Adjuvant Therapies in RCC: What we think we Know

Transcription

1 3/4/18 Adjuvant Therapies in RCC: What we think we Know Robert G. Uzzo, M.D. Willing G. Pepper Chairman of Surgery Fox Chase Cancer Center Temple University School of Medicine Chair, Department of Urology Urological Institute at Einstein Healthcare Network Philadelphia, PA USA We are all managers of health care risk We seek to understand, predict and prevent future health care events Adjuvant Biomarkers Clinical Models 1

2 Physicians: Managers of cancer RISK Identifying Risk - Screening - Population studies - Public health Risk tools - Big data - Predictive models - Biomarkers - Genomics Communicating Risk - Clinical decision making - Informed consent - RCTs Mitigating Risks - Surgically - Medically/XRT - Adjuvant Rx - Behavioral modification 2

3 Prognostic Biomarkers in ccrcc 3

4 4

5 Eur Urol June 2016 N=189 pts and 104 controls Statistically significant differences in 15/26 AA measured (13 lower/2 higher) J Urol: 186(4), 1206,

6 CMA on n=414 RCC Ther Adv Urol 10(1); 3-10; 2018 Clinical Biomarkers in RCC Stage Grade Histology 6

7 Risk Models for Localized RCC Model Presentation Reported/Externally validated C-index 1. TNM stage UISS N=814 MSKCC* N=701 SSIGN N=1801 Leibovich* N=1671 Karakiewicz N=2474/2530 KM estimates 0.73/ Nomogram 0.82/ Points based algorithm Points based algorithm 0.84/ / Nomogram 0.89/ Nuclear Grade 3. Tumor Size 4. Performance Status 5. Presentation (symptoms) 6. Age 7. Gender Yaycioglu Formula 0.65/ Condolo Formula 0.67/ Coagulative necrosis All models retrospective * Localized pts only Risk Models for Localized RCC Model 1 outcome # events in NoMo patients MSKCC* RFS 72 Leibovich* MFS 479 Karakiewicz RCC specific survival? SSIGN CSS? UISS OS events in NoMo patients predicted by these models 7

8 Risk Models for mrcc Model N Subtype Cohort C-index internal C-index validation MSKCC RCC pretx, PreTKIs ( ) French RCC Cytokine trials ( ) Mayo ccrcc Post Nx ( ) CCF ccrcc TKI or antivgef ( ) IMDC RCC TKI or antivgef ( ) IKCWG RCC Trial pts, 11 sites ( ) Motzer JCO Negrier Ann Oncol 3 Leibovich J Urol 4 Choueiri Can J Urol 5 Heng JCO Manola CCR Heng Lancet 2013l Eligibility for n=7 most recent adjuvant RCC RCT based on these predictive tools (with 565 events in NoMo pts) N= 8855 pts accrued 8

9 Estimated Costs of Adjuvant RCC Trials Trial Sponsor N Eligibility Model ASSURE sorafenib/ sunitinib S-TRAC Sunitinib ECOG PFE Bayer PFE Intermediate and high risk UISS High risk UISS Estimated Cost >$80 million ($40 million from industry) $100 million IMmotion Atezolizumab Genentech SUOCTC 1537 Intermediate and high ptnm risk Leibovich model $265 million Opportunity costs: IMmotion $265 million School of Medicine = $82,979,986 School of Law = $42,362,035 School of Pharmacy = $15,791,479 School of Public health = $34,705,584 School of Nursing = $18,744,487 School of Music/Dance and Theater = $37,406,205 School of Natural Resources/Environment = $10,174,566 School of Social Work = $22,124,186 Total = $264,288,

10 Are current models good enough to guide $300,000,000+ expenditure for adjuvant RCC trial design?... Risk Models for Localized RCC: Prospective Validation Model Presentation Reported/Externally validated C-index UISS KM estimates 0.73/ MSKCC** Nomogram 0.82/ SSIGN Leibovich** Points based algorithm Points based algorithm 0.84/ / Karakiewicz Nomogram 0.89/ Prospective ECOG validation C index ** Localized pts only Uzzo, Haas et al - unpublished 10

11 So how have we done with Adjuvant therapies? Adjuvant Rx in Cancer (RCC) Incompletely effective (high quality) surgery Completely effective systemic Rx The Dark Ages The Middle Ages The Renaissance?? 11

12 Adjuvant RCC Trials: The Dark Ages Incompletely effective surgery with completely ineffective systemic Therapy v almost Treatment Outcome Radiation vs observation (N=72) NO BENEFIT MPA vs observation (N=136) NO BENEFIT Tumor cells + BCG vs observation (N=120) NO BENEFIT Recombinant IFN-α2b vs observation (N=247) NO BENEFIT IFN-α vs observation (N=283) NO BENEFIT High-dose IL-2 vs observation (N=69) NO BENEFIT Tumor cell vaccine vs observation (N=558) 5-year PFS: 77.4% vs 67.8% (P=0.02) IL-2 + IFN-α2a + FU vs observation (N=203) Thalidomide vs observation (goal N=220 closed) Oncophage (HSPPC-96) vs observation (N >800) IL-2 + IFN-α2a + FU vs observation (N=550) NO BENEFIT NO BENEFIT NO BENEFIT NO BENEFIT Kunkle, Haas, Uzzo Current Urol Rept 8(1):19, 2007 Adjuvant RCC Trials: The Middle Ages Incompletely effective surgery with more effective systemic Therapy Trial Sponsor N Clear Cell Only? ASSURE sorafenib/ sunitinib Duration of Rx (yrs) Eligibility Model ECOG 1943 No 1 Intermediate and high risk UISS 1 endpoint DFS HR = 1.02 No change in DFS/OS S-TRAC Sunitinib PFE 615 Yes 1 High risk UISS DFS HR = 0.76 Improved DFS but not OS SORCE Sorafenib PROTECT Pazopanib ATLAS Axitinib MRC 1656 No 1 vs 3 Intermediate and high Leibovich risk (3-11) Novartis /GSK 1538 Yes 1 Intermediate or high risk AJCC TNM v.2010 PFE 700 Yes 3 Intermediate and high-risk, AJCC TNM v.2010 DFS DFS HR 0.86 OS HR 0.79 P>0.05 for ITT 600mg DFS ARISER G250 EVEREST Everolimus Wilex 864 Yes 25 weeks Intermediate and high risk UISS SWOG 1537 No 1 (9 cycles) Intermediate and high ptnm risk DFS and OS HR 0.97 and 0.99 No change in DFS/OS RFS 12

13 ccrcc pt1b-2 (G3-4) pt3a-4 pn+ R A N D O M I Z A T I O N 1: Girentuximab IV q1w for 24 weeks Placebo Primary Endpoint: DFS (Independent Central Review) Chamie K et al. JAMA Oncology Disease-Free Survival Overall Survival No difference No difference Chamie K et al. JAMA Oncology

14 Non-metastatic Kidney Cancer ³ G3T1bNany (resectable) M0 disease Surgery Stratify Risk Histology Performance status Surgery type Sunitinib for 1 yr Sorafenib for 1 year Placebo for 1 year Primary Endpoints DFS and OS Powered to improve DFS 33% (from 3 to 4 yrs) and OS 50% (from 7.4 to 11.1 yrs) Haas, Manola, Uzzo et al: Lancet 14; 387, 2016 Disease-Free Survival Overall Survival No difference No difference Haas, Manola, Uzzo et al: Lancet 14; 387,

15 DFS Preplanned ccrcc Subset Analysis No difference Haas, Manola, Uzzo et al: Lancet 14; 387, 2016 Median DFS Sunitinib 5.6 y Sorafenib 5.6 y Placebo 6.6 y S-TRAC : Sunitinib TRial in Adjuvant Renal Cancer ccrcc pt3-4 pn+ ECOG 0-2 R A N D O M I Z A T I O N 1: Sunitinib 50 mg PO qd (4/2 schedule) for 1 year Placebo Primary Endpoint: DFS (Independent Central Review) Ravaud A et al. NEJM

16 S-TRAC : Sunitinib TRial in Adjuvant Renal Cancer Disease-Free Survival Overall Survival Sunitinib better No difference Ravaud A et al. NEJM Adjuvant RCC Trials: The Middle Ages Incompletely effective surgery with more effective systemic Therapy STRAC ASSURE PROTECT Numbers total Sunitinib arm Clear cell population Risk definition used T-stages(n) - T1-2 - T3-4 - Central radiology review - 99% (n=609) - no central path review UCLA-UISS high risk group - T3, N0 or Nx, M0 - T4, N0 or Nx, M0 - Any T, N1-2, M0-615 (100%) Yes (Central review performed at baseline and relapse) met DFS endpoint but investigator review did not) 79% (n=1021) - Central path review UCLA-UISS intermediate-high to very high risk 469 (36.3%) 824 (63.7%) No At baseline but not relapse 16

17 Haas, Manola, Uzzo et al. JAMA Onc 2017 PROTECT TRIAL: 600mg vs 800mg 17

18 Primary Endpoint(s) ARISER ASSURE S-TRAC PROTECT DFS and OS DFS DFS DFS Median DFS ARISER ASSURE S-TRAC PROTECT Girentuximab: 5.9y Placebo: NR Sunitinib: 5.8y Sorafenib: 6.1y Placebo: 6.6y Sunitinib: 6.8y Placebo: 5.6y Pazopanib: Not attained in either arm Placebo: 4.5y To date adjuvant TKIs in RCC don t work well Incompletely effective (high quality) surgery Completely effective systemic Rx 1. Why not? 2. Now what? 18

19 Where does Adjuvant work? How effective is it even when approved? Micromedex, FDA Orange Book, DynaMed, UptoDate, Cochrane, Access Medicine, EMBASE, and PubMed NCCN guidelines for all solid tumors were reviewed to ensure completeness PubMed and clinicaltrials.gov were queried for adjuvant trials in kidney cancer Wholesale costs of approved adjuvant agents were calculated on a per month basis. Ristau and Uzzo What does work in adjuvant setting? Site Regimen DFS benefit OS benefit Monthly Cost Breast (n=2818) Breast (n=1975) Breast (n=2194) Breast (n=1491) Breast (n=3222) Colorectal (n=1987) Colorectal (n=2246) GIST (n=713) Melanoma (n=945) Melanoma** (n=1256) Tamoxifen vs placebo Anastrazole vs 11% 4% $13.20 Tamoxifen 2.7% NR $4.50 AC vs CMF AC + T Vs 0% 0% $ AC + F 7% 6% $ Traztuzumab Vs AC-T Capecitabine Vs 5-FU/FA Oxaliplatin +5-FU/FA Vs 5-FU/FA Imitanib vs placebo Ipilimumab vs placebo 9% 5% $6, % 3% $5, % 1.1% $ % 1% $10, mo 11 mo $64, PEG IFNa-2b ( Vs observation 6.7% 1% $15, One approved adjuvant systemic Rxs for GU tumors!! Ristau and Uzzo 19

20 Adjuvant Rx appears marginally effective even in approved settings in ,902 patients enrolled 9 adjuvant trials leading to FDA approval for adjuvant therapy in Breast Colon GIST melanoma 6 agents and 3 combinations Improvements in DFS range from 0-11% Improvements in OS with approved adjuvant agents 0-6% Median wholesale cost is $977.28/mo. ($4.50-$15,000+) No phase III trial leading to approval of an adjuvant agent measured quality-adjusted life years (QALYs) Why is Adjuvant Rx only marginally effective in solid tumors? Incompletely effective (high quality) surgery 1. Timing/Risk Tools 2. Biology 3. TKIs Completely effective systemic Rx 20

21 Timing of Adjuvant Rx Micrometastases (CTCs) (Halstedian) Clinical Stage 1 Clinical Stage 2 Subclinical Stage IV/ Clinical Stage IV Clinical Stage 3 0 Adjuvant Rx 1 x 10 9 /cm 3 centrifugal theory malignant inkblot CTCs Timing of Adjuvant Rx Micrometastases (CTCs) (Fisheresque NSABP) Sub clinical Stage IV / Clinical Stage IV Clinical Stage 2 Clinical Stage 3 0 Clinical Stage 1 Adjuvant Rx 1 x 10 9 /cm 3 seed and soil CTCs 21

22 How long is the process of micromets in RCC? Exceptionally variable! A 1 cm tumor = 10 9 cells (billion) +/- 40 tumor doublings Why is Adjuvant Rx only marginally effective in solid tumors? Incompletely effective (high quality) surgery 1. Timing/Risk Tools No Tools for Timing Adjuvant Rx 2. Biology 3. TKIs Completely effective systemic Rx 22

23 Tumors Progression Paradigms n driver mutations Think of cancer like an evolving ecosystem Paget, Halstead, centrifugal theory, malignant inkblot, seed and soil 23

24 MS Lawrence et al. Nature 000, 1-5 (2013) doi: /nature12213 Where we re heading Full Spectrum omic Heterogeneity DNA RNA Proteins Metabolytes epi kinome cancer Courtesy of Jonathan Chernoff, MD, PhD. 24

25 Where we re heading 25

26 Gerlinger et al, NEJM 2012 Branched Evolution in ccrcc Gerlinger et al Nat Genet Mar;46(3):

27 mirna with Differential Expression 723 human mirna in 94 ccrcc and 5 normal kidneys Upregulation of mir21-5p, 142-3p, let-7g-5p and 424-5p Downregulation of mir (high stage/grade/progression) Pathways predicted as targets of the most Disregulated mirnas included: - Signaling - Metabolism - EMT Cancer Biol Ther, 15 (3): 2014 MicroRNA expression signatures of stage, grade, and progression in clear cell RCC. Gowrishankar, Ibragimova, Zhou, Slifker, Devaraian, Al-Saleem, Uzzo and Cairns 27

28 Clonal evolution in 1pt - 4 Branched areas of initial evolution TURb an early event in primary - Post chemo LN and primary - LN met an early clone - Mets - Surgically at warm eradicated? autopsy - Mutations of genes predicting responsiveness (FoxP1) to platinum disappeared at recurrence Nature Genetics Oct 2016?? Nature Genetics Oct

29 The Clonal Origin of Colorectal Cancer: the basis of TNM staging Testing Halsted s model of the metastatic cascade T to N to M N=213 matched samples from 17pts (normal (germline)/t/n/m) Observed 81% of mutations were deletions ; 19% insertions. Significant correlation b/w clonal mutation frequency and patient age in normal and colorectal pts, but less than in CRC pts Mutational accumulation is common even in normal circumstances Additional determinants must be present to induce transformation In 65% of cases, N+ and M+ arose from independent subclones in the primary tumor (T) = Fisheresque In 35% of cases N+ and M+ shared the same subclones in the primary tumor (T) = Halsteadian 29

30 The Clonal Origin of Colorectal Cancer: the basis of TNM staging No difference in clonal origin based on any pathological features Tumor size, LVI, # of + nodes, synchronous vs metachronous No difference between origin and any treatments administered 30

31 Surgical Implications The Role of lymphadenectomy? RCC - Gershman et al: Euro Urol, 2016 N=606/1797 (34%) RN with Mo RCC had LND - N=111 (6.2%) N+ 1:1 Propensity matching no difference in DSS, OS UCC S1011 standard vs extended LN dissection 1 = DFS, 2 = OS and morbidity The Role of cytoreduction or metastasctomy? Drainage of LN into circulation via subclavian vein implications for lung M+ (may be more Halstedian)? The Role of neoadjuvant or adjuvant Rx???? Why is Adjuvant Rx only marginally effective in solid tumors? Incompletely effective (high quality) surgery 1. Timing/Risk Tools No Tools for Timing Adjuvant Rx 2. Biology and Risk Tools Bad luck and extreme/exponential heterogeneity 3. TKIs Cytostatic Rx targeting promiscuous pathways Completely effective systemic Rx 31

32 Adjuvant Rx for RCC (and other solid tumors) Is at best minimally effective in most solid tumors Level 1 evidence and FDA approval in breast, colon, melanoma, GIST increase OS by 0-6% Is costly but it can bring value depending on assumptions Has not been shown effective in RCC or with TKIs No Tools for Timing Adjuvant Rx Bad luck and exponential heterogeneity Current systemic therapies impose sanctions at best (cytostatic) We need to Attack less promiscuous further upstream targets ( tradeoff = toxicity) Attack tumor stem cells (need to identify) Improve timing (CTCs and biomarkers) Short circuit tumor induced immune dysfunction.keep Trying Adjuvant RCC Trials: The New Age Incompletely effective surgery with potentially more effective systemic Therapy Trial Sponsor n Clear cell only? EA8143 PROSPER (Nivolumab) (anti-pd1) ECOG 766 No but cap Non ccrcc at 15% Duration of Rx 10mo (1 neo then 9 mo adjuvant) = 240mg Eligibility Model Randomization 1 endpoint > ct2anomo Or TanyN+Mo Metastasectomy excluded Neoadjuvant then resect + adjuvant Vs Resect and Observe > 13% improvement in RFS W IMmotion (Atezolizumab) (anti-pdl1) Genentech through SUO-CTC 664 No Clear cell component Or Any subtype with sarcomatoid component 12 mo (16 cycles) > pt2 Gr4 N+ any T, (resected synchronous adrenal/lung metastases OR metastasectomy of lung, soft tissue, LN >12 months after nephrectomy) Adjuvant Vs Placebo DFS 32

33 Important Clinical Differences Preoperative biopsy PROSPER - ECOG mandatory IMmotion SUO-CTC None Time to surgery > 8 weeks ( ) immediate Control arm Observation Placebo Metastasectomy Ineligible Eligible if >12 mo Synchronous metastasectomy? Biopsy at recurrence Sequencing Ineligible mandatory Investigator discretion Eligible in lung/adrenal(s) mandatory Available without cost at time of recurrence Treatment-Related Adverse Events Reported in 10% or More of Treated Patients in Either Group CheckMate 025 Motzer RJ et al. N Engl J Med 2015;373:

34 PD1 Lab abnormalities in RCC Most autoimmune toxicities are reversible with immunosuppression (steroids) Implications for surgery 34

35 Endocrinopathies Hyper à Hypothyroid Central adrenal insufficiency Pneumonitis Diarrhea / Colitis Rash Myositis Neurotoxicity Guillain-Barré syndrome Cranial Nerve Palsy Science 351: 6280,

36 Blockchain, crytocurrency and Genomics Boston Globe Feb Controlling Big Genomic Data 36

37 Summary We make fundamentally important decisions ($$) with poor predictive tools Quantitatively and qualitatively inadequate Billions $ spent on negative adjuvant RCTs No effective/approved systemic adjuvant Rx in GU tumors Heterogeneity makes a single home run adjuvant Rx unlikely Understanding that we don t know what we don t know makes us more likely to be effective discoverers Enroll in clinical trials like IMmotion Thank You 37

38 Kidney Cancer A Patient s Perspective 38