Post-ASCO 2012 Urologische tumoren. Stefan Sleijfer

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1 Post-ASCO 2012 Urologische tumoren Stefan Sleijfer

2 Indeling Tumortypes: Kiemceltumoren Urotheelcelcarcinomen Prostaatcarcinomen Niercelcarcinomen

3 Kiemceltumoren: was eigenlijk niets bijzonders te zien..

4 Urotheelcelcarcinomen standaardbehandeling Gelokaliseerde ziekte: Oppervlakkige tumoren: lokale therapie Spierinvasief: (neo-adjuvante chemotherapie +) lokale therapie (chirurgie of radiotherapie) Gemetastaseerd: Eerste lijn: MVAC (q 28 d) Dose- dense MVAC (+ G-CSF q 14 d): Gem/cDDP: gem 1,000 mg/m2 d1,8,15; cddp 70 mg/m2 d2 q28 d

therapie (chirurgie of radiotherapie) Gemetastaseerd: Eerste lijn: MVAC (q 28 d)

5 Randomized phase II: Gem/cDDP +/- cetuximab (#4506) Advanced urothelial bladder cancer, chemo-naieve Gem/cDDP +/- cetuximab (d 1, 15; 500 mg/m2) Phase II; primary endpoint: RR (p0: 50%; p1: 65%) Results: RR: 57% vs 61% Median PFS: 8.5 vs 7.6 months Median OS: 14.4 vs 14.2 months Conclusion: no role in this setting

II; primary endpoint: RR (p0: 50%; p1: 65%) Results: RR: 57% vs 61% Median

6 Pazopanib in urothelial bladder cancer (#4507) Pazopanib Chemotherapy-pretreated patients Single arm phase II, Simon 2-stage (p0: 5%; p1: 20%) Primary endpoint RR RR: 7/41 (>5/41 required) Median PFS: 2.6 months Side-study: rise of IL-8 at wk 4: poor outcome Conclusion: Modest activity (of note other study on pazopanib: RR 0/16) In combi with chemo?

7 Prostaatcarcinoom standaardbehandeling Gelokaliseerde ziekte (afh stadium, Gleason etc): Observatie Prostatectomie Radiotherapie Androgeen suppressie Gemetastaseerd: Androgeen suppressie Castratie-resistent prostaatcarcinoom: docetaxel 3 wekelijks + prednison

Radiotherapie Androgeen suppressie Gemetastaseerd: Androgeen

8 Prostaatcarcinoom standaardbehandeling New 2nd line options in docetaxel pretreated CRPC: Abiraterone: Med OS 14.8 vs 10.9 mnths (placebo) De Bono, NEJM 2011 Cabazitaxel: Med OS 15.1 vs 12.7 mnths (mitoxantrone) De Bono, Lancet 2010

9 Abiraterone in chemo-naieve CRPC (#4518) Asymptomatic or minimally symptomatic metastatic CRPC, pre-chemo Abiraterone 1000 mg + prednison 5 mg BID vs placebo + prednison 5 mg BID (1088 pts) Phase III, double blind (HR 0.75 on primary endpoint, power 90%, alpha 5% 2-sided) Primary endpoint: OS and radiological PFS : rpfs: Bone scan: < 12 wks: 2 new lesions + 2 additional lesions at confirmation 12 wks 2 new lesions and confirmation CT: PD soft tissue lesions Secondary endpoints: Time to PSA progression Time to ECOG deterioration Time to chemo/opiates

75 on primary endpoint, power 90%, alpha 5% 2-sided) Primary endpoint: OS and radiological PFS : rpfs: Bone scan: < 12 wks: 2 new lesions

10 Interim analysis: rpfs and OS Median rpfs: NR vs 8.3 mnths HR.43 ( ) p<.0001 Median OS: NR vs 27.2 mnths HR.75 ( ) p=.0097

11 Other outcomes Secondary endpoints Time to opiates: Time to chemo: Time to ECOG decrease: NR vs 16.8 months (HR=.69; p=.0001) 25.2 vs 16.8 months (HR=.58; p<.0001) 12.3 vs 10.9 months (HR=.82; p=.0053) Time to PSA progression: 11.1 vs 5.6 months (HR=.49; p<.0001 ) Toxicity (all grades (gr 3/4)) abiraterone vs placebo Fatigue: 39 (2) vs 34 (2) Fluid retention: 28 (1) vs 24 (2) Hypokaliemie: 17 (2) vs 13 (2) Hypertension: 22 (4) vs 13 (3) ALT increase: 12 (5) vs 5 (1) AST increase: 11 (3) vs 5 (1)

12 Discussion Study was stopped at interim analysis by IDMC OS difference not statistically significant according to pre-specified criteria: Median OS: NR vs 27.2 months (HR.75 ( ); p=.0097) At 43% planned events, pre-specified alpha was.0008 Alpha: Accepted false-positive rate (mostly <.05 at final analysis) If you also look at interim analyses; false positive rate will get higher Correction needed: lower alpha at interim analyses (several models available) And now?: Pro: positive at multiple efficacy endpoints Contra: high false-positive rate for OS, not acceptable :

0008 Alpha: Accepted false-positive rate (mostly <.

13 Enzalutamide (MDV3100) in docetaxel pretreated CRPC (#4519) Phase III, placebo-controlled, double blind Prior: 1-2 chemo s (one docetaxel-based) 2:1 randomization: MDV 160 mg daily Primary endpoint: OS: HR.76 (power 90%; alpha.05) Secondary endpoints: PSA and soft tissue response Qaly/pain relief CTCs

2:1 randomization: MDV 160 mg daily Primary endpoint: OS: HR.

14 Primary outcome

15 Secondary outcomes and toxicity Secondary endpoints: Median PSA PFS: 8.3 vs 3.0 months (HR 0.25) rpfs: 8.3 vs 2.9 months (HR 0.40) RR RECIST: 29 vs 4% PSA response Time to first SRE: 16.7 vs 13.3 (HR 0.62) RR in FACT-P: 43 vs 18% Toxicity: Discontinuation due to Aes: 7.6 vs 9.8% (more in placebo-arm!) Most common: fatigue (all grades): 33.6 vs 29% Seizures: 0.6% vs 0%

7 vs 13.3 (HR 0.62) RR in FACT-P: 43 vs 18% Toxicity: Discontinuation due to Aes: 7.6 vs 9.

16 Other phase III studies Docetaxel/atrasentan vs docetaxel/placebo (#4511): PI to statisticus: you ve sent me only PFS and OS curves from one arm Update phase III Radium-223 vs placebo (#4512): Alpha-emitter, high affinity for bone, low marrow penetration Symptomatic CRPC, post-docetaxel or unfit for docetaxel OS benefit (median > 14.9 months) OS No QALY data Toxicity (gr 3/4): ANC: 13 vs 2% Thr: 38 vs 6% N/V: 10% vs 5%

affinity for bone, low marrow penetration Symptomatic CRPC, post-docetaxel or unfit for docetaxel OS

17 Novel drugs: Cabozatinib in docetaxel-pretreated CRPC (#4513) VEGFR2/MET TKI; 100 mg daily Primary endpoint: bone-scan response: Number of pixels above normal in pre-defined lesions area Decrease > 30%: RR Outcomes: Bone scan RR: 64% Pain response (64% decrease in VAS scores; 56% less narcotics) CTC response 39% (strongly associated with OS!) Toxicity (grade 3/4): Fatigue 26%, diarrhea 10%, nausea 10% Studies with lower doses and randomized studies ongoing

scan RR: 64% Pain response (64% decrease in VAS scores; 56% less narcotics) CTC response 39% (strongly associated

18 Standaardbehandeling niercelcarcinoom (RCC) Gelokaliseerde ziekte: Nefrectomie Gemetastaseerde ziekte: Afhankelijk van: Subtype RCC Lokalisatie metastases Motzer risicogroep

19 Motzer criteria Ongunstige prognostische factoren voor overleving na IFN-α. Karnofsky Performance < 80 Periode tussen diagnose en IFN-α behandeling < 12 maanden Hemoglobine < normaal LDH > 1.5 x normaal Gecorr. calcium > 2.5 mmol/l Goede prognose groep: geen ongunstige factoren Intermediaire prognose groep: 1-2 ongunstige factoren Slechte prognose groep: 3-5 ongunstige factoren Motzer, JCO 2001

normaal LDH > 1.5 x normaal Gecorr. calcium > 2.

20 1e lijns standaardbehandeling heldercellig RCC Goede en intermediaire prognose: Sunitinib IFN / bevacizumab Pazopanib Slechte prognose: Temsirolimus

21 Standaardbehandeling RCC Heldercellig, tweede lijn: Na cytokine: sorafenib/pazopanib (axitinib beter dan sorafenib, niet geregistreerd in Nederland) Na VEGF-R: everolimus Na mtor blokker: geen standaard Andere subtypes: Urotheelcelca: als blaascarcinoom Ander subtypes (papillair, chromofoob): geen standaard

22 Phase III tivozanib vs sorafenib (#4501) Tivozanib vs sorafenib in 1 st line clear-cell RCC; good and intermediate prognosis Primary endpoint: PFS (power 90%, 6.7->9.7 months) Outcomes: Median PFS: 11.9 vs 9.1 months PFS RR: 33 vs 23% (p=.014) Toxicity: Common VEGFR-TKI profile Less diarrhea and HFS Dose interruptions: 18 vs 35% Dose reductions: 12 vs 43% Why sorafenib as comparator?

23 Patient preference pazopanib vs sunitinib (#4502) Both approved in 1ste line Results of direct comparison will be reported shortly (COMPARZ study) Patient preference: double blinded Outcomes: 70% preferred pazopanib 22% preferred sunitinib 8% no preference

24 Outcome to anti-vegfr in RCC pts not meeting eligibility criteria for studies (#4536) Major RCC centers Non-eligible: Karnofsky <70; non-clear cell; brain mets; Hb < 6.4; creat>2xuln; hypercalciemie; thrombo < 100; ANC < pts: 894 non-eligible vs 1182 eligible pts Outcomes eligible vs non-eligible: RR: 21 vs 29% HR for death 1.5 (also corrected for prognosis groups)

25 Novel agents in phase II Cabozantinib in clear cell RCC VEGFR-TKI refractory clear cell RCC Single arm study; n=25; in context of drug-drug interaction study (with rosiglitazone) Outcomes: Median PFS 14.7 months RR: 7/25 Of note: current standard everolimus in pts failing to VEGFR-TKI: Med PFS 4.0 months, RR = 1% Not a head-to-head comparison!

26 Anti-PD1 Moab (BMS936558) in VEGFR-TKI refractory clear cell RCC PD-L1 on tumor cells kills PD1-expressing T-cells In context phase I trial; RCC cohort (16 at 10 mg/kg; 17 pts at 1 mg/kg) Toxicity: Gr 3/4 AEs: 14% PD-L1 expression on tumor cells Fatigue: 38(2)% Rash: 24(0)% Outcomes (RR): 27% (n=33 (phase I)) 24% (n= 17 at 1 mg/kg) 31% (n=16 at 10 mg/kg) PD-L1 expression on tumor cells predictive marker?

27 Conclusions Kiemceltumoren en blaascarcinomen: Geen grote veranderingen te verwachten op korte termijn (Heldercellig) niercelcarcinoom: Tivozanib: Ook actief in 1e lijn Meerwaarde tov andere middelen in 1e lijn? Pazopanib: voorkeur van pt boven sunitinib: Afwachten resulaten COMPARZ Sunitinib bij pt die niet aan studie eligibility criteria voldoen : slechtere uitkomst Veelbelovende middelen: cabozantinib; anti-pd1 MoAbs

28 Options in CRPC Pre-docetaxel: abiraterone (?) Docetaxel Post-docetaxel: Cabazitaxel Radium-223 Abiraterone (dependent on what will happen pre-docetaxel) Enzalutamide (MDV3100) To be revealed: Optimal sequence Direct comparisons Combinations Predictive factors Value at earlier stages How to pay for (i.e. abiraterone: 3300/28 days)

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