Adjuvant Therapies in RCC: What we think we Know Robert G. Uzzo, M.D.

Transcription

1 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

2 We are all managers of health care risk We seek to understand, predict and prevent future health care events Adjuvant Biomarkers Clinical Models

3 Prognostic Biomarkers in ccrcc Stage Grade Histology MicroRNA expression signatures of stage, grade, and progression in clear cell RCC. Cancer Biol Ther, 15 (3): 2014 Gowrishankar, Ibragimova, Zhou, Slifker, Devaraian, Al-Saleem, Uzzo and Cairns

4 Risk Models for Localized RCC Model Presentation Reported/Externally validated C-index 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/ Yaycioglu Formula 0.65/ Condolo Formula 0.67/ TNM stage 2. Nuclear Grade 3. Tumor Size 4. Performance Status 5. Presentation (symptoms) 6. Age 7. Gender 8. Coagulative necrosis All models retrospective * Localized pts only

5 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

6 Eligibility for n=7 most recent adjuvant RCC RCT based on these predictive tools N= 8855 pts accrued

7 Estimated Costs of Adjuvant RCC Trials Trial Sponsor N Eligibility Model Estimated Cost ASSURE sorafenib/ sunitinib ECOG PFE Bayer 1943 Intermediate and high risk UISS >$80 million ($40 million from industry) S-TRAC Sunitinib PFE 615 High risk UISS $100 million IMmotion Atezolizumab Genentech SUOCTC 1537 Intermediate and high ptnm risk Leibovich model $265 million

8 Risk Models for Localized RCC: Prospective Validation Model Presentation Reported/Externally validated C-index UISS KM estimates 0.73/ MSKCC** Nomogram 0.82/ Prospective ECOG validation C index SSIGN Points based algorithm 0.84/ Leibovich** Points based algorithm 0.82/ Karakiewicz Nomogram 0.89/ ** Localized pts only

9 So how have we done with Adjuvant therapies?

10 Adjuvant RCC Trials: The Dark Ages Incompletely effective surgery with completely ineffective systemic Therapy v almost Treatment Radiation vs observation (N=72) MPA vs observation (N=136) Tumor cells + BCG vs observation (N=120) Recombinant IFN-α2b vs observation (N=247) IFN-α vs observation (N=283) High-dose IL-2 vs observation (N=69) Tumor cell vaccine vs observation (N=558) 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) Outcome NO BENEFIT NO BENEFIT NO BENEFIT NO BENEFIT NO BENEFIT NO BENEFIT 5-year PFS: 77.4% vs 67.8% (P=0.02) NO BENEFIT NO BENEFIT NO BENEFIT NO BENEFIT Kunkle, Haas, Uzzo Current Urol Rept 8(1):19, 2007

11 Modern Adjuvant RCC Trials 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 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. 2016

13 Disease-Free Survival Overall Survival No difference No difference Chamie K et al. JAMA Oncology. 2016

14 Non-metastatic Kidney Cancer 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

15 Disease-Free Survival Overall Survival No difference No difference Haas, Manola, Uzzo et al: Lancet 14; 387, 2016

16 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

17 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. 2016

18 S-TRAC : Sunitinib TRial in Adjuvant Renal Cancer Disease-Free Survival Overall Survival Sunitinib better No difference Ravaud A et al. NEJM. 2016

19 Adjuvant RCC Trials: The Middle Ages Incompletely effective surgery with more effective systemic Therapy STRAC ASSURE Numbers total Sunitinib arm Clear cell population - 99% (n=609) - no central path review 79% (n=1021) - Central path review Risk definition used UCLA-UISS high risk group -T3, N0 or Nx, M0 -T4, N0 or Nx, M0 -Any T, N1-2, M0 UCLA-UISS intermediatehigh to very high risk T-stages(n) -T1-2 -T (100%) 469 (36.3%) 824 (63.7%) - Central radiology review Yes (Central review met DFS endpoint but investigator review did not) No

20 Haas et al.jama Onc 2017

21 Primary Endpoint(s) ARISER ASSURE S-TRAC PROTECT DFS and OS DFS DFS DFS Median DFS ARISER ASSURE S-TRAC PROTECT Girentuximab 5.9 y Placebo NR Sunitinib 5.8 y Sorafenib 6.1 y Placebo 6.6 y Sunitinib 6.8 y Placebo 5.6 y Pending

22 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?

23 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 IFNα-2b ( Vs observation 6.7% 1% $15, No approved adjuvant systemic Rxs for GU tumors!! Ristau and Uzzo

24 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)

25 Why is Adjuvant Rx only marginally effective in solid tumors? Incompletely effective (high quality) surgery 1. Timing/Risk Tools Completely effective systemic Rx 2. Biology 3. TKIs

26 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 CTCs

27 Timing of Adjuvant Rx Micrometastases (CTCs) (Fisheresque NSABP) Sub clinical Stage IV / Clinical Stage IV Clinical Stage 3 Clinical Stage 2 Clinical Stage 1 0 Adjuvant Rx 1 x 10 9 /cm 3 CTCs

28 How long is the process of micromets in RCC? Exceptionally variable! A 1 cm tumor = 10 9 cells (billion) +/- 40 tumor doublings

29 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 Completely effective systemic Rx 2. Biology 3. TKIs

30 Tumors Progression Paradigms n driver mutations

31 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

32 Where we re heading Full Spectrum omic Heterogeneity DNA RNA Proteins Metabolytes epi kinome cancer Courtesy of Jonathan Chernoff, MD, PhD.

33 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 Completely effective systemic Rx 2. Biology and Risk Tools Bad luck and extreme/exponential heterogeneity 3. TKIs Cytostatic Rx targeting promiscuous pathways

34 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 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

35 Adjuvant RCC Trials: The New Age Incompletely effective surgery with potentially more effective systemic Therapy Trial Sponsor n Histology Duration of Rx Eligibility Model Randomization 1 endpoint EA8143 PROSPER (Nivolumab) ECOG 766 Capped nonccrcc at 15% 10mo > ct2anomo Or N+ Metastasectomy excluded Neoadjuvant then resect + adjuvant Vs Resect and Observe > 13% improvement in RFS Immotion 010 (Atezolizumab) Genentech with SUO-CTC 664 ccrcc Or any sarcomatoid 12 mo (16 cycles) > pt2 Gr4 or N+ OR some metastasectomy Adjuvant Vs Placebo DFS KEYNOTE564 (pembrolizumab) Merck 950 Same as IMmotion Same as IMmotion Same as Immotion Same as IMmotion DFS CHECKMATE 914 BMS 800 ccrcc or any sarcomatoid 24 weeks > pt2a G3 or N1 Ipi/Nivo Vs Placebo DFS

36 Most autoimmune toxici.es are reversible with immunosuppression (steroids) Implica(ons for surgery

37 Endocrinopathies Hyper à Hypothyroid Central adrenal insufficiency PneumoniEs Diarrhea / ColiEs Rash MyosiEs Neurotoxicity Guillain-Barré syndrome Cranial Nerve Palsy

38 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