Meet the expert: Melanom - Oncology Conferences · 2/19/2016 1 Meet the expert: Melanom Christoph...

2/19/2016

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Meet the expert:Melanom

Christoph Höller

Universitätsklinik für Dermatologie

Medizinische Universität Wien

DESO St. Gallen 18.&19. Februar 2016

Certified Skin Tumor Center

Sprecher‐Honorare, Advisor von

Mögliche Interessenskonflikte

•BMS•GSK•MSD•Novartis•Roche•Amgen

C. Höller 2016

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Inhalt

• Melanom‐Basics

• Prävention

• Operatives Vorgehen Stadium I‐III

• Adjuvante Therapie

• Therapie im nicht operable metastasierten Stadium• Lokoregionäre Therapie

• Systemische Therapie

Interrupt me whenever you like….

C. Höller 2016

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Melanominzidenz Europa

C. Höller 2016

The real incidence of melanoma in Austria

C. Höller 2016 Monshiet al. Europ. J Cancer, 2016

Incidence: 25/100.000

84

133

Tis + T1 T2+T3 T4

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C. Höller 2016 Bild zur Verfügung gestellt von H. Kittler

40% der Melanome werden entdecktbevor sie die Oberhaut verlassen

haben (“in situ” Melanome)

C. Höller 2016 Bild zur Verfügung gestellt von H. Kittler

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Ultraviolet light – Sunlight:The major oncogene in skin cancers

C. Höller 2016 Berger et al., Nature. ; 485(7399): 502–506

Acral melanomaMucosla melanoma

• Typical C/G > T/A transititions ‐mutational pattern of UV

Lentigo malignaMelanom / CSD

Landscape of oncogenic mutations in melanoma

C. Höller 2016

GNAQ, GNA11

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C. Hoeller 2016

Melanoma has the highest mutational burden

Alexandrov et al. Nature 2013; Furney et al, Cancer Discovery 2013

Chirurgie‐Primärtumor

• Erstoperation im Gesunden, Probeentnahmensollen vermieden werden.

• Zweitoperation nach Pathohistologie:

C. Höller 2016

≤ 2mm

> 2mm

In situ

*

* Keine Nachexcision nur wenn primär bereits 0.5cm SA vorhanden

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Tumordicke und Ulzeration, Mitosenals prognostische Parameter

C. Höller 2016

0.01‐1mm T1 ohne Ulzeration, < 1 Mitose/mm2 T1amit Ulzeration, > 1 Mitose/mm2 T1b

AJCC IAAJCC IB

2.01‐3mm T2 ohne Ulzeration T2amit Ulzeration T2b

AJCC IBAJCC IIA

3.01‐4mm T3 ohne Ulzeration T3amit Ulzeration T3b

AJCC IIAAJCC IIB

ab 4.01 mm T4 ohne Ulzeration T4amit Ulzeration T4b

AJCC IIBAJCC IIC

Sentinel Node Chrirurgie• Patienten > 1mm Tumordicke (ab T2a)

• > 0.75mm bei zusätzlichen Risikofaktoren(Ulzeration, > 1 Mitose/mm2) (ab T1b)

• Derzeitiger Wissensstand:

• guter Prognosemarker ✓• Bedeutung in der AJCC‐Klassifikation ✓• Verbessertes rezidivfreies Überleben ✓• Verbessertes Gesamtüberleben ???

C. Höller 2016

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MSLT‐1 trial

C. Hoeller 2016

2001 patients with Melanoma >1 mm or > Clark IV

Wide excision alone Wide excision + SLN

SLN + SLN -

Observation

Immediate CLNDCLND for Recurrence

Randomization

No recurrence: observation

DSS: Primary EndpointDFS: Secondary Endpoint

40% 60%

C. Hoeller 2016 Morton et al, N Engl J Med 2014; 370:599‐609

MSLT‐1 trial ‐ design

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• Stratifikation: Niedrigrisiko‐ (1,0‐1,19 mm TD, 340 Pat.), intermediäres Risiko‐ (1,2‐3,5 mm TD, 1.347 Pat.) und Hochrisiko‐MM (>3,5 mm TD, 314 Pat.)

• Primäres Studienziel: Melanom‐spezifisches Überleben

• WLE ohne SNB (Gruppe A): 78,3% vs. WLE mit SNB (Gruppe B): 81,4%

• Statistisch nicht signifikanter UnterschiedHR: 0,84; (VB: 0,64‐1,09); p=0,18

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MSLT‐1‐Studie: ErgebnisseMorton et al, N Engl J Med 2014; 370:599‐609

C. Höller 2016

• SLND – kein Einfluß auf OS

• SLND: verbessertes rezidivfreies Überleben • SN = hervorragender Prognosemarker

• Wenig Morbidität durch SLND‐Prozedur

• SN‐Status = wichtigstes Kriterium für Indikation zur adjuvanten Therapie !

Fazit für Klinik und Praxis

C. Höller 2016

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Comparison of Survival Rates at Stages I, II, and III (AJCC 2009)

Wer benötigt eine adjuvante Therapie?„High‐Risk Melanom“

Balch et al. J Clin Oncol 2009;27:6199 -6206

High Risk Patienten: Höhere relapse-Rate und schlechteres Überleben

After 3 years

C. Höller 2016

Adjuvante MelanomtherapieMany trials – little success….

• BCG

• Corynebacteriumparvum

• Levamisole

• Transfer factor

• Vaccinia Oncolysat

• Extremitätenperfusion

• Strahlentherapie

• DTIC

• DTIC + BCG o. C. parvum

• DTIC + Nitrosourea

• Autologe KMT

• IFN • IFN 2a/b

C. Höller 2016

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Interferon benefits (RFS): Hazard ratios

• HDI (4 trials): 0.80 (‐20% risk)

• IDI (2 trials): 0.82 (‐18% risk)

• LDI (7 trials): 0.81 (‐19% risk)

• PegIFN (1 trial): 0.82 (‐18% risk)Relapse‐free survival benefits

(OS benefits significantly smaller)

23C. Hoeller 2016 Slide courtesy of A. Hauschild

C. Höller 2016

Years0 2 4 6 8

0

Patients Alive Without Relap

se (%)

10

20

30

40

50

60

70

80

90

100

Interferon (IFN)/PEG‐IFNEORTC 18952/EORTC 189911

IIB/III‐N1: IFN/PEG‐IFN IIB/III‐N1: Observation

III‐N2: IFN/PEG‐IFN III‐N2: Observation

Subgroup Analyses of RFS: Microscopic (N1) vs Clinically Palpable (N2) Lymph Nodes

Stage IIB/III‐N1: HR 0.78 (99% CI: 0.61–0.99)

O N Number of Patients at Risk357 770 501 234 26204 384 221 79 7

1Eggermont AM, et al. Eur J Cancer 2012;48:218–25.

2185 Patients

467 655 241 108 13261 376 144 52 2

Stage III‐N2: HR 0.91 (99% CI: 0.74–1.12)

Eggermont AM, ASCO 2014

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C. Höller 2016

EORTC 18071/CA184‐029: Study Design

INDUCTIONIpilimumab 10 mg/kg

Q3W X4High-risk, stage III, completely resected

melanoma INDUCTIONPlaceboQ3W X4

R

MAINTENANCE Ipilimumab 10 mg/kgQ12W up to 3 years

MAINTENANCE Placebo

Q12W up to 3 years

Treatment up to a maximum 3 years, or until disease progression, intolerable toxicity, or withdrawal

N=475

N=476

Week 1 Week 12 Week 24

Stratification factors:

• Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)

• Regions (North America, European countries and Australia)

N=951


C. Höller 2016

Primary Endpoint: Recurrence‐free Survival (IRC)

Ipilimumab Placebo

Events/patients 234/475 294/476

HR (95% CI)* 0.75 (0.64–0.90)

Log-rank P value* 0.0013

2-Year RFS rate (%) 51.5 43.8

3-Year RFS rate (%)** 46.5 34.8

Ipilimumab 10 mg/kg

Placebo

Patients at RiskO N

Ipilimumab

Placebo

Pat

ien

ts A

live

Wit

ho

ut

Rel

apse

(%

)

100

90

80

70

60

50

40

30

20

10

00 12 24 36 48 60

Months

475

476

276

260

205

193

67

62

5

4

0

0

Median: 17.1 mo

Median: 26.1 mo

*Stratified by stage. **Data are not yet mature.

234

294


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C. Höller 2016

Years0 2 4 6 8

0


se (%)

10

20

30

40

50

60

70

80

90

100

Interferon (IFN)/PEG‐IFNEORTC 18952/EORTC 189911

IpilimumabEORTC 18071

IIB/III‐N1: IFN/PEG‐IFN IIB/III‐N1: Observation

III‐N2: IFN/PEG‐IFN III‐N2: Observation

Subgroup Analyses of RFS: Microscopic (N1) vs Clinically Palpable (N2) Lymph Nodes

Stage IIB/III‐N1: HR 0.78 (99% CI: 0.61–0.99)

O N Number of Patients at Risk357 770 501 234 26204 384 221 79 7

Stage III‐N1: HR 0.68 (99% CI: 0.47–0.99)

O N Number of Patients at Risk83 210 108 2108 193 98 3

Years0 2 4 6

0

10

20

30

40

50

60

70

80

90

100


se (%)

1Eggermont AM, et al. Eur J Cancer 2012;48:218–25.

III‐N1: Ipilimumab III‐N1: Placebo

III‐N2: Ipilimumab III‐N2: Placebo

2185 Patients 951 Patients

467 655 241 108 13261 376 144 52 2

Stage III‐N2: HR 0.91 (99% CI: 0.74–1.12)

151 265 97 3186 283 95 1

Stage III‐N2: HR 0.83 (99% CI: 0.63–1.10)


% Patients

Ipilimumab (n=471) Placebo (n=474)

All grades

Grade 3 Grade 4All

gradesGrade 3 Grade 4

Any irAE 90.4 36.5 5.5 38.6 2.3 0.2Dermatologic 63.3 4.5 0 20.9 0 0Rash 34.4 1.3 0 11.0 0 0

Gastrointestinal 46.3 14.9 1.1 17.7 0.6 0.2Diarrhea 41.4 9.6 0 16.7 0.4 0Colitis* 15.9 6.8 0.8 1.3 0.2 0

Endocrine 37.6 7.9 0.6 6.5 0 0Hypophysitis 18.3 4.7 0.4 0.4 0 0Hypothyroidism 8.9 0.2 0 0.8 0 0

Hepatic 25.1 7.9 2.8 4.4 0.2 0LFT increase 19.7 3.8 1.5 4.0 0 0

Neurologic 4.5 1.1 0.8 1.9 0 0Other 23.6 7.4 0.4 4.4 1.7 0

LFT=liver function test.*Gastrointestinal perforations: ipilimumab, 6 related (1.3%); placebo, 3 unrelated (0.6%).

Safety: Immune‐related Adverse Events

C. Höller 2016 Eggermont AM, ASCO 2014

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• Five patients (1.1%) died due to drug‐related AEs in the ipilimumab group:

– Three patients with colitis (2 with gastrointestinal perforations)

– One patient with myocarditis

– One patient with Guillain‐Barré syndrome

• No deaths related to study drug were reported in the placebo group

Deaths Related to Study Drug

C. Höller 2016 Eggermont AM, ASCO 2014

Derzeitige adjuvante Studien

• Interferon (pegyliert) bei ulzeriertemPrimmärtumor

• Vemurafenib (BRIM 8; IIC‐III) – recruitment ongoing

• Dabrafenib/Trametinib (Combi‐Ad, III) – fully recruited, study ongoing

• Ipilimumab vs. HD‐Interferone

• PD1‐antibodies vs. placebo/Ipilimumab ± HD‐Interferon

C. Höller 2016

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Metastasiertes Melanom100

90

80

70

60

50

40

30

20

10

0

5‐Yea

r Su

rvival (%)

Alle Stadien LokaleErkrankungStadium I+II

RegionaleErkrankungStadium III

91.5%

99.0%

64.9%

FernmetastasierungStadium IV

15.3%

C. Höller 2016

“Standard” Chemotherapie

Response Rate (%) Survival (Month)

Dacarbazin (DTIC) 5‐23% 5,6 – 7,7

Temozolomid 13,5–21% 5,3 – 7,2

Fotemustin 7,4–24,2% 5,4 – 7,2

Vindesin 12 –26% 5

BHD (BCNU, Hydroxyurea, DTIC) 12,7–30,4% ‐‐‐‐‐‐‐

BOLD (Bleomycin, Vincristin, CCNU, DTIC) 22–40% 6 – 7,7

DVP (DTIC, Vindesin, Cisplatin) 24–45% 6,5

DBCT (DTIC, BCNU, Cisplatin, Tamoxifen) 18,5–31,9% 6,4 ‐ 6,7

C. Höller 2012C. Höller 2016 Gogas et al, Cancer 2007; 109:455‐64; Garbe et al, The Oncologist 2011, 16:5‐24;

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C. Höller 2016

0

50

100

150

200

250

300

350

400

450

2012 2013 2014

Verbrauch DTIC in Stk. Dermatologie AKH Wien

*

Quelle: Anstaltsapotheke AKH, * Daten aus 1. Halbjahr 2014 hochgerechnet

Neue Therapieoptionen für das inoperabel metastasierte Melanom

CellularProliferation

RAFVEMURAFENIBDABRAFENIB

ATP

ATP

ERK

MEK

BRAFV600E

RAS

MHC

TCR

IPILIMUMAB

T-cell

APC

B7

CD28

C. Hoeller 2016

40‐60%

TRAMETINIBCOBIMETINIB

PD-1

CTLA-4

NIVOLUMAB

PEMBROLIZUMAB

PDL-1c-kitmut

eg. IMATINIBeg. IMATINIB

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The mutational landscape ofmelanoma

C. Hoeller 2016 Cancer Genome Atlas Group, Cell 2015

B‐raf Mutation in Melanoma

Mel.=melanoma; Colo.=colorectal; Ca.=cancer; STC=soft tissue cancer.

BRAF mutations Cancer cell lines Primary tumours

Nucleotide Amino acid(1)Mel.

T1796ATG1796‐97AT

No. samples screenedPercent (%)

V599EV599DTotal

191203459

(2)Colo. ca

5

74018

(3)Glioma

4

43811

(4)Lung ca.

41313

(5)Sarcoma

5

5599

(6)Breast

1

1452

(7)Ovarian

1264

1

11720.6

(8)Other

(1)Mel. STC

11

121580

5

6967

(2)Mel.

(3)Colo. ca

2

42212

3

53514

(4)Ovarian

1

11820.5

(5)Sarcoma

(6)Other

0

01040

571719238

Total

Tumour Ov18TT1796AV599E

V600E

G12VHRAS

9E10

ppERK

ERK1

BRAFBRAF

ERK1ERK2

ERK1

‐ + ‐ + ‐ + ‐ + ‐ + ‐ +

C. Höller 2016 Davies H, et al. Nature 2002;417:494–54.

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E

> 85%

C. Höller 2016

BRAF‐inhibition:• A…Hohe Ansprechrate• B…Rasches Ansprechen• C…Resistenzentwicklung im Mittel nach 6.9 Monaten• D…verbessertes Gesamtüberleben

C

B

Vemurafenib, tested against DTIC, First‐line, BrafV600

A

Clinical benefit withinonly 2 weeks

8W

SCR

d0d0

w2

w8 w8

DWeek 18

Chapman et al, N Engl J Med 2011, 364: 2507‐16

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BREAK‐3 / BRIM‐3 –reproducible response of target lesions under B‐raf inhibition

Gepunktete Linie bei 20 % repräsentiert den Cut‐off für PD; gepunktete Linie bei ‐30 % repräsentiert den Cut‐off für PR

Max

imu

m c

han

ge

in s

ize

of

targ

et ll

esio

n

Dabrafenib180

60

40

20

0

-20

-40

-60

-80

-100

50

0

-50

-100

Vemurafenib2

C. Höller 2015 Hauschild A, et al. Lancet 2012;380:358–65 Chapman et al, N Engl J Med 2011, 364: 2507‐16

BREAK‐3: Overall Survival

C. Höller 2016 Grob JJ, et al. Poster presented at SMR 2014

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Ausgewählte Nebenwirkungen von B‐rafInhibitoren

C. Höller 2016

Nebenwirkung Häufigkeit

Exantheme 30‐41% (TEN! DRESS!)

Alopezie 8‐27%

Arthralgien 19‐56%

Hyperkeratosen 6‐19%

Übelkeit 14‐38%

Phototoxizität 41‐51% (Vemurafenib)

Pyrexie 16% (Dabrafenib)

Keratoakanthome / Plattenepithelcarcinome

10‐26%

B‐raf Inhibitors Side effects

C. Höller 2016

New primary melanomas wo BRAF‐mutations havebeen observed in 2% of patients in the respective

Vemurafenib/Dabrafenib arms of the pivotal studies

Zimmer et al. J Clin Oncol. 2012 Jul 1;30(19):2375‐83

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B‐raf Inhibition and SCC/KA

Wildtype BRAF undergoes an autoinhibition that is lost in BRAF V600E mutated cells. In cells carrying an NRAS mutation BRAF specific inhibitors block the autoinhibition of BRAF, subsequently leading to a superactivation of the MAP-Kinase signaling pathway (Heidorn SJ et al, Cell 2010)

C. Höller 2016 Heidorn SJ et al, Cell 2010

BRAF amplification 8%

Reactivation of MAP‐Kinase Signalling is the major resistance mechanism

*8,29 tumours progressing on dabrafenib or vemurafenib were included in the analysis.†n=38IGF‐1R=insulin‐like growth factor 1 receptor.

AKT1 3%

BRAF splice variant 29%

Unknown 42%

BRAF splicevariant

& N‐RAS 3%

MEK2 3%

IGF‐1R 3%

MEK1 5%

NRAS5%

BRAF inhibitor resistance mechanisms†

MAPK inhibited 21%

MAPK reactivated 79%

MAPK activation status in progressing tumours following BRAF inhibitor

monotherapy*

C. Höller 2016 Rizos H, et al. Clin Cancer Res 2014;20:1965–77.

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Resistenz gegen B‐raf Inhibitoren

C. Höller 2016

Nazarian R et al, Nature 468: 973‐7, Johannessen et al, Nature 468: 968‐72, Paraiso et al, Br J Cancer 102: 1724‐30, all 2010

RTK Aktivierung

BRAF V600E

MEK 1/2

ERK 1/2

NRAS

CRAF

COT

MEK unabhängigeResistenz

MEK abhängigeResistenz

BRAF spliceVariante

Kombinierte B‐raf und MEK Inhibition

Zellteilung

RTK

RAFATP

ATP

ERK

MEK

BRAFV600E

RAS

40-60% of melanomas B-raf InhibitorenDabrafenib, Vemurafenib

Encorafenib

MEK InhibitorenTrametinib, Cobimetinib

Binimetinib

C. Höller 2016

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B‐raf + MEK Inhibitor Kombinationen

C. Höller 2016 Long G. et al, NEJM 2014; Atkins V. et al., SMR 2016

PBO + Vem n = 248

Cobi + Vem n = 247

OS events, n (%) 141 (56.9) 114 (46.2)

OS, median (95% CI), mo

17.4 (15.0-19.8)

22.3 (20.3-NE)

HR (95% CI) 0.70 (0.55-0.90)P = 0.005

Median follow-up, mo 18.5

Median (95% CI), moPhase 1/2 D + T 25.0 (17.5–36.5)COMBI-d D + T 25.1 (19.2–NR)COMBI-d D + P 18.7 (15.2–23.7)COMBI-v D + T 25.6 (22.6–NR)COMBI-v V 18.0 (15.6–20.7)

B‐raf/MEK Inhibition and SCC/KA

C. Höller 2016 Heidorn SJ et al, Cell 2010

Wildtype BRAF undergoes an autoinhibition that is lost in BRAF V600E mutated cells. In cells carrying an NRAS mutation BRAF specific inhibitors block the autoinhibition of BRAF, subsequently leading to a superactivation of the MAP-Kinase signaling pathway (Heidorn SJ et al, Cell 2010)

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Combi‐V/Co‐Brim – ausgewählteNebenwirkungen

AE Term VemurafenibCombi‐V (%)

VemurafenibCo‐Brim (%)

Dabrafenib & Trametinib (%)

Vemurafenib & Cobimetinib (%)

Cutaneous SCC + KA 18 19 1 4

Rash 43 35 22 39

Serous retinopathyChorioretinopathyBlurred vison

< 3 < 1 < 3 20

Decreased ejection fraction 0 3 8 7

Diarrhea8 28 32 56

Pyrexia21 22 53 26

Phototoxicity36 15 4 28

C. Höller 2016 Long G. et al, NEJM 2014; Larkin J. et al., NEJM 2014

c‐KIT

Garrido and Bastian, JID 2009

C. Höller 2016

Exon 11 Exon 13

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Phase II study with imatinib in selected patients with c‐kit mutations

51 pts with KIT mutation oramplification

Confirmed Response Rate: 2 CR, 4 PR and 5 SD > 12 weeksMedian time to progression 12 weeks

C. Höller 2016 Carvajal RD, JAMA 2011

Neue Therapieoptionen für das inoperabel metastasierte Melanom

CellularProliferation

RAFVEMURAFENIBDABRAFENIB

ATP

ATP

ERK

MEK

BRAFV600E

RAS

MHC

TCR

IPILIMUMAB

T-cell

APC

B7

CD28

C. Hoeller 2016

40‐60%

TRAMETINIBCOBIMETINIB

PD-1

CTLA-4

NIVOLUMAB

PEMBROLIZUMAB

PDL-1c-kitmut

eg. IMATINIBeg. IMATINIB

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Immunotherapy of Melanoma

C. Hoeller 2016

Vaccines High‐dose Il2 Adoptive T‐Cell Therapy

Response Rate 3‐30% 16% 49‐72%

Overall Survival (months)

No overall survival benefit

12 months (11% durable response >5 a)

NA (8‐44% Complete Response)

Applicability Peptide based good, DCs require specialized lab, HLA restriction

Low due to severe side effects

Low due to specialized technique and high cost

Current Status experimental Approved (US, Denmark)

experimental

Erstbeschreibung von CTLA‐4 1987

C. Hoeller 2016

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“Immune checkpoints” regulate T‐cell activation

• T cell activation determined by the balance of CD28 (stimulatory signal) and CTLA4 (inhibitory signal)1-3

• CTLA-4 blockade can induce antitumor immunity4

C. Hoeller 2016

1. Walunas TL et al. Immunity. 1994 Aug;1(5):405‐13. 2. Green JM et al. Immunity. 1994 Sep;1(6):501‐8. 3. Krummel MF et al. J Exp Med. 1995 Aug 1;182(2):459‐65. 4. Leach DR et al. Science. 1996 Mar 22;271(5256):1734‐6.

James P. Allison

Regulation der T‐Zell Aktivierung• “Immune checkpoints” kontrollieren das Ausmaß der Immunantwort

• VerhindernGewebsschaden durchüberschiessendeEntzündungsreaktion

APC/tumour

T cell

PD-1

B7-1 (CD80)

PD-L1

PD-L2

CD40 CD40L

CD137

OX-40

CD137L

OX-40L

LAG-3

MHC

CD28 ActivationB7-2 (CD86)

B7-1 (CD80) CTLA-4 Inhibition

TCR

Inhibition

Inhibition

Activation

Activation

Activation

Inhibition

APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T cell receptorPardoll DM. Nat Rev Cancer 2012;12:252–264

C. Höller 2016

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Die Zytotoxische T‐Zelle im Kampf gegen das metastasierte Melanom

MHC

TCR

IPILIMUMAB

T-Zelle

APC

B7

CD28

C. Höller 2016

CTLA-4

CTLA-4

Vollständig humaner IgG1 Antikörper welcher gegen CTLA4 gerichtet ist. Halbwertszeit: 12.5 Tage

MHC

TCR

3

C. Höller 2016 Hodi FS et al, N Engl J Med, 2010,711‐23

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Ipilimumab – 3mg/kg

Hodi FS et al, N Engl J Med, 2010,711‐23 C. Höller 2012C. Hoeller 2016 Hodi FS et al, N Engl J Med, 2010,711‐23

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ipilimumab provides long term survival to a subgroup of patients

Patients at riskIpilimumab 1861 839 370 254 192 170 120 26 15 5 0

N=1861

0 12 24 36 48 60 72 84 96 108 120

Pro

po

rtio

n a

live

Months

Median OS, months (95% CI): 11.4 (10.7–12.1)a

3-year OS rate, % (95% CI): 22 (20–24)a

IpilimumabCENSORED

aIpilimumab was given at different doses and lines of therapy, and using different schedules across the 12 studiesSchadendorf D, et al. ECC Congress. 2013 Abs 124LBA

C. Höller 2016

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IpilimumabAnsprechen während der Therapie

W 1 W7 W12 W16

C. Hoeller 2016

C. Hoeller 2016 Harmankaya K et al, Med Oncol 2010

Initial PD with delayed response and CRCorresponding CT-Scans

Screening Week 12 Week 16 CR for 7.5 years

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mWHO vs. irRCCR PR SD PD

mWHO

Criteria

All lesions gone

SPD of index lesions decreases > 50%

new lesions

not allowed

SPD index lesions neither CR, PR or

PD;

new lesions

not allowed

SPD index lesions increases

> 25% &/OR

PD is based on SPD and/or new

lesions

irCR irPR irSD irPD

irRC

All lesions gone

SPD of index + any new lesions

Decreases > 50%

new lesions allowed

SPD of index + any new lesions neither irCR, irPR nor irPD

new lesions allowed

SPD of index + any new lesions increases > 25%

PD is based on SPD only

SPD = sum of the product of the perpendicular diameters

C. Hoeller 2016 Wolchok JD, Hoos A, O'Day S, Weber JS, Humphrey R, Hodi FS Clin Cancer Res 2009;15(23):7412-20.

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Progression needs to be confirmed at least 4 weeks later

Check point inibitor induced T‐Cell Activation

Efficacy: Anti‐tumor

response throughT‐cells infiltrating

metastases

+ ‐Safety:

Immune relatedAdverse Events (IrAE) through T‐cell activation

C. Hoeller 2016

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Side effects observed under treatment with check point inhibitors

Encephalitis

Thyroiditis

FatigueHypophysitis

Pneumonitis

Myositis, Myasthenia gravis

Neuritis, Guillaine BarreSyndrome

Hepatitis

Adrenal insufficiency

Nephritis

Pancreatitis, Hyperglycemia, Diabetes

Uveitis

Arthritis

Colitis

Vasculitis

Thrombopenia

Rash (including but not limited to Dermatomyositis, Bulluous Pemhigoid, SJS/TEN, Psoriasis)

C. Hoeller 2016

C. Hoeller 2016

What happens to the tumor response if you use immunomodulatingagents?

46

Baurain et al. ASCO 2012, Abstract 8539

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PD‐1 blockade in tumor models

65

C. Hoeller 2016 Iway et al.,PNAS 2002

Tasuku Honjo

CD8+ T‐cell Exhaustion Due to Chronic Antigen Simulation

Cytotoxic capacity

Proliferative

Potential

Apoptosis

Naïve CD8+

T cell Antigen +costimulation

Effector CD8+ T cell

PD‐1

LAG‐3

CD244 (2B4)

CD160 (and so on)

Highly polyfunctional memory CD8+ T cell

CD8+ T‐cell Exhaustion

Antigen persists

Antigen cleared

66

C. Hoeller 2016 Modified from: Wherry et al. Nat Immunol. 2011;12(6):492‐499.

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PD1 – Blockade: Mode of action

Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD‐L1/2

upregulation on tumour

Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen‐presenting cells

MHC

PD‐L1

PD‐1 PD‐1

PD‐1 PD‐1

PD1 Receptor Blocking Ab

T‐cellreceptor

T cellreceptor

PD‐L1PD‐L2

PD‐L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumour cell

IFNγIFNγR

Shp‐2

Shp‐2

67

C. Hoeller 2016 Pardoll DM. Nat Rev Cancer. 2012 Mar 22;12(4):252‐64.

C. Höller 2016

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C. Hoeller 2016 G Long et al., N Engl J Med. 2015 Jan 22;372(4):320‐30

Checkmate‐066 ‐ Nivolumab vs. DTIC: 2‐year OS

C. Hoeller 2016 G Long et al., N Engl J Med. 2015 Jan 22;372(4):320‐30; Atkinson et al, SMR 2015

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C. Hoeller 2016

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PD‐1 has unexpected „sideeffects“

C. Höller 2016

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Active immunotherapy

Adoptive cell transfer (ACT)immunotherapy

IL-2IFNIL-15IL-21

Peptide vaccineDC vaccineGenetic vaccine

OX40

CD137

CD40

PD-1CTLA4

T cell cloningTIL therapy

T cell checkpointblocking and

stimulatingantibodies

TCR or CAR genetic engineering

Immunotherapy– T cell versus melanoma

C. Höller 2016 Slide courtesy of Toni Ribas, UCLA

CA209‐067: Study Design

Randomized, double‐blind, phase III studyto compare NIVO + IPI or NIVO alone to IPI alone

Unresectable orMetatastic Melanoma

• Previously untreated

• 945 patients

Treat until progression**

orunacceptable

toxicity

NIVO 3 mg/kg Q2W +IPI‐matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then

NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO‐matched placebo

Randomize1:1:1

Stratify by:

• PD‐L1 expression*

• BRAF status

• AJCC M stage

*Verified PD‐L1 assay with 5% expression level was used for the stratification of patients; validated PD‐L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol‐defined circumstances.

N=314

N=316

N=315

C. Hoeller 2016 Larkin et al., N Engl J Med 2015; Wolcok J, presented at ASCO 2015

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PFS (Intent‐to‐Treat)

NIVO + IPI (N=314)

NIVO(N=316)

IPI (N=315)

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

HR (99.5% CI)vs. IPI

0.42 (0.31–0.57)*

0.57(0.43–0.76)*

‐‐

HR (95% CI)vs. NIVO

0.74 (0.60–0.92)**

‐‐ ‐‐

*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

No. at Risk

314NIVO + IPI 173 151 65 11 1219 0

316NIVO 147 124 50 9 1177 0

315IPI 77 54 24 4 0137 0

0 6 9 12 15 183 21

NIVO

NIVO + IPI

IPI

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Proportion alive and progression‐free


Response to Treatment

NIVO + IPI(N=314)

NIVO(N=316)

IPI(N=315)

ORR, % (95% CI)* 57.6 (52.0–63.2) 43.7 (38.1–49.3) 19.0 (14.9–23.8)Two‐sided P value vs IPI <0.001 <0.001 ‐‐

Best overall response — %

Complete response 11.5 8.9 2.2

Partial response 46.2 34.8 16.8

Stable disease 13.1 10.8 21.9

Progressive disease 22.6 37.7 48.9

Unknown 6.7 7.9 10.2

Duration of response (months)

Median (95% CI) NR (13.1, NR) NR (11.7, NR) NR (6.9, NR)

*By RECIST v1.1.

NR, not reached.


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Safety Summary

Patients Reporting Event, %

NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)

Any GradeGrade 3–4 Any Grade

Grade 3–4

Any GradeGrade 3–4

Treatment‐related adverse event (AE) 95.5 55.0 82.1 16.3 86.2 27.3

Treatment‐related AE leading to discontinuation

36.4 29.4 7.7 5.1 14.8 13.2

Treatment‐related death* 0 0.3 0.3

*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).

• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment‐related AEs developed a response


„Lokale“ onkolytischeImmuntherapie• Verwendet Viren, welche die

Tumorzellen zerstören und

gleichzeitig Entzündungszellen

anlocken.

• Talimogen Laherparepvec (TVEC)

C. Höller 2016

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Talimogene Laherparepvec (TVEC)• Humanes Herpes‐Simplex Virus Typ I

• Exprimiert GM‐CSF

• Repliziert “selektiv” in Tumorzellen

• Zulassung für Patienten im nichtoperablen Std. III und IVa – nichtzugelassen für Pat. Mit Organ, Hirn‐ oderKnochenmetastasen.

• OPTIM‐Studie: Ph 3 T-VEC vs GM-CSF1

• Verbesserte “Durable Response Rate” (Ansprechen ≥ 6 Monate)

• 16% vs 2%, p<0.0001

C. Hoeller 2016 1. Andtbacka RHI et al. J Clin Oncol 2015

Proposed Mechanism of Action of T-VEC With PD-1 Inhibitor

TDA: tumour-derived antigenT-VEC: talimogene laherparepvecExact MoA of T-VEC is not known

1

T‐VEC

Systemiceffect

3

Mature dendritic

cell

T cell

GM‐CSF

TDAMHC TCR

CD80/CD86

CD28

4T cell

5

TDA

MHCTCR

PD‐L1 PD‐1pembrolizumab

Cancer ImmunityCycle

Localeffect

2

Healthy cells

T‐VEC

GM‐CSF

TDAImmature

dendritic cell

Tumor cells

TDA

C. Hoeller 2016 Long G V et SMR 2015

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Change in Tumor Burden Over Time

T-VEC only T-VEC + pembrolizumabScreening

Median tumor follow-up time from first dose: 16.9 weeks

-4 -2 0 2 4 6 8 10 12 14 16 18 20 22

Weeks from treatment initiation

-100-80-60-40-20

020406080

100110

400600

% C

hang

e fr

om B

asel

ine

= Stage IIIB= Stage IIIC

= Stage IVM1a= Stage IVM1b= Stage IVM1c

T-VEC: talimogene laherparepvec83

N = 21

C. Hoeller 2015 Long G V et SMR 2015

Slide 3

Presented By Antoni Ribas at 2015 ASCO Annual Meeting

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Study design and population

C. Höller 2015 Presented By Antoni Ribas at 2015 ASCO Annual Meeting

Manufacturing of the individualized vaccine

Mutation discovery, confirmation, and selection

3 month

C. Hoeller 2016

T cell expansion

Lymph node

systemicdistribution

ultrasound‐guidedintranodal injection

intranodal injection oftwo RNAs formulated in Ringer solution (RNA(RIN))

IVAC‐MUTANOME: personalisierte Vakzine

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Welche Therapie ist die beste fürmeinen Patienten?

C. Hoeller 2016

BIOMARKER

Laktat‐Dehydrogenase

• Marker für schlechtere Prognose

• Ipilimumab – kaum responses bei Patienten mit >2x erhöhter LDH (Blank & Larkin, 2014)

• Paradigma: Patienten mit erhöhter LDH sind schlecht für eine Immuntherapie und sollten, falls B‐raf mutiert einen B‐raf Inhibitor erhalten, da B‐raf Inhibitoren auch bei diesen Patienten noch effektiv sind.

• Stimmt das auch in Zeiten von B‐raf&MEK, PD‐1 bzw. PD1&CTLA‐4?

C. Hoeller 2016

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COMBI‐v: OS and PFS for Patients With Baseline LDH ≤ ULN

89

OS, Baseline LDH ≤ ULN1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Time From Randomization, months

233 228 227 221 216 204 193 185 175 162 145 108 59 33 14 5 0238 231 222 211 197 184 165 153 134 121 104 74 36 20 6 0 0

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

233 212 201 183 166 147 133 119109 100 85 50 26 22 4 0 0238

D + TVem 197 169 130 106 86 69 60 52 50 43 20 6 2 0 0 0

Time From Randomization, monthsP

rop

ort

ion

Ali

ve a

nd

Pro

gre

ss

ion

Fre

e

Vemurafenib Median OS, 21.5 mo (95% CI, 18.3 mo‐NR)

HR, 0.56 (95% CI, 0.42‐0.75)

Dabrafenib + Trametinib Median OS, NR (95% CI, NR‐NR)

Vemurafenib Median PFS, 9.2 mo (7.6‐11.0 mo)

HR, 0.55 (95% CI, 0.43‐0.70)

Dabrafenib + Trametinib Median PFS, 17.5 mo (95% CI, 15.5‐21.4 mo)

PFS, Baseline LDH ≤ ULN

D + TVem

Proportion Alive

C. Hoeller 2016 Caroline Robert, ESMO 2015

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

118 97 68 45 35 27 24 20 15 14 12 5 3 3 0 0 0

114

D + T

Vem 84 53 32 21 14 12 9 9 9 6 3 2 2 0 0 0


Pro

port

ion

Aliv

e an

d P

rogr

essi

on F

ree

OS, Baseline LDH > ULN

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32


Vemurafenib Median OS, 8.9 mo (95% CI, 7.3‐10.7 mo)

HR, 0.81 (95% CI, 0.59‐1.10)

Dabrafenib + Trametinib Median OS, 10.8 mo (95% CI, 8.9‐14.4 mo)

COMBI‐v: OS and PFS for Patients With Baseline LDH > ULN

90

PFS, Baseline LDH > ULN

Vemurafenib Median PFS, 4.0 mo (95% CI, 3.7‐5.4 mo)

HR, 0.70 (95% CI, 0.53‐0.94)

Dabrafenib + Trametinib Median PFS, 5.5 mo (95% CI, 4.9‐7.2 mo)

D + TVem

118113 108 89 69 55 51 44 41 35 27 19 8 4 1 0 0114 110 93 75 55 47 36 34 32 31 25 14 10 8

1 0 01 0 0

C. Hoeller 2016 Caroline Robert, ESMO 2015

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NIVO+IPI (N=314)

NIVO(N=316)

IPI (N=315)

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

HR (99.5% CI)vs. IPI

0.42 (0.31–0.57)*

0.57(0.43–0.76)*

--

HR (95% CI)vs. NIVO

0.74 (0.60–0.92)**

-- --

*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

PFS (Intent-to-Treat)

No. at Risk

314NIVO+IPI 173 151 65 11 1219 0

316NIVO 147 124 50 9 1177 0

315IPI 77 54 24 4 0137 0

0 6 9 12 15 183 21

NIVO

NIVO+IPI

IPI

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0


911. Larkin et al. N Engl J Med 2015; 373:23-34. 2. Oral presentation by Dr. Jedd Wolchok at the ASCO 2015 Annual Meeting.

Total population57.6% (314) 38.6% (31.3–45.2)43.7% (316) 24.6% (17.5–31.4)

BRAF

Wild-type 53.3% (212) 35.6% (26.8–43.6)46.8% (218) 29.1% (20.5–37.1)

Mutant 66.7% (102) 44.7% (31.5–55.6)36.7% (98) 14.7% (2.0–26.8)

M Stage

M1c51.4% (185) 37.1% (27.9–45.4)38.9% (185) 24.6% (15.8–33.0)

Baseline LDH

≤ULN65.3% (199) 40.6% (31.1–48.9)51.5% (196) 26.8% (17.3–35.6)

>ULN44.7% (114) 35.2% (24.1–45.2)30.4% (112) 20.8% (10.5–30.7)

>2x ULN37.8% (37) 37.8% (20.0–53.9)21.6% (37) 21.6% (6.3–37.2)

Age (yr)

≥65 and <7557.4% (94) 39.5% (25.8–51.0)48.1% (79) 30.1% (16.0–42.8)

≥7554.3% (35) 27.0% (5.3–45.8)43.6% (39) 16.3% (-4.1–35.2)

PD-L1 Expression Level

<5%54.8% (210) 36.9% (28.0–45.0)41.3% (208) 23.5% (14.8–31.8)

≥5%72.1% (68) 50.7% (35.0–62.8)57.5% (80) 36.2% (21.0–49.0)

NIVO+IPI NIVOUnweighted ORR

difference vs IPI (95% CI)

70 -10103050 0

IPI betterNIVO or NIVO+IPI better

ORR in Patient Subgroups

92

ORR (Patients)

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Total population151/314 0.43 (0.35–0.53)174/316 0.57 (0.47–0.69)

BRAF

Wild-type 103/212 0.41 (0.32–0.53)117/218 0.50 (0.39–0.63)

Mutant 48/102 0.47 (0.32–0.68)57/98 0.77 (0.54–1.09)

M Stage

M1c100/185 0.48 (0.37–0.62)111/185 0.59 (0.46–0.76)

Baseline LDH

≤ULN82/199 0.38 (0.29–0.50)

100/196 0.54 (0.42–0.70)

>ULN69/114 0.47 (0.35–0.65)73/112 0.62 (0.46–0.85)

>2x ULN28/37 0.41 (0.23–0.72)30/37 0.63 (0.37–1.10)

Age (yr)

≥65 and <7548/94 0.39 (0.27–0.56)37/79 0.36 (0.24–0.53)

≥7515/35 0.51 (0.27–0.95)24/39 0.84 (0.49–1.43)

PD-L1 Expression Level

<5%103/210 0.42 (0.32–0.54)122/208 0.59 (0.47–0.75)

≥5%28/68 0.39 (0.25–0.62)33/80 0.41 (0.26–0.63)

PFS in Patient Subgroups

93

NIVO+IPI NIVOHazard Ratio

(95% CI)Events/patients

0.1 1.60.2 0.4 0.8

IPI betterNIVO or NIVO+IPI better

1.0

PD‐L1 Expression?

C. Hoeller 2015 Topalian et al. N Engl J Med 2012

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OS by PD‐L1 Expression Level (5%) ‐ Checkmate 066Nivolumab vs. Dacarbazine

†PD‐L1 positive: ≥ 5% tumor cell surface staining*OS difference is not displayed if sample size is less than 10 subjects in any treatment group LDH=lactate dehydrogenase; ULN=upper limit of normal range

Nivolumab DacarbazineN No. of death / No. randomized

All patients 418 50/210 96/208PD‐L1 status†

Positive 148 11/74 29/74Negative/indeterminate 270 39/136 67/134

M‐stage at study entryM0/M1a/M1b 163 11/82 29/81M1c 255 39/128 67/127

History of brain metastasesYes* 15 1/7 2/8No 403 49/203 94/200

Baseline LDH≤ ULN 245 16/120 38/125> ULN 153 29/79 53/74

OS DifferenceUnstratified HR for death (95% CI)

Nivolumab better Dacarbazine better

0 1 2

C. Hoeller 2015 G Long et al., N Engl J Med. 2015 Jan 22;372(4):320‐30

No. at Risk

IPI –202 82 44 31 12 1

NIVO 208 108 88 74 31 5 2

NIVO + IPI 210 142 112 96 42 9 2

0 3 6 9 12 15 17

Months

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 17

No. at Risk

IPI 075 40 22 17 9 2

NIVO 80 57 51 43 16 4 0

NIVO + IPI 68 53 44 39 16 1 0

Months

NIVO + IPINIVOIPI

NIVO + IPINIVOIPI

PFS by PD‐L1 Expression Level (5%)

PD‐L1 ≥5%* PD‐L1 <5%*

*Per validated PD‐L1 immunohistochemical assay based on PD‐L1 staining of tumor cells in a section of at least 100 evaluable tumor cells.



1.0

0.8

0.6

0.4

0.2

0.0

mPFS HR

NIVO + IPI 14.0 0.40

NIVO 14.0 0.40

IPI 3.9 ‐‐

mPFS HR

NIVO + IPI 11.2 0.42

NIVO 5.3 0.60

IPI 2.8 ‐‐


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C. Hoeller 2015

Association of a Neoepitope Signature with a Clinical Benefit from CTLA-4 Blockade.

Alexandrov et al. Nature 2013; Snyder A et al. N Engl J Med 2014;371:2189‐2199

Signature Expanded in Validation Set<br />(While Blinded to Clinical Outcome)

Presented By Antoni Ribas at 2015 ASCO Annual Meeting

Tumor microenvironment‐associated biomarkers –IFN gene signatures (pembrolizumab in melanoma)

C. Höller 2015 Presented By Antoni Ribas at 2015 ASCO Annual Meeting

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What guides our therapeuticdecision?

C. Hoeller 2016 Cancer Genome Atlas Group, Cell 2015

DTIC

25%

Ipilimumab

45%

Vemurafenib

56%

Dabrafenib+ Trametinib

72%

Nivolumab/Pembroli‐zumab

74%

Ipi++Nivo*

85% ?

* no phase 3 data

1 Jahres Überleben unter ZielgerichteterTherapie und Immuntherapie

C. Höller 2015 Slide courtesy of Christian Blank, Netherlands Cancer Institute

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Meet the expert: Melanom - Oncology Conferences · 2/19/2016 1 Meet the expert: Melanom Christoph...

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