REAL WORLD PRACTICE: ADJUVANT THERAPY READY FOR PRIME TIME? PRO

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1 REAL WORLD PRACTICE: ADJUVANT THERAPY READY FOR PRIME TIME? PRO Alain Ravaud, MD.PhD Bordeaux. France

2 DISCLOSURES Consultant for: Pfizer, Novartis, GlaxoSmithKline, Roche, Bristol-Myers Squibb Institutional research grant from: Pfizer, Novartis Transportation and housing for meetings or speeches from: Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Astra Zeneca, MSD

3 REAL WORLD PRACTICE: ADJUVANT THERAPY READY FOR PRIME TIME? PRO I will support adjuvant therapy for prime time AS AN OPTION TO BE DISCUSSED WITH PATIENTS (population similar to pivotal study STRAC) not as a standard but not systematically rejected for discussion

4 ADJUVANT TREATMENT Previous adjuvant trials Immuno, hormone, cell therapy, all negative Does anti angiogenic relevant? Involved when neo angiogenesis is on construction : M+ setting When µm+? Delaying angiogenesis framework including impairment of cancer stem cell endothelial differentiation 1 VEGFR2 at renal tumor cell surface 2 Could be cytotoxic on tumor cell lines 3,4 Impact of lymphangiogenesis Impact on immune tumoral surroundings : Treg, myeloid-derived supressor cells 5 Direct or indirect impact : involution, apoptosis, dormancy? Hypothesis If relevant, patients with high risk tumors for recurrence have more chance that angiogenesis is implicated and/or sunitinib to be active than for lower risk patients 1. Brossa A, et al. Oncotarget 2015;6: ; 2. Gallego GA, et al. Int J Med Sci 2012;13: ; 3. Canter D, et al. Can J Urol 2011;8: ; 4. Xin H, et al. Cancer Res 2010;70: ; 5. Ozao-Choy J, et al. Cancer Res 2009;69:

5 Survival estimate RISK OF RECURRENCE Patard JJ, et al. J Clin Oncol : ; Leibovitch BC, et al. Cancer 2003;97: ; Zisman A et al. J Clin Oncol :

6 DECISIONS THAT MAY HAVE INFLUENCED THE POSITIVITY OF STRAC High risk population Only Clear cell carcinoma Exclude patients with already M+ Starting dose maintained during all the study Decrease to only one level to maintain the more optimal drug exposure

7 S TRAC Study Design Clear-cell RCC Stratified by UISS risk groups ECOG PS (<2 vs 2) Country N=615 R A N D O M I S A T I O N 1:1 Sunitinib 50 mg/day 4/2 schedule* Placebo 50 mg/day orally, 4/2 schedule* Ravaud A, et al. N Engl J Med 2016 ;375: Dose reduction only to 37.5 mg/day allowed. No alternative schedule as 2/1

8 Study Design (II) Key Eligibility Criteria Clear cell, loco-regional ( T3 and/or N+) RCC Systemic treatment-naïve ECOG PS 0 2 pre-nephrectomy Lack of metastasis, confirmed by blinded independent central review Patients received treatment for 1 year, until recurrence, second cancer, significant toxicity, or consent withdrawal Diagnosis of recurrence was based on centrally confirmed imaging and/or histology findings

9 615 patients enrolled Characteristics Sunitinib n=309 Placebo n=306 Age, median (range), years 57.0 (25 83) 58.0 (21 82) Male / Female, % 71.8 / / 25.2 Baseline ECOG PS, % Unknown Clear cell/non-clear cell, % 99.0/ /0 UISS risk groups, % T3 low* T3 high T4 N0 or NX Any T, N * N0 or NX, Any Fuhrman s grade, ECOG PS 0 or Fuhrman's grade 1, ECOG PS 1. N0 or NX, Fuhrman s grade 2, ECOG PS 1. Any Fuhrman s grade, any ECOG PS. 9

10 Patient Disposition and Treatment Dosing Information Sunitinib n=306 Placebo n=304 Treatment duration*, median (range), months ( ) ( ) Treatment completion, % Treatment discontinuation, % Reasons for discontinuation, % Adverse events Disease progression/relapse Other Dose reductions, n (%) Dose interruptions, n (%) Relative dose intensity, median (range) 88.4 ( ) 99.7 ( ) 10

11 Proportion Disease-Free Disease-Free Survival By Blinded Independent Central Review 3-year DFS rate: 64.9% 5-year DFS rate: 59.3% P=0.030* 59.5% 51.3% Disease-Free Survival (years) Two-sided P value from log-rank test stratified by UISS high-risk group. 11

12 Patient groups Subgroup Analysis Sunitinib mdfs, y (95% CI) Placebo mdfs, y (95% CI) HR (95% CI) P Higher-risk (central review) 6.2 (4.9 NR) 4.0 ( ) ( ) Higher-risk (investigator review) Higher risk patients defined as: 5.9 ( ) 3.9 ( ) ( ) T3, N0 or NX, M0, Fuhrman s grade 2, ECOG PS 1 T4 N0 or Nx, M0, any Fuhrman s grade and any ECOG PS Any T, N1-2, M0, any Fuhrman s grade and any ECOG PS

13 Subgroup Analysis Staehler M, et al. EAU 2017

14 Overall Survival Data for overall survival were not mature at the data cutoff Deaths were reported in 64 (20.7%) sunitinib-treated patients and 64 (20.9%) placebo-treated patients Median overall survival was not reached in either arm HR (sunitinib to placebo) was (95% CI, ); P=

15 Common Treatment-Emergent Adverse Events* Sunitinib (n=306) Placebo (n=304) Adverse Event, % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any adverse event Diarrhea PPE Hypertension Fatigue Nausea Dysgeusia Mucosal inflammation Dyspepsia Stomatitis Neutropenia Asthenia Hair color change Thrombocytopenia

16 Common Serious Adverse Events* Adverse Event, % Sunitinib (n=306) Placebo (n=304) Any adverse event Hypertension Thrombocytopenia Pulmonary embolism Pyrexia Abdominal pain Myocardial infarction Vomiting No deaths were attributed to sunitinib or placebo * In 1% of patients. 16

17 Common Adverse Events Leading to Treatment Discontinuation* Adverse event, % Sunitinib (n=306) Placebo (n=304) Patients discontinuing treatment due to AE PPE Hypertension Asthenia Fatigue Pulmonary embolism Gastroesophageal reflux

18 ANTI ANGIOGENIC TRIALS ASSURE - STRAC + SORCE PROTECT - ATLAS PATIENTS RISK POPULATION M0 pt1b N0 (grade 3-4), pt2-pt4 N0 pt(any)n1 pt3 N0 (grade 2-4) pt4 N0, pt(any) N1 pt1a N0 (grade4), pt1b N0 (grades 3-4), pt2-4 N0 pt1b-4 N1 pt2 N0 (grades 3-4), pt3-4 N0 pt(any) N1 pt2-4 N0 pt(any) N1 HISTOLOGY All Clear cell All Clear cell Clear cell TREATMENT Vs placebo Sunitinib Sorafenib sunitinib sorafenib pazopanib axitinib DURATION 1 yr 1 yr 1 or 3 yrs 1 yr 1 to up 3 yrs END-POINT DFS DFS DFS DFS DFS STARTING- DOSE Standard then 1/2 standard Standard then 1/2 Standard then 1/2 Standard DOSE DECREASE 37.5 mg 25 mg 37.5 mg 1 every 2 days Mandatory CT scan pré inclusion

19 NO METANALYSIS BETWEEN SO DIFFERENT STUDIES METAANALYSIS : «GARBAGE IN, GARBAGE OUT» STRAC and ASSURE : NO PLACE ~20-30 % T3, high risk, 50 mg/d similar population between ASSURE and STRAC But ECOG pre nephrectomy Mandatory CT scan? % similar 0% similar And The way in conducting the trial with different starting dose during trial + 2 levels vs. 3 levels of dose decrease While each of these parameters could be of importance HIGH RISK PATIENTS IN ASSURE* : No gain but still major discrepancies between both studies ASSURE and PROTECT : High similarity between both studies * Haas N, et al. JAMA Oncol 2017 Mar 9. doi: /jamaoncol

20 3 trials in adjuvant setting reported Conclusions STRAC, ASSURE, PROTECT (press release) Only adjuvant treatment with sunitinib prolonged disease-free survival (HR, 0.761; 95% CI, ; P=0.030) in patients with high-risk, loco-regional clear-cell RCC The effect of 1-year adjuvant treatment was sustained over time: more sunitinib-treated patients were event-free at 3 years (5.4%) and 5 years (8%) vs placebo-treated patients No gain in overall survival at data cut-off was reported but not mature Grade 3/4 AEs were more frequent in the sunitinib group. 20

21 DID I CONVINCE YOU TO MY POSITION? I will support adjuvant therapy for prime time as an option to be discussed with patients (population similar to pivotal study STRAC) In addition real world will include 2/1 schedule based on patient tolerance that should increase patients tolerance and patient s reported outcome

22 PATIENTS POSITION Patient representatives from the IKCC network (n = 22) were asked: After surgery for kidney cancer, if your doctor told that you are at high risk of recurrence (spread), would you consider taking sunitinib (Sutent) for one year in the hope you could delay the onset of recurrence even if your overall survival was not improved? 25 % All STRAC population 50 % High risk STRAC population Axel Bex, Laurence Albiges, Börje Ljungberg, Karim Bensalah, Saeed Dabestani, Rachel H. Giles, Fabian Hofmann, Milan Hora, Markus A. Kuczyk, Thomas B. Lam, Lorenzo Marconi, Axel S. Merseburger, Michael Staehler... Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma Eur Urol, 2017;71:719 22