Click to edit Master /tle style. Cardiovascular Toxicity in Renal Cell Carcinoma Pa/ents

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1 Click to edit Master /tle style Cardiovascular Toxicity in Renal Cell Carcinoma Pa/ents Bernhard J. Eigl MD FRCPC Medical Oncologist, BC Cancer Agency Clinical Associate Professor, University of Bri/sh Columbia Provincial Director, Clinical Trials

2 Click to edit Master /tle style Disclosures Consultant: Pﬁzer, Sanoﬁ, Janssen, Roche, AstraZeneca Research funding: Pﬁzer, Janssen Educa/onal support: Roche

3 Click to edit Master /tle style Objec/ves Gain general understanding of ﬁrst- line treatment op/ons for RCC Gain understanding of cardiac toxici/es of TKIs Mechanism Relevance Management

4 RCC Overview The disease More than 200,000 new cases of RCC worldwide annually RCC incidence has been rising by 2% per year for the past 6 decades Approx. 25% of RCC pa/ents present with metasta/c disease Treatment prior to 2005 Cytokine based therapies had low efficacy, median PFS 3-5 months, median OS 13 months Since targeted agents FDA- approved for treatment of RCC Outcomes (survival, QOL) have greatly improved

5 Suni.nib vs. Interferon Alfa in mrcc Suni/nib Median: 11 months IFN Median: 5 months Motzer NEJM 2007; JCO 2009

6 Impact of new agents on BC pa.ent survival Group B+C: first- /second- line SuniBnib 1 year OS 75% Group A: IFN alone 1 year OS 40% Log rank p<0.0001

7 First- line Treatment of mrcc: Current Op.ons Study ORR, % Median PFS, mo* Median OS, mo* Sunitinib vs IFN-α 1 47 vs. 12 Bevacizumab + IFN-α vs IFN-α 2 31 vs. 13 Bevacizumab + IFN-α vs IFN-α vs Pazopanib vs placebo 6 32 vs vs. 5 P < vs. 5.4 P = vs. 5.2 P = vs. 4.2 P = vs 21.8 P = vs P = vs P = vs P = Pazopanib vs Sunitinib 7 31 vs vs. 9.4 noninferior 28.4 vs 29.3 noninferior *Intent to treat analysis 1. Motzer RJ et al. J Clin Oncol. 2009; 2. Escudier B et al. Lancet Rini B et al. J Clin Oncol. 2008; 4. Escudier B et al. J Clin Oncol. 2009; 5. Hudes G et al. N Engl J Med Sternberg C et al. J Clin Oncol. 2010; Motzer et al NEJM 2013

COMPARZ Study Key Eligibility Criteria Advanced/metasta/c RCC Clear- cell

0) KPS 70 Adequate organ func/on Stra/fica/on factors: Karnogsy Performance Status

8 COMPARZ Study Key Eligibility Criteria Advanced/metasta/c RCC Clear- cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS 70 Adequate organ func/on Stra/fica/on factors: Karnogsy Performance Status (KPS; vs ) Prior nephrectomy (yes vs. no) N=1110 Randomised 1:1 Baseline lactate dehydrogenase (LDH; >1.5 vs. 1.5 x ULN) Pazopanib 800 mg OD ConBnuous dosing SuniBnib 50 mg OD 4 wk on/2 wk off 1. Motzer R, et al. ESMO 2012 oral presenta/on; abstract LBA8_PR.

9 COMPARZ: Suni.nib and Pazopanib are only real first line op.ons 1. Motzer R, et al. NEJM 2013

Most common adverse events 30% 1 (treatment-emergent) Pazopanib (n = 554) % Sunitinib (n = 548) % Adverse Event All Grades All Grades Any event a >99 >99 Diarrhea 63 57 Fatigue 55 63 Hypertension 46

10 Most common adverse events 30% 1 (treatment-emergent) Pazopanib (n = 554) % Sunitinib (n = 548) % Adverse Event All Grades All Grades Any event a >99 >99 Diarrhea Fatigue Hypertension Nausea Decreased appetite ALT increased Hair colour changes Hand-foot syndrome Taste alteration Thrombocytopenia a 2% of pa/ents in pazopanib arm and 3% of pa/ents in suni/nib arm had grade 5 adverse events Blue Highlight: Risk greater for suni/nib and 95% CI for rela/ve risk does not cross 1 Yellow highlight: Risk greater for pazopanib and 95% CI for rela/ve risk does not cross 1 1. Motzer R, et al. ESMO 2012 oral presenta/on; abstract LBA8_PR.

11 Evolu.on of Overall Survival (OS) with Targeted Agents in mrcc Median OS (Months) Before Targeted Agents Treatment expectations in mrcc have evolved from short term palliation to long-term treatment/survival and therefore toxicities! Era of Targeted Agents Coppin C, et al. Cochrane Collab. 2006;2:CD001425; 2. Escudier B, et al. N Engl J Med. 2007;356: ; 3. Bayer Healthcare. Nexavar (sorafenib) Summary of Product Characteristics, 2008; 4. Escudier B, et al. Lancet. 2007;370: ; 5. Motzer RJ, et al. J Clin Oncol. 2009;27:

12 VEGF Mayor, S. CancerWorld e- Grand- Round (2015)

13 Cardiac Toxici.es of mrcc Therapies Hypertension Myocardial Dysfunc/on ECG changes Thromboembolic events Friday 8:00 Dr. M. Mauro

14 Hypertension

15 Mechanisms of hypertension (HTN) induced by angiogenic inhibitors: the therapeutic low free vascular endothelial growth factor (VEGF) activity contributes to the increase of systemic vascular resistances as a result of vascular rarefaction and downregulation of nitric oxide production, dysregulation of renal endothelial cells and podocyte VEGF expression leading to thrombotic microangiopathy and thereby HTN. H. Izzedine et al. Ann Oncol 2009;20:

16 An.angiogenic Agent- related Hypertension Agent All Grades Grade 3/4 Bevacizumab 9% 1% Pazopanib 13% <1% Sorafenib 17% 4% Sunitinib 30% 17% Axitinib 27% 15% Cediranib 16% 19% NS = not specified l Class effect l Often does not require dose reduction l Regular monitoring of blood pressure is important DiLorenzo G, et al. Eur Urol 2011; Veronese ML, et al. J Clin Oncol. 2006;24: ; Sica DA. J Clin Oncol. 2006;24:

17 Suni.nib mediated hypertension Can be rapid onset Close (home) monitoring and interven/on important Azizi N. et al, NEJM 2008

18 Hypertension - Management Kollmannsberger et al. CUAJ 2007

19 But, hypertension is likely a biomarker of an.tumor efficacy In a retrospec/ve analysis, suni/nib- associated HTN was associated with improved clinical outcome HTN was a significant independent predictor of survival Probability of overall survival With HTN (n=441) Median OS, 30.5 months Without HTN (n=93) Median OS, 7.8 months P< Time (months) Patients should be monitored in the clinic for HTN and treated as necessary Use of anti-htn agents did not reduce sunitinib antitumor activity These findings warrant further study and validation in prospective clinical trials Rini B et al IKCS 2009

20 Suni.nib: Toxicity and Efficacy Toxicity in Sunitinib Study (N pts) PFS (mons) P value Hypertension Hand Foot Syndrome Pooled analysis of trials (544) Pooled analysis of trials (770) 12.5 vs 2.5 P< vs. 8.3 P<0.001 Hypothyroidism Retrospective (50) 21.7 vs 14.2 P<0.001 Rini et al JNCI 2011 Michaelson et al GU Cancers Symp 2011 Abstr 320 Pinto et al GU Cancers Symp 2012 Abstr 466

21 Dose intensity and survival (a digression) COMPARZ told us Pazo is non- inferior to suni/nib (4 weeks on: 2 weeks off) Toxicity is beser (assessed at day 28 of 6 week cycle) BUT: if toxicity correlates with response, are we dosing suni/nib right?

Sunitinib Dose Response Relationship Probability of a response 1.0 0.8 0.6 0.4 0.2 0.0 Mean 95% CI p=0.023 for AUC 0.5 1.0 1.5 2.

22 Sunitinib Dose Response Relationship Probability of a response Mean 95% CI p=0.023 for AUC AUC sunitinib (ug hr/ml) Fraction pts surviving OS in mrcc High AUC (n=120) Low AUC (n=119) l Inhibition of VEGFR and PDGFR phosphorylation in tumors is doseand time-dependent l Sunitinib exposure is a function of dose and individual clearance l Highest sunitinib exposure resulted in highest probability of response l Higher sunitinib exposure resulted in improved survival Mendel DB, et al. Clin Cancer Res. 2003;9: Houk BE, et al. J Clin Oncol. 2007;25(Suppl 18s):5027 (Abstract) Historical placebo median Time (days) 22

23 Phase II study of individualized sunitinib as first-line therapy for metastatic clear cell renal cell cancer Bjarnason GA, Knox JJ, Kollmannsberger C, Soulières D, Ernst S, Canil C, Winquist E, Zalewski P, Hotte, S, North S, Heng DY, Macfarlane RJ, Czaykowski P, Venner P, Basappa NS. Patients entered in 13 Cancer Centers in Canada: Toronto, Edmonton, London, Vancouver, Ottawa, Halifax, Calgary, Oshawa, Hamilton, Montréal, Kingston and Winnipeg Supported by a Pfizer Investigator Initiated Research Grant to Dr. Bjarnason Bjarnason et al ASCO 2015

Dose/schedule allocation of patients during first and

on first course Subsequent Cycles First cycle Grade-2

Stop Rx for 7 d* Modify dose/schedule DL-1: Pts than

days / 7 days off DL-2: Pts than cannot take 50 mg for 7

# of days / 7 days off DL-3: Pts than cannot take 37.

Grade-1 toxicity: Continue Rx Toxicity evaluation after

for 7 d* Escalate dose DL+1: 62.5 mg 14/7 DL+2: 75.

Reduce off-rx time to 7d* DL+: 50mg 28/7d Individually

24 Dose/schedule allocation of patients during first and subsequent Rx cycles Toxicity evaluation after 2 weeks on first course Subsequent Cycles First cycle Grade-2 toxicity: Stop Rx for 7 d* Grade-2 tox before 4 weeks: Stop Rx for 7 d* Modify dose/schedule DL-1: Pts than cannot take 50 mg for 28 d - 50 mg individualized # of days / 7 days off DL-2: Pts than cannot take 50 mg for 7 d mg individual. # of days / 7 days off DL-3: Pts than cannot take 37.5 mg for 7-25 mg individualized # of days / 7 days off Grade-1 toxicity: Continue Rx Toxicity evaluation after 4 weeks on first course Grade-1 tox At 4 weeks: Stop Rx for 7 d* Escalate dose DL+1: 62.5 mg 14/7 DL+2: 75.0 mg 14/7 Grade-2 tox At 4 weeks: Stop Rx for 7 d* Reduce off-rx time to 7d* DL+: 50mg 28/7d Individually maximize days on Rx during conbnued therapy based on toxicity * Or until toxicity has resolved Bjarnason et al ASCO 2015

25 Response and PFS* for 108 evaluable patients Study OZM 42 EFFECT COMPARZ Drug Individualized Sunitinib Sutent standard dose Axitinib vs. Sorafenib Phase-III 1 st line Sunitinib Pazopanib Axitinib data N CR % 3.9 (n=4) 0 <1 < 1 0 PR % 44.1 (n=45) CR+PR % 48.0 (n=49) SD % 41.2 (n=42) CR+PR+SD 89.2 (n=74) PD % 10.8* (n=11) PFS (mo) Pending* % CI /102 (43.1%) evaluable pts still on therapy* COMPARZ and Axitinib pts had better prognostic factor Bjarnason et al ASCO 2015

Individualized therapy = Personalized therapy for all n Safe and feasible in a multicenter setting w An effective way to manage toxicity n Responses are among the best for any TKI in RCC w

26 Individualized therapy = Personalized therapy for all n Safe and feasible in a multicenter setting w An effective way to manage toxicity n Responses are among the best for any TKI in RCC w Implications for dosing of Sutent in other indications and other TKI s w Potential use in combinations with immunotherapy n Associated with improved dose intensity w Individualizing days on treatment overcomes oral dosing limitations w PK data pending. n Compensates for other variables w Diet / Drug interactions, gender, declining AUC over time, SNP s n Empowers patients to take an active role w Understand well the concept of toxicity vs. activity w More receptive to moderate toxicity Bjarnason et al ASCO 2015

27 Myocardial Dysfunc.on

28 Mechanism Force T, et al. Nat Rev Cancer 2007

29 An.angiogenic Agent- related LVF Agent All Grades Grade 3/4 Bevacizumab 1-6% <1% Pazopanib 13% <1% Sorafenib 4% 0% Sunitinib 13% 3% NS = not specified l CRDC Type II l Usually reversible l TKI treatment can continue (with dose modification) if CHF is managed DiLorenzo G, et al. Eur Urol 2011; Hall P, et al. JACC: Heart Failure 2013; Szmit S, et al. Acta Oncologica 2009.

30 Suni.nib and CHF Meta- analysis of available phase II and III studies (not only RCC) N=6935 Incidence of CHF: all- grade = 4.1%; high- grade = 1.5% RR of CHF (rela/ve to placebo): all- grade 1.81; high- grade 3.3 Richards CJ, et al. JCO 2011

31 Real world seung common if you look for it. Hall P, et al. JACC: Heart Failure 2013

32 Cardiac Toxicity Management Kollmannsberger et al. CUAJ 2007

33 ECG Changes TKIs including suni/nib have poten/al to increase QTc in dose dependent manner However meta- analysis data on >5,000 pa/ents demonstrated <2.3% grade 3 and <0.1% Torsade in suni/nib exposed pa/ents. Even lower for pazopanib (<0.3% grade 3) Risk- stra/fied monitoring and evalua/on of concomitant medica/ons is warranted. Bello C, et al. Clin Cancer Res 2009; Ghatalia P, et al. BJC 2015

34 Click to edit Master /tle style Summary The treatment landscape of metasta/c RCC has evolved greatly over the last 10 years Median survivals measured in years rather than months Evolu/on con/nues now with immunotherapeu/cs Side eﬀect management and treatment individualiza/on is crucial Mul/- disciplinary care of toxici/es is increasingly important

35 Click to edit Master /(slides) Acknowledgements tle style C. Kollmannsberger G. Bjarnason

36 Click to edit Master /tle style Thank You.

David N. Robinson, MD

David N. Robinson, MD Background and Treatment of mrcc Background ~ 64,770 new cases of kidney/renal pelvis cancers will be diagnosed in the US in 2012 with an estimated 13,570 deaths [1] ~ 75% are clear-cell