Post-ASCO 2014
Urologische tumoren
Stefan Sleijfer
Disclosures
Research funding by:
GSK, Pfizer, Roche, Lytex, Amgen, Johnson&Johnson, Novartis, Astra
Zeneca, PharmaMar, Esai, Lilly, Boehringer Ingelheim, Vertex, Serviano,
Taiho
Partner in EU-FP7 project CareMore (Cancer Responsiveness Monitoring based
on Resistance mutations in CTCs), which includes industrial partners (Philips,
Olink, Cytotrack).
Indeling
 Tumortypes:
• Kiemceltumoren
• Urotheelcelcarcinomen
• Prostaatcarcinomen
• Niercelcarcinomen
Standardbehandeling stadium I
testisca.
 Seminoma:
 Adjuvant radiotherapie (20 Gy)
 1-malig carboplatin (AUC 7)
 Wait-and-see
 Non-seminoma:
 Wait-and-see
 (2x BEP)
 (Retroperitoneale LK-dissectie, evt gevolgd door 2x BEP)
Observational study seminoma stage I:
surveillance or adjuvant carboplatin (#4508)
 Risk factors: rete testis inv + size > 4cm:
 0-1: recommendation surveillance
 2: recommended carboplatin
 Pt could choose opposite
 Results:
 50% 0-1RF: choose carbo; 10% 2RF: surveillance
 RFR 93% (0 RF: 97%; 1-2: 77%)
 Excellent outcome CSS 99.7%
 Confirmation RF (size: HR 2.7; rete invasion: 1.8)
 Minimal added value for adjuvant carbo in 0 RF
(RFR 97.1% vs 97.7% with carbo)
 Comments:
 0 RF: surveillance
 1-2 RF: patient choice
Long-term toxicity after chemotherapy (#4518)
 Long term toxicity:
 2nd malignancies: RR 1.55
 CVD mortality: RR 2,0
Gr 3/4
tox
 Nephrotoxicity (GFR < 60 ml/min): 10%
 Neuropathy: 30%
 Ototoxicity: 24%
 Platinum detectable for more than 20 yrs after adminstration
 Study (n=292; treated between 1980-1994)
 Association between serum platinum levels and neurotoxicity (self reported scale)
 Strong correlation (higher quartiles, more grade 3/4 tox)
 Comments: intervention studies needed to decline long-term tox (i.e. 3xBEP vs 4xEP with
markers for long term toxicity as endpoint)
Quality of care (#4519)
 Impact of volume on outcome:
 2447 pts (stage III) at 860 centers (1998-2011)
 OS and patient volume per year:
 Low < 2
 Moderate 2-4
 High 4-20
 Elite: > 20
 Results:
 7% treated at centers > 20
 Elite vs low: HR 0.48
Quality of care
 Relationship between volume and outcome already known for years (JNCI 1999):
 Combination of more chemo-induced deaths, peri-operative mortality (90-days mortality: high vs
low volume 0.8% vs 6.0%); more relapses
 Germany: > 40% of the 2nd opinions discordant to 1st opinion (28% less and 15% more
extensive treatment).
 Netherlands: Guideline ≥5, SONCOS ≥10 pt/year more for chemo treatment
 Kankerzorg in beeld (blz 97, feb 2014):
 “Slechts 5 van de 33 ziekenhuizen die gemetastaseerde testiscarcinoompatienten met
chemotherapie behandelen, doen dat jaarlijks gemiddeld voor 10 of meer gemetastaseerde
patienten, de norm zoals vastgelegd….”
 “Uitgaande van gemiddeld 5 patienten ….., voldoen slechts 6 centra aan deze norm.”
Urotheelcelcarcinomen standaardbehandeling
 Gelokaliseerde ziekte:
• Oppervlakkige tumoren: lokale therapie
• Spierinvasief: (neo-adjuvante chemotherapie +) lokale therapie (chirurgie
of (chemo)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
Phase III: muscle invasive bladder ca; adjuvant vs
at time of metastatic disease (#4500)
 60% relapse rate after cystectomy:
 Adjuvant: ongoing discussion
 Design:
 Randomisation: < 90 days within cystectomy 4 cycles GC/MVAC/DD-MVAC vs
chemotherapy at relapse (6 cycles)
 Primary endpoint:
 OS (5yr OS: 35% -> 42%; p=.05; power 80%: n=1344 pts (864 events))
 Eligibility:
 pT3-4 and/or pTN1-3, M0
 WHO PFS 0-1
 Good organ function
Phase III: adjuvant vs at time of
metastatic disease
 Results:
 Amendment: high %N+pts (660 pts: 436 events)
 Poor accrual: closed 284 pts
 Both arms: well balanced in prognostic factors
 85% received GC
 Significant improvement in RFS:
 All subgroups (N- vs N+)
 OS: non-significant (5 yr: 53,6 vs 47,7% (HR .78;
0,56-1.08))
 Comments:
 Meta-analysis
 Supports role of peri-operative chemo
 No standard
Neo-adjuvant chemotherapy
 # 4512: gem/cis looks equivalent to MVAC: pCR 25 vs 31%
 #4510 and 4538: Indications DNA repair gene SNPs (ERCC2; ATM/FANCC) strongly
associated with outcome to cisplatin-based neo-adjuvant chemotherapy.
 Comments: why is neo-adjuvant chemotherapy so underused?:
 Neo-adjuvant meta-analysis: 5% OS benefit (HR 0.86), more pt eligible compared to adjuvant
 In daily routine: only 5%! (Canada, Ann Oncol 2014)
 Need for more studies in neoadjuvant setting:
 Beter prognostic (CirGuidance study) and predictive factors
 Better treatments: DD-MVAC and Paclitaxel/Gem-cis (much higher RR in M+)
Prostate cancer: the new sexy tumor type
Prostaatcarcinoom standaardbehandeling
 Gelokaliseerde ziekte (afh stadium, Gleason etc):
• Observatie / prostatectomie / radiotherapie / androgeen suppressie
 Gemetastaseerd:
• Androgeen suppressie
• Castratie-resistent prostaatcarcinoom: docetaxel 3 wekelijks + prednison
• Post-docetaxel: abiraterone / cabazitaxel / enzalutamide:
• No direct comparisons
• Sequence probably matters
Chemo-hormonal vs hormonal therapy for hormone
sensitive newly metastatic prostate cancer (#LBA 2)
 Androgen deprivation (ADT) vs ADT + docetaxel (75 mg/m2, q 3 wks x 6):
 ECOG PFS 0-2, good organ function, no prior docetaxel
 Primary endpoint: overall survival (33% OS improvement, 1-sided α 2.5%, power 80%):
 Original: high volume disease only:
 visceral mets and/or ≥ 4 bone mets (incl 1 beyond pelvis and vertebral column)
 Later, also low volume disease
 790 pts accrued: planned interim analysis; study stopped
 Both arms well balanced:
 Majority high volume disease (65%)
 73% no prior local treatment
Chemo-hormonal vs hormonal therapy for hormone
sensitive newly metastatic prostate cancer
 Further results:
 OS benefit seen in all subgroups (age; Gleason score; prior local treatment; etc)
 All secondary endpoints favoring chemo-hormonal treatment (PSA responses, time
to CRPC, time to clinical PD)
 Therapy beyond progression:
 ADT group: 129/174 relapsed pts received docetaxel (75% of all relapsed ADT patients)
 Mild toxicity profile, no remarkable events:
 28% grade 3/4 toxicity
Chemo-hormonal vs hormonal therapy for hormone
sensitive newly metastatic prostate cancer
 Conclusions:
 Benefit in high volume pts is clear and justifies treatment
 Impact in low volume disease requires further follow-up
 Comments:
 Unprecedented prolongation of OS
 In contrast to GETUG 15 (Lancet 2013): No OS difference
 But in that study mainly low volume pts (77%)
 Other studies with early use of docetaxel ongoing; but not
similar designs, other eligibility criteria, etc?
 Definition of high volume pts (CTCs?)
 Agree with main conclusions
Phase III in mCRPC, pre-docetaxel:
enzalutamide vs placebo (#5007)
 1:1 randomization
 Co-primary endpoints: radiographicPFS and OS
 Stopped at interim-analysis: placebo arm pts were offered enza
 Results:
 Both arms were well balanced
 Delayed time to cytotoxic chemotherapy
 Better quality of life
Phase III in mCRPC, pre-docetaxel:
orteronel/pred (TAK700) vs prednisone (#5007)
 TAK-700: non-steroidal inhibitor 17,20-lyase (androgen synthesis blocker): In postdocetaxel setting: PFS benefit, but not OS
 Large study pre-docetaxel in mCRPC (1560 pts), primary endpoint: OS and rPFS
 Results:
 Active drug in rPFS
 No impact on OS probably also due to wide-spread available effective treatments post-study
(docetaxel, abiraterone, enza, caba) + prednisone as control (impact on testosterone levels)
Androgen receptor splice variant and
resistance to enza and abi (#5001)
 ARv7: splice variant; constitutively active variant (so independent from
androgen binding to AR)
 Hypothesis: presence of ARv7 in CTC yields worse outcome
 Prospective study:
 85% power to detect difference in PSA response from 10% in ARv&7+ to 60% in
ARv7- pts at p=.1 (30 pts needed per drug)
 CTCs: Adna-test (prostate select kit based on immuno-magnetic enrichment (used
antibodies unknown)) followed by PCR
ARv7 and enza/abi resistance
Enzalutamide
 Enza: 12/31 ARv7+: PSA-resp: 0% vs 52% in ARv7-
 Abi: 6/31 ARv7+: PSA-resp: 0% vs 68% in ARv7-
 Prevalence ARv7+ in all 62 pts at baseline:
 Pre-enza, pre-abi: 11%
 Post-enza only: 25%
 Post-abi only: 51%
 Post-enza and post-abi: 67%
 Comments:
 Association ARv7 and outcome to caba?
Abiraterone
Standaardbehandeling niercelcarcinoom
(RCC)
 Gelokaliseerde ziekte:
• Nefrectomie
 Gemetastaseerde ziekte:
• Afhankelijk van:
• Subtype RCC
• MSKCC risk score (interval diagnose-start behandeling, WHO
PFS, Hb, Ca, LDH)
Standaardbehandeling RCC
 1ste lijn heldercellig RCC:
 Goede en intermediaire prognose:
• Sunitinib or pazopanib (equivalent, voorkeur pt voor pazopanib)
• IFN / bevacizumab
 Slechte prognose:
• Temsirolimus
 2e lijn heldercellig:
• Na cytokine: sorafenib/pazopanib/axitinib
• Na VEGF-R: everolimus
• Na mTOR blokker: geen standaard
 Andere subtypes:
• Urotheelcelca: als blaascarcinoom
• Ander subtypes (papillair, chromofoob): geen standaard (behalve poor risk: temsirolimus)
Observation in mRCC prior to Tx start
(#4520)
 Asymptomatic treatment-naive pts
 Staging at fixed time points
 Descriptive study (no statistical plan): n=52
 Results:
 Group with low tumor burden: median 3.2 cm
 Median observation time: 14 mnths
 Median tumor growth: 0,09 cm/month (-0,51 – 3,6 cm/month)
 Low anxiety scores
 No poorer risk group
 Comments:
 group of pts that can be safely observed (but exact definition?)
 Randomized study?
Everolimus vs sunitinib in non-clear cell
mRCC (#4505)
 No standard Tx apart from poor-risk non-clear cell (temsirolimus)
 Randomized phase II: everolimus vs sunitinib (cross-over at PD)
 Primary endpoint: PFS (12 wks su -> 20 wks eve; α:.05; 1- β 80%)
 Results:
 DSMB recommended stop at interim
 Well balanced; majority papillary subgroup, intermediate risk
 Everolimus: RR: 1/35; med PFS 4.1 mnths (2.7-10.5)
 Sunitinib; RR: 2/33; med PFS 6.1 mnths (4.2-9.4)
 Comments:
 Modest efficacy for both drugs, not enough to consider standard
 Trends for better outcome for sunitinib, but more toxicity
 Studies for specific subgroups (MET inhi in type I papillary)
Outcome to Tx cessation (#4521)
 Retrospective study of pts stopping VEGFR-TKI/mTOR-inh for reasons
other than PD and for > 3 months
 112 pts:
 57% stopped because of tox; 26% dr choice
 Comments:
 Often durable stabilisation after treatment stop
 Of note, selected group (already >3mnths stop)
 Randomized study interrupted vs continuous treatment in 1st line ongoing
(STAR study)
Conclusies
 Kiemceltumoren:
 Seminoma st I zonder rete testis invasie en < 4 cm: surveillance (RFR 97.1%)
 Concentratie van zorg!
 Blaascarcinomen:
 Activiteit van adjuvante chemotherapie (geen OS voordeel, studie underpowered):
 Bevestiging activiteit peri-operatieve chemotherapie:
 Ondersteuning neo-adjuvante chemo (bewezen OS voordeel, meer pt voor
in aanmerking): studies prog/pred factoren
 Grote behoefte aan nieuwe actieve middelen (immunotherapie?)
Conclusies
 Prostaatcarcinoom:
 Treatment-naive prostaatca M+, high volume: ADT/docetaxel (med OS voordeel: 17 maanden)
 Enza OS voordeel in mCRPC, pre-docetaxel, TAK700 niet
 ARv7 veelbelovende marker voor treatment decision making
 Veel studies nodig naar directe vergelijkingen, sequentie en combinaties
 Niercelcarcinoom:
 Zonder behandeling soms langdurige ziektestabilisatie (zowel voor starten als
behandelinsinterruptie om andere redenen dan PD): gerandomiseerde studies
 Geen standaard voor non-clear cell RCC: studies in specifieke subtypes nodig
 Combinatie nivolumab/ipiIimumab: veelbelovend: gerandomiseerde studies nodig