Post-ASCO 2012 Urologische tumoren. Stefan Sleijfer

Post-ASCO 2012 Urologische tumoren

Stefan Sleijfer

Indeling  Tumortypes: • Kiemceltumoren • Urotheelcelcarcinomen • Prostaatcarcinomen

• Niercelcarcinomen

Kiemceltumoren: was eigenlijk niets bijzonders te zien…..

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

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

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?

Prostaatcarcinoom standaardbehandeling  Gelokaliseerde ziekte (afh stadium, Gleason etc): • Observatie • Prostatectomie • Radiotherapie

• Androgeen suppressie

 Gemetastaseerd: • Androgeen suppressie • Castratie-resistent prostaatcarcinoom: docetaxel 3 wekelijks + prednison

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

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

Interim analysis: rPFS and OS Median rPFS: NR vs 8.3 mnths

HR .43 (.35-.52) p<.0001

Median OS: NR vs 27.2 mnths HR .75 (.61-.93) p=.0097

Other outcomes  Secondary endpoints  Time to opiates:

NR vs 16.8 months (HR=.69; p=.0001)

 Time to chemo:

25.2 vs 16.8 months (HR=.58; p<.0001)

 Time to ECOG decrease:

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)

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 (.61-.93); 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”:

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

Primary outcome

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%

 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%

PSA response

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 11.3 -> 14.9 months)  No QALY data  Toxicity (gr 3/4):  ANC:

13 vs 2%

 Thr:

38 vs 6%

 N/V:

10% vs 5%

OS

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

Standaardbehandeling niercelcarcinoom (RCC)  Gelokaliseerde ziekte:

• Nefrectomie

 Gemetastaseerde ziekte: • Afhankelijk van: • Subtype RCC

• Lokalisatie metastases • Motzer risicogroep

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

1e lijns standaardbehandeling heldercellig RCC  Goede en intermediaire prognose: • Sunitinib • IFN / bevacizumab • Pazopanib

 Slechte prognose: • Temsirolimus

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

Phase III tivozanib vs sorafenib (#4501)  Tivozanib vs sorafenib in 1st 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  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?

PFS

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

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 < 1.5

 2076 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)

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!

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?

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

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)