nephrol. 2011; 4Iff S, et al. Am J Kidney Dis 2014

Links Renal insufficiency  Survival The physio-pathological hypothesis Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency The pharmacological hypotheses

Renal insufficiency patients are at risk for renal TOXICTY Renal insufficiency => Risk factor for Acute Kidney Injury (AKI) More frequent More severe

Cancer drugs with a renal risk Immune checkpoint inhibitors Toxicity Incidence Ipilimumab Nivolumab Pembrolizumab Estimated cost Renal failure 13,9% 9,9% $8854 Colitis 10,2% 10,9% 9,7% $8563 Hypopituitarism 20,4% 4,0% 7,6% $4979 Nephritis 1,6% 2,0% 0,0% $4218 Peripheral neuropathy 12,8% 33,7% 16,7% $3960 Oliguria/Anuria 1,0% $3807 Pancreatitis 1,8% 2,8% $3590 Dyspnea 8,4% 31,7% 8,3% $3345 Fever 17,8% 22,8% 20,8% $3304 Pneumonitis 0,5% 0,7% $2580 Ventricular arythmia 18,8% $2246 Seizures 5,6% $2167 Fatigue 72,0% 87,1% 91,0% $2069 Myalgia/Pain 8,1% 7,9% $1947 Nausea/Vomiting 47,9% 59,4% 54,9% $1442 Neutropenia 21,5% 16,8% 26,4% $859 Thrombocytopenia 12,0% 14,9% 10,4% $854 Anemia 42,9% 34,0% $851 Diarrhea 15,8% 40,3% $775 Hypo/Hyperthyroidism 33,5% 39,6% 38,2% $583 Hepatitis 3,5% $529 Renal toxicities: - 10-14% incidence - Highly costly Mason NT. et al.- ASCO® 2016 - Abs 6627

Acute Kidney Injury impacts survival In cancer patients (MD Anderson study) An increase in SCr of 10% as compared to baseline is associated with increased in-hospital mortality An increase in SCr of 25% during the first 72 hours in ICU is associated with a doubling in mortality: 14.3 versus 30.1%, p<0.001 NCI-CTCAE v4 Increase of 50 to 100% SamuelsJ et al. Support Care Cancer 2011

Links Renal insufficiency  Survival The physio-pathological hypothesis Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency The pharmacological hypotheses Patients at risk for AKI => increased mortality

Non-optimal use of cancer drugs If RI has not been identified or If RI has been identified but no dosage adjustment OVERDOSAGE Dose-related toxicities Consequences these toxicities: - Delayed courses - Change in treatment - Switch to palliative care (Elderly +++)

Non-optimal use of cancer drugs If RI has not been identified or If RI has been identified but no dosage adjustment If RI has been identified But dosage adjustment: Too much reduced Empirical adjustment OVERDOSAGE Toxicity UNDER -DOSAGE Lack of efficacy Crucial to prescribe the right dosage, adjusted to patient’s renal function

Non-optimal use of cancer drugs This is not only theory: This is real-life Monocentric prospective observational study Metastatic colorectal cancer, all patients treated the same, « normal » SCr Capecitabine + Oxaliplatin (4 courses) Capecitabine: 1000 mg/m2, twice daily, D1-14, Q3W Oxaliplatin: 130 mg/m2, D1, Q3W Chen J, et al. Support Care Cancer 2015

Non-optimal use of cancer drugs This is not only theory: This is real-life Increased toxicity Chen J, et al. Support Care Cancer 2015

Non-optimal use of cancer drugs This is not only theory: This is real-life More treatment interruptions or modifications Reduced survival (Time to progression) => Adjusted HR TTP 1.57 [1.09–2.25] P=0.015 Chen J, et al. Support Care Cancer 2015

Links Renal insufficiency  Survival The physio-pathological hypothesis Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency The pharmacological hypotheses Patients at risk for AKI => increased mortality Patients at risk for a non-optimal use of cancer drugs: When dosage is not adjusted to renal function, survival is reduced (time to progression, metastatic colorectal cancer)

Non-optimal use of cancer drugs This is not only theory: This is real-life Prospective interventional study Adjuvant breast cancer (Age ≥ 65 years) Patients treated with: CMF (Cyclophosphamide, Methotrexate, Fluorouracile) AC (Doxorubicine, Cyclophosphamide) Capecitabine Dosage adjusted to renal function Lichtman SM, et al. J Clin Oncol 2016

Non-optimal use of cancer drugs This is not only theory: This is real-life Endpoints : Overall survival (OS) Relapse-free survival (RFS) Analyses of the effect of renal function on survival: GFR as a discontinuous variable: « early » vs. « late » => Survival curves GFR as a continuous variable => Hazard Ratios Stade DFG N (%) CMF AC Capé 1 ≥90 3 (2) 5 (3) 5 (2) 2 60-89 34 (25) 61 (34) 71 (24) 3 30-59 95 (70) 112 (62) 224 (74) 4 15-29 4 (2) 2 (1) 5 <15 0 (0) CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide ; Capé : Capécitabine Only 7% of patients with normal GFR Lichtman SM, et al. J Clin Oncol 2016

Non-optimal use of cancer drugs This is not only theory: This is real-life RELAPSE-FREE SURVIVAL CMF AC Capé Endpoint HR [95% CI] P Relapse-free survival   CMF 1,06 [0,86-1,33] NS AC 1,08 [0,90-1,28] Capecitabine 0,93 [0,80-1,08] CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide Lichtman SM, et al. J Clin Oncol 2016

Non-optimal use of cancer drugs This is not only theory: This is real-life OVERALL SURVIVAL CMF AC Capé Endpoint HR [95% CI] P Overall survival   CMF 1,10 [0,87-1,41] NS AC 1,05 [0,87-1,27] Capecitabine 0,92 [0,78-1,09] CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide Lichtman SM, et al. J Clin Oncol 2016

Links Renal insufficiency  Survival The physio-pathological hypothesis Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency The pharmacological hypotheses Patients at risk for AKI => increased mortality Patients at risk for a non-optimal use of cancer drugs: When dosage is not adjusted to renal function, survival is reduced (time to progression, metastatic colorectal cancer) When dosage is adjusted to renal function, survival in RI patients is similar to that of normal renal function patients (OS and RFS, adjuvant breast cancer in the elderly)

Renal insufficiency and TKIs Hepatic metabolism => No dosage adjustment required in patients with RI Hepatic metabolism may be reduced in CKD Uremic toxins may alter: The hepatic uptake of drugs CYP activity MYTH

Renal insufficiency and TKIs Hepatic metabolism => No dosage adjustment required in patients with RI Hepatic metabolism can be reduced in CKD Do not forget the metabolites ! MYTH Van Erp NP, et al. Cancer Treatment Reviews 2009

Renal insufficiency and TKIs THE REALITY Example of Vandetanib: Oral tyrosine kinase inhibitor (VEGFR-2, EGFR, and RET) Renal excretion accounts for less than 25% of the administered drug Hepatic metabolism / biliary excretion are the main routes of elimination However, vandetanib PKs are altered in renal impairment: Clearance reduced by 30% and AUC increased by 40%1 AUC increased from 1.5 to 2-fold in mild to severe renal impairment2 Dosage adjustment is required Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

Vandetanib PKs in liver and renal impairment x 1,08 x 0,93 x 1,41 x 0,71 Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

Renal insufficiency and TKIs THE REALITY Example of Vandetanib: Oral tyrosine kinase inhibitor (VEGFR-2, EGFR, and RET) Renal excretion accounts for less than 25% of the administered drug Hepatic metabolism / biliary excretion are the main routes of elimination Vandetanib PKs are altered in renal impairment: Clearance reduced by 30% and AUC increased by 40%1 AUC increased from 1.5 to 2-fold in mild to severe renal impairment2 Dosage adjustment is required Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

Renal insufficiency and TKIs THE REALITY Example of Vandetanib: PKs are altered in RI Dosage adjustment is required Example of Sunitinib: Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

Decreased exposition to sunitinib AND its metabolite in RI AUC(0-48) Normal Severe RI ESRD Sunitinib 1892 1781 998 SU12662 719 580 504 Sum 2611 2361 1502 Difference vs. Normal -9,6% -42,5% Sunitinib Decreased exposition to sunitinib AND its metabolite in RI Authors conclude that the safety is OK What about the efficacy ? Metabolite Khosravan R et al. J Clin Pharmacol 2009

Renal insufficiency and TKIs THE REALITY Example of Vandetanib: PKs are altered in RI Dosage adjustment is required Example of Sunitinib: PKs are altered Dosage adjustment ? Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

Renal insufficiency and TKIs THE REALITY TKI Pharmacokinetic modifications in CKD ? Risk Dosage adjustment in CKD Axitinib No data ? Erlotinib No - Not required Lapatinib Sorafenib  Toxicity has been reported Sunitinib YES: exposition  Under-Dosage Theoretically yes, but how ? Vandetanib YES: exposition  Over-Dosage 200 mg in moderate RI Not recommended in severe RI SiteGPR (www.sitegpr.com)

CONCLUSIONS Renal insufficiency is highly frequent in cancer patients Renal Insufficiency is associated with increased cancer- related mortality The main cause is a non-optimal use of cancer drugs (dosage adjustment) TKI can require dose adjustment, even if the liver is the main route of elimination Data are lacking on how to adjust TKI dosage in Renal Insufficiency

Education and research on cancer and renal insufficiency www.SiteGPR.com www.C-KIN.com Dosage adjustments Education and research on cancer and renal insufficiency

Thank you… …for your attention ! vincent.launay-vacher@aphp.fr