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)