Die Therapielandschaft des fortgeschrittenen Urothelkarzinoms

Jan Roigas

Klinik für Urologie und Kinderurologie Vivantes Klinikum im Friedrichshain

Berlin

Update

fortgeschrittenes Urothelkarzinom

16.04.2021

Die Therapielandschaft

des fortgeschrittenen Urothelkarzinoms

Es bestehen keine persönlichen Interessenskonflikte.

Es besteht eine Kooperation in Bezug auf eine Vortrags- oder Beratungstätigkeit mit folgenden Firmen:

- Astellas - Johnson&Johnson

- Bayer - MSD

- BMS - Medac

- Eisai - Merck

- EUSA - Novartis

- Intuitive Surgical - Pfizer

- Ipsen - Roche

- Janssen-Cilag - Sanofi-Aventis

potentielle persönliche Interessenskonflikte

Harnblasenkarzinom in Deutschland

Krebs in Deutschland für 2015/2016. 12. Ausgabe. Robert Koch-Institut (Hrsg) und die

Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). Berlin, 2019

Neuerkrankungen Frauen Männer

Absolute Zahl 7.210 22.270

Mittleres Erkrankungsalter 73,4 71,9

Rohe Rate 17,5 56,4

Altersstandardisierte Rate 9,1 36,1

Aktueller Trend

+1,0% +0,6%

Altersstandardisierte Rate (EU) 6,1 29,1 Prognose für 2020 (absolute Zahl) 8.100 24.700

Sterbefälle Frauen Männer

Absolute Zahl 1.937 3.996

Mittleres Sterbealter 80,3 77,8

Rohe Rate 4,7 10,2

Altersstandardisierte Rate 1,9 6,2

Aktueller Trend

-2,0% -2,3%

Altersstandardisierte Rate (EU) 1,9 8,5

Aktueller Trend (EU)

-0,8% -1,2%

Überlebensraten

Relatives 5-Jahres-Überleben 72% 77%

Relatives 10-Jahres-Überleben 69% 70%

Prävalenz

5-Jahres-Prävalenz 24.710 81.920

10-Jahres-Prävalenz 40.970 131.210

Inkl. nicht-invasiver Formen (C67, D09.0, D41.4), Deutschland, 2013; zum Vergleich ausgewählte Ergebnisse für die EU, 2012 (Inzidenz) bzw. 2013 (Mortalität) Männer dreimal häufiger betroffen als

Frauen

Leicht bessere 5-Jahres- Überlebensraten für Männer

Harnblasenkarzinom in Deutschland

Urothel- bzw. Harnblasenkarzinom – Fakten

 90 % der Urothelkarzinome sind in der Harnblase lokalisiert

 10 % UTUC (upper tract urothelial carcinoma)

 von den Harnblasenkarzinomen sind ca. 70 – 80 % oberflächliche Karzinome ( NMIBC – non-muscle-invasive bladder cancer)

 Histologie: - 90 % Urothelkarzinome

- selten sind Plattenepithelkarzinome,

neuroendokrine Karzinome, Adenokarzinome,

Sarkome

fortgeschrittenes Urothelkarzinom

lok. Rez.

M1oss N+

eigene Bilder

D at a r el ease R egul at or y appr ov al

Monotherapy Combination therapy FDA-approved drugs

1989 1993 1997 2001 2005 2009 2013

MVAC (Phase II)²

Paclitaxel (Phase II)³

Docetaxel (Phase II)⁵

Gemcitabine + cisplatin (Phase III)⁶

HD-MVAC (Phase III)⁷ Gemcitabine + paclitaxel (Phase II)⁸

Vinflunine (Phase III)¹⁰ Gemcitabine

+ carboplatin vs M-CAVI (Phase II/III)¹²

Gemcitabine + cisplatin

+ paclitaxel (Phase III)¹³

Nivolumab (Phase II)¹⁹ Pembrolizumab (Phase II)²⁰

Gemcitabine authorization in UK

(Oct 1995)⁴

Gemcitabine EMA harmonization

(Sep 2008)⁹

Vinflunine EMA approval

(Sep 2009)¹¹

Durvalumab FDA BTD (Feb 2016)¹⁶

Atezolizumab FDA approval

and BTD (May 2016)¹⁷

Atezolizumab (Phase II)¹⁴ Durvalumab (Phase I)¹⁵

Avelumab (Phase I)¹⁸

Nivolumab FDA/EMA approval

and BTD (Feb/Jun 2016)^{21, 22}

2016 2017

Avelumab FDA approval

(May 2017)²³

Pembrolizumab FDA approval

and BTD (May 2017)²⁵

Atezolizumab EMA approval (Sep 2017)²⁴ Durvalumab

FDA approval (May 2017)²⁶

Pembrolizumab EMA approval

(Jul 2017)²⁷ 1976

BCG first tested for superficial bladder tumors^1*

2019

Erdafitinib FDA approval

(Apr 2019)²⁹ Erdafitinib (Phase II)²⁸

*BCG was the first and traditional IT for bladder cancer. BCG, Bacillus Calmette–Guérin; BTD, breakthrough therapy designation; HD-MVAC, high-dose methotrexate, vinblastine, doxorubicin, cisplatin; M-CAVI, methotrexate, carboplatin, and vinblastine; MVAC, methotrexate, vinblastine, doxorubicin, cisplatin.

Entwicklung der Systemtherapie in den letzten Jahren

References

1. Morales A et al. J Urol 1976;116:180–3;

2. Sternberg CN et al. Cancer 1989;64:2448–58;

3. Roth BJ et al. J Clin Oncol 1994;12:2264–70;

4. Eli Lilly. SmPC Gemzar® 01 Jul 2014.

Available at: http://www.medicines.org.uk;

5. McCaffrey JA et al. J Clin Oncol 1997;15:1853–7;

6. von der Maase H et al. J Clin Oncol 2000;18:3068–

77; 7. Sternberg CN et al. J Clin Oncol 2001;19:2638–46;

8. Meluch AA et al. J Clin Oncol 2001;19:3018–24;

9. EMA. EMEA/CHMP/512295/2008; 24 Sep 2008.

Available at: http://www.ema.europa.eu;

10. Bellmunt J et al. J Clin Oncol 2009;27:4454–61;

11. EMA. EMEA/H/C/000983; 2012. Available at:

http://www.ema.europa.eu;

12. De Santis M et al. J Clin Oncol 2009;27:5634–9;

13. Bellmunt J et al. J Clin Oncol 2012;30:1107–13;

14. Rosenberg JE et al. Lancet 2016;387:1909–20;

15. Massard C et al. ASCO 2016. Abstract 4502 and oral presentation;

16. AstraZeneca. Press release 17 Feb 2016.

Available at: http://www.astrazeneca.com;

17. FDA. Press release 18 May 2016. Available at:

http://www.fda.gov;

18. Apolo AB et al. ASCO 2016. Abstract 4514 and poster;

19. Galsky MD et al. ESMO 2016. Abstract

#LBA31_PR;

20. Balar A et al. ESMO 2016. Abstract #LBA32_PR;

21. FDA. Press release 2 Feb 2017. Available at https://www.fda.gov/;

22. BMS. Press release. 2 June 2017.

https://news.bms.com/press-

release/bladdercancer/european-commission- approves-bristol-myers-squibbs-opdivo-nivolumab- prev;

23. FDA. Press release 9 May 2017. Available at https://www.fda.gov/;

24. EMA. Atezolizumab authorization details.

Available at: /www.ema.europa.eu;

25. FDA Press release 18 May 2017. Available at:

https://www.fda.gov/;

26. FDA Press release 1 May 2017. Available at:

https://www.fda.gov/;

27. EMA Press release; 25 Jul 2017.

https://www.esmo.org/Oncology-News/EMA-Adopts- a-New-Indication-for-Pembrolizumab2;

28. Loriot Y et al. N Engl J Med 2019;381:338–41 29. FDA Press release 12 Apr 2019. Available at https://www.fda.gov/;

All references accessed February 2020

Die klinische Situation: aktuelle Fallpräsentationen

 ein 59jähriger Patient …, ein monströser Tumor

eigene Bilder

Die klinische Situation: aktuelle Fallpräsentationen

 Frage adjuvante Therapie?

 Problem: Kreatinin p.o. um 5 mg/d

(gerade so keine Dialyse)

 neue Daten: CheckMate 274

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients who

underwent radical surgery for high-risk muscle-invasive urothelial carcinoma

Dean F. Bajorin, ¹ Johannes Alfred Witjes, ² Jürgen E. Gschwend, ³ Michael Schenker, ⁴ Begoña P. Valderrama, ⁵ Yoshihiko Tomita, ⁶ Aristotelis Bamias, ⁷ Thierry Lebret, ⁸ Shahrokh F. Shariat, ⁹ Se Hoon Park, ¹⁰ Dingwei Ye, ¹¹ Mads Agerbaek, ¹² Sandra Collette, ¹³ Keziban Unsal-Kacmaz, ¹³ Dimitrios Zardavas, ¹³ Henry B. Koon, ¹³

Matthew D. Galsky ¹⁴

1

Memorial Sloan Kettering Cancer Center, New York, NY;

Radboud University, Nijmegen, the Netherlands;

Technical University Munich, Munich, Germany;

Nectarie Oncology Center, Craiova, Romania;

Hospital Universitario Virgen del Rocío, Sevilla, Spain;

Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

National and Kapodistrian University of Athens, Athens, Greece;

Urology Department Hopital Foch, Paris-Saclay University UVSQ, Versailles, France;

Medical University of Vienna, Vienna General Hospital, Vienna, Austria;

10

Samsung Medical Center, Seoul, South Korea;

Fudan University Shanghai Cancer Center, Shanghai, China;

Aarhus University Hospital, Aarhus, Denmark;

Bristol Myers Squibb, Princeton, NJ;

Icahn School of Medicine at Mount Sinai, New York, NY

Abstract Number 391

Session: Navigating Uncertain Times in Muscle-Invasive and Advanced Bladder Cancer

Clinical Trials

(Lopez-Beltran et al., Cancers 2021;13,131)

Die metastasierte Situation: aktuelle Fallpräsentationen

 ein 73jähriger Patient, primäre PD unter 2x Gem/Cis

I-O-Therapie geplant

eigene Bilder

Chemotherapie des mBCA – Erstlinie

Chemotherapie des mBCA – Erstlinie

Chemotherapie des mBCA – Erstlinie

Presented By Matt Galsky at 2018 ASCO Annual Meeting

Approximately 50% of patients with treamtment-naive

Metastatic bladder cancer are „cisplatin-ineligible“

Chemotherapie des mBCA – cisPlatin-Eligibility

17

MVAC (N=181)

Recommended maximum duration of 1L platinum-based chemotherapy is ≤6 cycles

Longer durations are not recommended because of cumulative toxicities and a lack of additional benefit ^4,5

1L, first-line; CR, complete response; DCR, disease control rate; ITT, intention-to-treat; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease;

UC, urothelial carcinoma

* Derived disease control rates based on ITT analysis in all patients with measurable disease, consistent with RECIST 1.1 guidelines⁶; ^† Patient numbers with SD were derived from rates reported in evaluable patients in the publication (33.5% of 164, 32.5% of 151); ^‡ Patients with measurable disease

1. von der Maase H, et al. J Clin Oncol. 2000:17:3068-77; 2. Dogliotti L, et al. Eur Urol. 2007;52:134-41; 3. De Santis M, et al. J Clin Oncol. 2012;30:191-9; 4. Sonpavde G, et al. J Urol. 2018;200:1207-14; 5. NCCN Guidelines: Bladder Cancer, V6.2020. https://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf.

Cisplatin + gemcitabine

(N=182)

Cisplatin + gemcitabine

(N=55)

Carboplatin + gemcitabine

(N=55)

Carboplatin + gemcitabine

(N=119)

In randomized trials,

≈65%-75% of patients with locally advanced or metastatic

UC achieved disease control with 1L platinum-containing

chemotherapy

74.7%*

70.9%*

65.5%*

73.0%

Pa tie nts (% ) 65.2%*

Was ist eigentlich mit Carboplatin?

18

Cisplatin + gemcitabine vs MVAC

phase 3 (N=405)1 Carboplatin + gemcitabine vs M-CAVI

phase 3 (N=238)

Cisplatin + gemcitabine vs

carboplatin + gemcitabine phase 2 (N=110)

Randomized trials of 1L platinum-based chemotherapy for advanced UC

Patients with Bajorin risk factors (visceral metastases and/or poor performance status) have shorter OS ^1,3,4

1L, first-line; M-CAVI, methotrexate, carboplatin, and vinblastine; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; OS, overall survival; PFS, progression-free survival; UC, urothelial carcinoma 1. von der Maase H, et al. J Clin Oncol. 2005;23:4602-8; 2. Dogliotti L, et al. Eur Urol. 2007;52:134-41. 3. De Santis M, et al. J Clin Oncol. 2012;30:191-9; 4. Bajorin DF, et al. J Clin Oncol. 1999;17:3173-81.

Median OS

Carboplatin + gemcitabine: 9.3 months M-CAVI: 8.1 months

p=0.64

0

M-CAVI 119 37 13 7 3 1 1

GC 119 44 15 5 2 2 1

Years 100

80 60 40 20

1 2 3 4 5 6 7

Months Median OS

Cisplatin + gemcitabine: 12.8 months Carboplatin + gemcitabine: 9.8 months 0

100 80 60 40 20

16 14 12 10 8 6 4 0 2

Overall survival (%)

0 100

80 60 40 20

0 12 24 36 48 60 72 84

203202 118

125 50

62 36

40 30

34 23

29 7

9 0

GC 1 MVAC

No. at risk Months

Median OS

Cisplatin + gemcitabine: 14.0 months MVAC: 15.2 months

HR 1.09 (95% CI 0.88-1.34) p=0.44

0 No. at risk

Overall survival (%) Overall survival (%)

Carboplatin OS ca. 9 Mo., cisPlatin OS ca. 14 Mo.

Pembrolizumab Keynote-361 Atezolizumab

IMvigor 130

mBCA First-Line: Wo stehen wir aktuell?

IMvigor 130: Galsky MD et al.

Lancet 2020;395(10236):1547-1557 KEYNOTE361: Alva A et al.

Presented on ESMO 2020, Abstr. LBA23.

Mod. Grande E et al. ESMO 2019, Proffered Paper session – Presidential Symposium III, Abstract No. LBA14_PR

IMvigor130 – Results

Interim OS: ITT (Arm A vs. Arm C)

Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients).

5% of patients from Arm A and 20% of patients from Arm C received non-protocol immunotherapy.

b

Did not cross the interim efficacy boundary of 0.007 per the O’Brien-Fleming alpha spending function.

Arm A Atezo + Plt/Gem

(n=451)

Arm C

Placebo + Plt/Gem (n=400)

OS events

, n (%) 235 (52) 228 (57)

Stratified HR (95% CI) 0.83 (0.69, 1.00) p=0.027 (one-sided)

100

90 80 70 60 50 40 30 20 10 0

OS (%)

0 3 6 9 12 15 18 21 24 27 30 33

13.4 mo

(12.0, 15.2) 16.0 mo (13.9, 18.9)

Months

No. at Risk

Atezo + Plt/Gem

Placebo + Plt/Gem 451

400 408

359 360

308 301

255 229

182 163

123 117

79 72

49 36

25 16

8 3

NE NE

NE

Atezo + Plt/Gem

Placebo + Plt/Gem

OS: Pembro + Chemo vs Chemo, ITT Population

Pembrolizumab Alone or Combined With Chemotherapy vs Chemotherapy Alone as First-Line Therapy for Advanced Urothelial Carcinoma: KEYNOTE- 361

Alva et a., (Abstr #LBA26) – ESMO 2020

Nur Immuntherapie? … Danube-Trial

(Powles et al., ESMO 2020) CO-PRIMARY ENDPOINTS:

• OS (D vs SoC in PD-L1 high)

• OS (D+T vs SoC in all comers)

SELECT SECONDARY ENDPOINTS:

• OS (D vs SoC in all comers)

• OS (D+T vs SoC in PD-L1 high)

• PFS, ORR and DoR

Data cutoff date (final analysis):

January 27, 2020

Minimum follow-up from date last patient randomised:

34 months

Median follow-up for survival:

41.2 months for all patients Durvalumab 1500 mg q4w until progression

(n=346)

Durvalumab 1500 mg q4w until progression

Tremelimumab 75 mg q4d for up to 4 doses +

(n=342)

SoC Chemotherapy

(gemcitabin + cisplatin or carboplatin, up to 6 cycles) (n=344)

Stratification 1. Cisplatin eligibility 2. PD-L1 status („high“ vs „low“)*

3. Presence/absence of liver and/or lung metastases

R

1:1:1

Patients with untreated, unresectable, locally advanced or metastatic UC

N = 1032

Nur Immuntherapie? … Danube-Trial, OS (all comers, ITT)

(Powles et al., ESMO 2020)

NUR I-O-Therapie scheint NICHT zu funktionieren!

Co-primary Endpoint – OS with Durvalumab + Tremelimumab vs Chemotherapy in the ITT Population

Durvalumab +

Tremelimumab 342 292 246 224 197 173 153 140 133 118 108 99 89 61 33 12 0 0

Chemotherapy 334 311 273 216 168 136 119 107 95 86 81 71 68 46 27 11 2 0

Probability of OS

Time from randomisation (months)

Durvalumab + Tremelimumab Chemotherapy

Durvalumab + Tremelimumab

(n = 342)

Chemotherapy (n = 344) Median OS,

months (95% CI) 15.1(13.1 –18.0) 12.1(10.9 – 14.0)

HR (95% CI) 0.85(0.72 – 1.02)

Log-rank P value* 0.0751

Number at risk

*Considered statistically significant if p < 0.0134

Neues therapeutisches Konzept!

Erhaltungstherapie

bei Patienten mit klinischem Benefit nach Platin-basierter Chemotherapie

Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line

chemotherapy in advanced urothelial carcinoma:

JAVELIN Bladder 100 phase III results

(Powles et al., ASCO 2020)

Ist die Immuntherapie allein beim UCA ausreichend?

NEIN!

Wir benötigen neue Substanzen!

Erdafitinib

Enfortumab Vedotin Sacituzumab Govitecan

Ansprechrate (ORR) von 13 – 29 %

Was passiert mit den Non-Respondern?

aStratification variables were ECOG performance status (0 or 1), regions of the world (United States, western Europe, or rest of world), liver metastasis (yes or no) I ^bIf used in the adjuvant/neoadjuvant setting, progression must be within 12 months of completion I ^cInvestigator selected prior randomization I ^dIn countries where approved; overall proportion of patients receiving vinflunine capped at 35%. I Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PD-1/L1, programmed cell death protein-1/programmed death-ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; UC, advanced urothelial carcinoma.

Enfortumab vedotin (N = 301)

1,25 mg/kg on Days 1, 8 and 15 of each 28-day cycle

Preselected chemotherapy

(N = 307) ^c

Docetaxel 75 mg/m

or Paclitaxel 175 mg/m

or

Vinflunine

320 mg/m

on Day 1 of each 21-day cycle

Primary endpoint: Overall survival Secondary endpoints

• Progression-free survival

• Disease control rate

• Overall response rate

• Safety

1:1 randomization with stratification^a

Investigator- assessed per RECIST v1.1

Key eligibilty criteria:

• Histologically/cytologically confirmed UC, including wth squamous differentioation or mixed cell types

• Radiographic progression or relapse during or after

PD-1/L1 treatment for advanced UC

• Prior platinum-containing regimen for advanced UC ^b

• ECOG PS 0 or 1

Enfortumab Vedotin – Trial EV 301 (Drittlinie) (ASCO-GU 2021)

(Präsentation: Jozefina Casuscelli unter: www.asco-direct-gu.de)

Enfortumab Vedotin – Trial EV 301 (Drittlinie) (ASCO-GU 2021)

Zusammenfassung

Vielen Dank für Ihre Aufmerksamkeit!

 Beim fortgeschrittenen Urothelkarzinom der Harnblase stellt die Platin-

basierte Chemotherapie eine (die?) entscheidende Säule der Therapie dar!

 Die Immunonkologie (Pembrolizumab, Atezolizumab, Nivolumab,

Avelumab) hat in den letzten Jahren die Therapieoptionen revolutioniert!

 Mit der Sequenz von Gem/Platin und Avelumab als Erhaltungstherapie gibt es einen neuen Therapiestandard!

 Aber die I-O-Therapie ist kein „Allheilmittel“!

 Neue Therapieansätze sind notwendig und auch auf dem „Vormarsch“!

Transparenzinformation

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