MALIGNE MELANOOM en NIET-MELANOOM HUIDTUMOREN
POSTGRADUAAT ONCOLOGIE 3 Oktober 2012 Christine Langenaeken
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OVERZICHT (1) MALIGNE MELANOOM (MM)
Epidemiologie & risicofactoren
Diagnostiek
Staging
Heelkunde & Schildwachtklier
Adjuvante behandeling ?
Follow-up
Behandeling bij herval (lokaal-in transit-nodaal)
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OVERZICHT (2) MALIGNE MELANOOM (MM) Systemische behandeling • • • • • •
BRAF inhibitie MEK inhibitie BRAF + MEK inhibitie Anti-cytotoxische T-lymfocyt antigen 4 (anti-CTLA-4) antistof KIT inhibitie Angiogenese inhibitie
BASAAL CEL CARCINOOM (BCC)
Systemische behandeling
• Hedgehog inhibitie
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Maligne melanoom INCIDENTIE
Bron: Stichting Kankerregister
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Maligne melanoom INCIDENTIE
- Malignant melanoma is the 10th most frequent tumour in males (2.3%) and the 5th most frequent in females (4.2%). - Malignant melanoma is an uncommon cause of cancer death in males (1.1%) and females (1.3%). - No major differences in incidence rates are observed between the regions. - Mean age at diagnosis is 60 years in males and 55 years in females. Bron: Stichting Kankerregister
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Maligne melanoom INCIDENTIE
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Maligne Melanoom RISICOFACTOREN Huidtype
-
Bleke huid Haarkleur: blond/hoogrood Kleur ogen: blauw Sproeten
Door omgeving
- Neiging tot zonnebrand, slecht bruinen - Voorgeschiedenis van zonnebrand met blaarvorming in jeugd - Intermittente intensieve zonblootstelling - Zonnebanken - PUVA therapie (laattijdig, > 15-20j.) Exacte golflengtespectrum verantwoordelijk voor MM (UVA/UVB) niet gekend
Voorloper letsels
- Dysplastische naevi: risicomerker, niet noodzakelijk voorloper - Congenitale moedervlek (vooral zeldzame zeer grote) - Lentigo maligna = melanoma in situ = altijd voorloperletsel
Andere
- Hoog aantal naevi - Persoonlijke antecedenten van melanoom - Familiaal voorkomen (10%), familiaal dysplastisch naevus S, xeroderma pigmentosum - Niet-melanoma huidkanker (vnl. basocellulaire carcinomen)
College voor Oncologie – Nationale richtlijnen 2007
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Maligne Melanoom RISICOFACTOREN Moleculaire Genetica • Cycline-afhankelijke kinase inhibitor 2A (CDKN2A) o Tumor suppressor gen: belangrijke functie bij controle van toegang tot celcyclus en celdeling o Mutatie aangetoond in 30 % melanoom-families • Cycline-afhankelijk kinase 4 (CDK4) o “Melanoma-gevoeligheids-gen” o Mutatie aangetoond in vijf families wereldwijd • Melanocortine 1 receptor (MC1R) o Celreceptor voor produktiepad van eu-melanine (donker) en phaeo-melanine (rood) o Interactie met CDKN2A in familiaal melanoom ? o Mogelijk relevant in niet-familiale melanomen ? o Associatie melanoom met varianten van genen coderend voor MC1R antagonist en tyrosinase (enzym in melanine productie) ? 8
Maligne melanoom DIAGNOSTIEK KLINISCHE DIAGNOSTIEK = Anamnese en klinisch onderzoek Volledige huidinspectie Palpatie klierstations en drainagegebied o Zeven punten-check list
Verandering in grootte Verandering in vorm Verandering in kleur Ontsteking Korsten of bloeding Verandering gevoeligheid (jeuk, pijn,..) Vergroten van diameter tot > 7 mm
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Maligne melanoom DIAGNOSTIEK o ABCD(EF) regel
Asymmetry Border Color Diameter Elevation Funny
asymmetrie onregelmatige begrenzing kleurvariatie, inhomogeen > 6 mm verheven, vergroting, evolutie niet ABCD, wel verdacht
o Dermatoscopie • Manueel apparaat, laat 10x vergroting huidletsel toe • Correcte diagnose tot 95 % bij ervaren onderzoeker (huidartsen > huisartsen/andere specialisten) • Laat toe andere huidletsels uit te sluiten en nutteloze excisies te vermijden 10
DIAGNOSE-KLINIEK- PATHOLOGIE DIAGNOSE
KLINISCH ASPECT
HISTOLOGISCH ASPECT
Superficieel spreidend maligne melanoom
• Vrouwen > Mannen • Onderste ledematen (V), rug (M) • Intermittente UV expositie
• Proliferatie atypische M, alleen of in nesten, alle niveaus dermis • Dermale invasie (nesten, bundels)
Lentigo maligne melanoom
• Geen voorkeur geslacht • Chronische zonblootstelling • Oudere pat met lichte huid, vrnl. gelaat en nek, traag groeiend
• Epidermale component atypische M, alleen of in nesten, in basale laag • Dermale invasie mogelijk • Maligne voorloper (= in situ)
Acraal lentigineus melanoma
• Palmen, vingers, voetzolen, tenen (pigment uitvloei in nagelwal !) • 5-10% blanken • 35-90% Aziaten, afroamerikanen, hispanics
• Radiale groeifase met een lentigineus patroon van atypische M, deels nesten, deels alle niveaus dermis (pagetoïde spreiding)
Nodulair melanoma
• Uniform donkere nodule met duidelijke rand, groeit snel en verticaal vanaf het begin
• Solide dermale tumor zonder intraepidermale component van atypische M, DD metastase
(SSMM) (50-75%)
(LMM) (5-15%)
(ALM)
(NM) (15-35%)
Varia
• Desmoplastisch/neurotroop • Naevocytoïd melanoma • Melanocytic tumor of uncertain malignant potential (MELTUMP) 11
Maligne melanoom APO VERSLAG Essentieel
Dikte (Breslow) Anatomisch niveau (Clark) Chirurgische snedevlakken Prognostische factoren
Ulceratie Aantal mitosen Regressie Vaatinvasie Peri-neurale invasie AJCC stadium
aantoonbaar/niet aantoonbaar per mm als aantoonbaar: zone, liefst % aantoonbaar/niet aantoonbaar aantoonbaar/niet aantoonbaar (pT)
Informatief Minimale tumorvrije marge Tumor infiltrerende lymfocyten ? Microsatellieten ? Immuunhistochemie 12
Maligne melanoom KLINISCHE STADIERING Rationale Opsporen metastasen Basisbilan, referentie voor vergelijking tijdens FU Maar… Beperkte gevoeligheid van testen Ontdekken van andere pathologie Risico’s van (invasieve) procedures bij verder onderzoek Welke onderzoeken ? Geen consensus – voorstel: in functie van stadium1
1NCCN
V3.2012
2
Stadium I
Niets1… (optioneel: labo, rx thorax, echo abdomen)
Stadium II
Rx thorax1 (optioneel: + labo, echo abdomen)
Stadium III
CT thorax-abdomen, PET, +/- CT/MRI hersenen
Stadium IV
LDH (overige optioneel); CT thorax-abdomen, PET, +/- MRI hersenen (ifv symptomen)
College voor oncologie 2007
3Zorgprogramma
Voorkempen
2,3
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2, 3
AJCC 2009 Melanoma staging & classification Tumor (T)
Dikte
Ulceratie Mitosen
T is
Niet van toepassing
Niet van toepassing
T1
< 1.00 mm
a: geen ulceratie EN mitosen < 1/mm²
b: met ulceratie OF mitosen > 1/mm²
T2
1.01 – 2.00 mm
a: geen ulceratie
b: met ulceratie
T3
2.01 – 4.00 mm
a: geen ulceratie
b: met ulceratie
T4
> 4.00 mm
a: geen ulceratie
b: met ulceratie
Balch et al. J Clin Oncol 27:6199-6206, 2009
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AJCC 2009 Melanoma staging & classification Lymfeklieren (N)
Aantal klieren Aantasting
N0
0
Niet van toepassing
N1
1
a: micrometastase
b: macrometastase
N2
2-3
a: micrometastase
b: macrometastase c: in transit metastasen/ satellietletsels zonder metastatische lymfeklieren
N3
4+
OF vlekkige aantasting
OF in transit metastasen/ satellietletsels met metastatische lymfeklieren
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AJCC 2009 Melanoma staging & classification Metastasen (M)
Plaats
LDH
M0
Geen metastasen op afstand
Niet van toepassing
M 1a
Huid-, onderhuidse, of kliermetastasen op afstand
Normaal
M 1b
Longmetastasen
Normaal
M 1c
Alle andere viscerale metastasen
Normaal
Eender welke metastase op afstand
Verhoogd
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AJCC 2009 Melanoma staging & classification 0 I A I B II A II B II C III
Clinical staging T N T is N0 T 1a N0 T 1b N0 T 2a N0 T 2b N0 T 3a N0 T 3b NO T 4a N0 T 4b N0 elke T N +
M M0 M0 M0 M0 M0 M0 M0 M0 M0 M0
0 I A I B II A II B II C III A III B
III C
IV
elke T
elke N
M1
IV
Pathologic staging T N T is N0 T 1a N0 T 1b N0 T 2a N0 T 2b N0 T 3a N0 T 3b N0 T 4b N0 T 4b N0 T 1‐4a N 1a T 1‐4a N 2a T 1‐4b N 1a T 1‐4b N 2a T 1‐4a N 1b T 1‐4a N 2b T 1‐4a N 2c T1‐4b N 1b T1‐4b N 2b T1‐4b N 2c elke T N 3 elke T elke N
M M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
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Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for stages I and II melanoma. For patients with stage III disease, survival curves are shown comparing (C) the different N categories and (D) the stage groupings. ©2009 by American Society of Clinical Oncology
Balch C M et al. JCO 2009;27:6199-6206
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Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic disease and (B) serum lactose dehydrogenase (LDH) levels.
Balch C M et al. JCO 2009;27:6199-6206
©2009 by American Society of Clinical Oncology
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Maligne melanoom HEELKUNDE Behandeling primaire tumor Breslow
Marge
Fascia
< 0,5 mm
0,5 cm
/
0,5 – 1 mm
1 cm
Tot aan
>1 mm OF regressie OF ulceratie
2 cm
Tot aan
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Maligne melanoom HEELKUNDE Schildwachtklier (‘sentinel node’) Belang: pathologische stadiëring prognostische factor Overlevingsvoordeel ? Multicenter selective lymphadenectomy trial-I (MSLT-I) Interim analyse bij 5 jaar follow-up:
Geen verschil in melanoma-specifieke overleving (87-86%) Langere ziektevrije overleving (78-73%) Overleving wel beter in pt met klieruitruiming voor positieve sentinel versus pt in observatiegroep met klieruitruiming bij optreden van pathologische klieren (72-52%) Overleving vergelijkbaar tussen pt met negatieve sentinel en pt in observatiegroep bij wie geen pathologische klieren optraden (92%)
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Maligne melanoom HEELKUNDE Indicaties voor schildwachtklierbiopsie * Tumor > 1 mm – 4 mm dikte Tumor < 1 mm dikte met een risicofactor • dikte < 1mm maar groter dan 0,75 mm • ulceratie • mitosen > 1/mm² • lymfovasculaire invasie • positieve diepe snijranden • (regressie) ? Tumor > 4 mm dikte: ? • Prognostische informatie • Lokale controle Besluit: schildwachtklierbiopsie is aangewezen voor Hoog risico stadium I A Stadia IB – II C *NCCN V3.2012, ASCO-SSO 2012
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Maligne melanoom HEELKUNDE APO schildwachtklier Seriële coupes Immuunhistochemie: S100, Melan A, HMB 45, Ki 67 Kapseldoorbraak ? Aanwezigheid van geïsoleerde cellen is relevant (N 1a)
(er is geen ondergrens om aantasting van de schildwachtklier niet te rapporteren)
Combinatie van tumormassa (Rotterdam criteria) en topografie van aantasting (Dewar criteria) in sentinel klier zijn prognostisch voor de kans op aantasting van de overige klieren (niet-sentinel klier positiviteit (NSNP) en overleving* • •
Submicrometasase (< 0,1 mm): 9% NSNP, 5j OS 91% Submicrometasase enkel subcapsulair: 2% NSNP, 5j OS 95%
*van der Ploeg et al. JCO 29: 2206-2214 (2011)
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Maligne melanoom HEELKUNDE Wat doen bij een positieve schildwachtklier ? Standaard • volledig lymfeklierevidement Studie • Multicenter Selective Lymphadenectomy Trial II • Pt met tumordikte > 1.2 mm en Clark level III, of Clark level IV-V (ongeacht tumordikte) • Vergelijking onmiddellijk lymfeklierevidement versus opvolging met lymfeklierevidement bij herval in regionale lymfeklieren • Primair eindpunt: melanoma-specifieke overleving
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Maligne melanoom HEELKUNDE Klinisch ‘positieve’ klieren Lymfeklierevidement = therapie aantal aangetaste klieren is prognostisch nog behoorlijke overleving mogelijk (20-40 % op 10 j.) bij inguinale klieren: overweeg uitbreiding evidement • • • • •
bij + CT/PET + klier hoog-inguinaal klinisch+ klieren > 3 oppervlakkige klieren aangetast Cave morbiditeit !
APO verslag Totaal aantal klieren Aantal aangetaste klieren Kapseldoorbraak Macro- en/of micrometastasen
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Maligne melanoom ADJUVANTE BEHANDELING Rationale Verminderen van het risico op herval bij pt na heelkunde en vrij van aantoonbare ziekte Interferon Lage en intermediaire dosis interferon (IFN) Tegenstrijdige gegevens Soms verbetering van de ziektevrije overleving Soms trend tot betere globale overleving (niet significant) Meestal geen duidelijk effect op ziekte herval-vrije of globale overleving (RFS, OS)
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Maligne melanoom ADJUVANTE BEHANDELING Hoge dosis (HD) IFN en gepegyleerd (peg) IFN ECOG 1684 “Kirkwood” • • • •
HD IFN vs. observatie Pt met stadium IIB of III Na 6.9 jaar FU: significante verbetering in RFS en OS Na 12.6 jaar FU: verschil nog significant voor RFS, niet meer voor OS
Intergroup E1690 • • • • •
HD IFN (ECOG 1684) vs. lage dosis IFN (WHO) vs. observatie Stadium IIB, III; bij klinisch N0 geen staging lymfeklierevidement Betere overleving voor HD IFN én observatie dan in ECOG 1684… Significante verbetering van RFS, maar geen verschil in OS voor HD IFN vs. observatie; resultaten ‘intermediair’ voor lage dosis IFN vs. observatie Geen overlevingsvoordeel ?: belangrijk effect van ‘salvage’ behandeling (heelkunde, IFN) bij herval van pt in observatie-arm
E1694 • • • •
HD IFN vs. GM2-KLH vaccin Stadium IIB, III Betere RFS en OS (2j. FU) Maar… EORTC 18961 voortijdig gestopt wegens significant slechtere overleving in de vaccin-arm 27
Maligne melanoom ADJUVANTE BEHANDELING Meta-analyses •
ECOG/Intergroup studies o verbetering in RFS, geen verschil in OS
•
Meta-analyse Mocellin et al. 2009 o verbetering in RFS en OS o optimaal IFN HD schema of duur van behandeling niet duidelijk
Beleid ? • •
Beslissing ifv. individuele pt Rekening houden met risico op herval, co-morbiditeit, wensen pt, toxiciteit !
•
Te bespreken met ‘hoog risico’ groep: stadium IIB-IIC, stadium III
•
Schema: o o
IFN 20 MIU/m² IV 5d/week (4 wk) – 10 MIU/m² SC 3/wk (11 mo.) Peg IFN 6mcg/kg/wk SC (8wk) – 3 mcg/kg/wk (tot 5 jr.)
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Maligne melanoom BEHANDELING Radiotherapie Indicaties •
Primaire setting: Indien inoperabel o o
•
Bij inoperabele tumorlokalisaties (hoofd-hals) Bij lokale recidieven, in-transit metastasen, regionale lymfeklieraantasting waar heelkunde niet mogelijk is
Adjuvant: bij hoog-risico pt o o
Bij nauwe marges (hoofd-hals) Indien hoog risico op herval na lymfeklierevidement: N3 en kapseldoorbraak
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Maligne melanoom FOLLOW-UP Handboek Zorgprogramma = Nationale Richtlijnen In situ melanoom: 1x/jaar dermatoloog Overige melanomen: • Anamnese en klinisch onderzoek: (totale huidinspectie, volledig KO, palpatie drainagegebied, palpatie klieren):
om de 3 maanden (eerste 2 jaren) om de 6 maanden (tot 5 jaren) (kans op regionaal herval) om de 12 maanden (jaarlijks, levenslang)(late recidieven, metastasen op afstand) • Labo, Rx thorax, echo abdomen: om de 12 maanden (jaarlijks)(Nationale Richtlijnen: geen consensus, op individ. basis
Iedereen: • •
1x per jaar dermatoloog Bij klachten gericht onderzoek !
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Maligne melanoom BEHANDELING van HERVAL Lokaal litteken herval Na onvolledige initiële excisie • • •
Staging zoals voor primair letsel Re-excisie met adequate marges (2 cm) Evt. schildwachtklierbiopsie
Na vroegere volledige ruime excisie • • • •
Staging om lokalisaties elders uit te sluiten Indien negatieve staging: heelkunde, marge 2 cm (doel: R0 resectie) Schildwachtklierbiopsie ? Verder beleid: opvolging; studie ?, ‘adjuvant’ IFN ???
In-transit metastasen Een of enkele letsels, lang interval • •
Heelkunde (ruime excisie met negatieve snijranden) Indien heelkunde niet mogelijk: radiotherapie (risico voor herval binnen RTveld), laser, intralesionele therapie (BCG, IFN, imiquimod)
‘Veel’ letsels, in-transit recidief na kort interval •
Lidmaatperfusie met chemotherapie
(melphalan)
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Locaal recidief en satellieten (lymfatische metastasering) na brede resectie MM + huidgreffe
Regionale lymfatische uitbreiding
Satellieten
In transit metastase Regionale klieren
Lidmaatperfusie
Maligne melanoom BEHANDELING van HERVAL Herval in regionale lymfeklieren Te doen
Histologische bevestiging (biopsie) Staging onderzoeken (uitsluiten van metastasen op afstand)
Behandeling
Lymfeklierevidement (volledige uitruiming) Aanvullende radiotherapie bij belangrijke klieraantasting (N3) of kapseldoorbraak
Metastasen op afstand
Solitair, operabel, lang ziektevrij interval (> 1 jaar): R/ resectie Symptomatische, inoperabele letsels: palliatieve radiotherapie Uitgebreide metastasering: systemische behandeling
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Maligne melanoom SYSTEMISCHE BEHANDELING VROEGER Chemotherapie DTIC (standaard) Temodal, Taxol, fotemustine…
o o
Immunotherapie IL-2 IFN IL-21
o o o
Combinatietherapie • Combinatie chemotherapie o
•
DTIC – cisplatina
(hogere respons dan DTIC mono)
Bio-chemotherapie o o
Chemotherapie + IFN Chemotherapie + IFN + IL-2
(meta-analyse: wel hogere respons, geen overlevingsvoordeel)*
*Ives et al. JCO 2007, 25: 5426-5434
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Maligne melanoom SYSTEMISCHE BEHANDELING Welkom in het tijdperk van de gerichte therapieën ! Braf inhibitie (gemuteerd Braf V600) • • •
Vemurafenib (Zelboraf®, Roche)(FDA, EMEA goedkeuring) Dabrafenib (GSK) Sorafenib (Nexavar®, Pfizer)
MEK inhibitie • • •
Trametinib (GSK 1120212) Selumetinib (AZD6244, ARRY-142886) MEK 162
Braf inhibitie + MEK inhibitie •
Dabrafenib + trametinib
(studie opgestart in KLINA september 2012)
Anti-cytotoxische T-lymfocyt antigen 4 (anti-CTLA-4) antistof • •
Ipilimumab (Yervoy®, Bristol-Myers Squibb)(FDA, EMEA goedkeuring) Tremelimumab (CP-675206, Pfizer)
KIT inhibitie •
Imatinib
Inhibitie angiogenese • •
Axitinib bevacizumab 37
Mitogeen geactiveerd proteïne kinase (MAPK) pad
38
Vemurafenib (Zelboraf ®)
Oncogenic BRAF signalling
Growth factors
RTK RAS
Mutated BRAF V600
Zelboraf MEK
potently inhibits oncogenic BRAF kinase
ERK Leading to arrested cell proliferation
Zelboraf SPC 2012
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BRAF inhibitie: vemurafenib Final European approval February 2012: Zelboraf is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma Based on the results of Phase II (BRIM2) in pre-treated patients Randomized phase III (BRIM3) in previously untreated patients where Zelboraf was compared to dacarbazine (DTIC)
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Vemurafenib: high objective response rates (BRIM2)
Sosman J et al. N Eng J Med 2012;366:707-714.
Vemurafenib: rapid Responses (BRIM2)
Median duration of response = 6.7 months (95% CI, 5.6 to 8.6)
Sosman J et al. N Eng J Med 2012;366:707-714.
Zelboraf efficacy in previously untreated patients - BRIM3 (cut-off Dec 2010) •
Overall Survival in 1L stage IIIC and IV melanoma: Zelboraf vs DTIC
•
Median Progression-free survival tripled in Zelboraf arm (5.3 mo) vs. DTIC (1.6 mo) Overall Response Rate 9x higher in Zelboraf arm (48%) vs DTIC (5.5%)
•
Zelboraf SPC 2012
43
Zelboraf efficacy in previously untreated patients - BRIM3
(update ASCO, cut-off Feb 2012)
•
Improved Overall Survival
•
Improved Objective Response Rate in Zelboraf arm (57%) vs DTIC (8.6%)
Chapman et al. Abstract 8502, J Clin Oncol 30, Oral presentation ASCO 2012.
44
Survival Data across Zelboraf Clinical Trial Program
Population
1. 2. 3.
Phase I 1,5 (extension cohort)
Phase II BRIM-2 2,3
Phase III BRIM-3 3,4
Previously treated (24) untreated (8)
Previously treated (n=132)
Previously untreated (n=337) ASCO 2011 cut-off Dec ‘10
ASCO 2012 cut-off Feb ‘12 (post-hoc)
Median PFS (months)
>7
6.7
5.3
6.9
Median OS (months)
13.8
15.9
-
13.6
12-months survival rate
50 %
58 %
-
56%
Flaherty KT, et al. N Engl J Med 2010;363:809–19. Sosman J et al. N Eng J Med 2012;366(8):707‐714. Zelboraf (vemurafenib) Summary of Product Characteristics Feb 2012.
4.Chapman et al. Abstract 8502, J Clin Oncol 30, oral presentation ASCO 2012. 5 .McArthur A, oral presentation ECCO ESMO Sep 2011
45
BRAF testing Zelboraf potently inhibits the activity of different BRAF kinases with activating codon V600 mutations (BRAF V600E, K, R, D, G, M) • Before taking Zelboraf, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test • In BRIM 2 & 3 patients were identified using the cobas 4800 BRAF V600 Mutation Test (FDA-approved, CE-IVD labeled) •
–
–
Zelboraf SPC 2012
cobas was designed to detect the predominant V600E mutation but also detects the less common BRAF V600D & K mutations (with lower sensitivity) 46
Vemurafenib: posology & administration Zelboraf is an oral treatment, to be given in monotherapy. • Recommended dose is 960 mg = 4 tablets of 240 mg, twice a day. •
–
First dose to be taken in the morning
–
Second dose in the evening ± 12 hours later
–
Each dose to be taken in the same manner i.e. either with or without a meal
–
Tablets to be swallowed whole with water (no crushing or chewing)
Patients are treated until progression or unacceptable toxicity (see dose modifications). • If a dose is missed, it can be taken up to 4 hours prior to the next dose. Both doses should not be taken at the same time. • In case of vomiting no additional dose should be taken. •
Zelboraf SPC 2012
47
Vemurafenib: Adverse Drug Reactions Very Common 1/10 CuSCC , seborrheic keratosis, skin papilloma
Common ≥1/100 to <1/10 Folliculitis
Uncommon ≥1/1000 to <1/100
Basal cell carcinoma
Decreased appetite Headache, dysgeusia
7th nerve paralysis Uveitis
Neuropathy peripheral Retinal vein occlusion Vasculitis
Cough Diarrhoea, vomiting, nausea, constipation Photosensitivity reaction, actinic Palmar-plantar erythrodysaesthesia keratosis, rash, pruritus, syndrome,erythema nodosum, keratosis pilaris hyperkeratosis, erythema, alopecia, dry skin, sunburn
Toxic epidermal necrolysis, Stevens-Johnson syndrome
Arthralgia, myalgia, pain in Arthritis extremity, musculoskeletal pain, back pain Fatigue, pyrexia, oedema peripheral, asthenia GGT increase
Zelboraf SPC 2012
ALT, alkaline phosphatase & bilirubin AST increase increase weight decreased 48
RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors
Model of extracellular signal–regulated kinase (ERK) activation by RAF inhibitors in RAS mutant tumours. Lacouture M E et al. JCO 2012;30:329-330 ©2012 by American Society of Clinical Oncology
49
Vemurafenib: special warnings and precautions for use •
Hypersensitivy reaction discontinue permanently
•
Dermatologic reactions if severe (Steven-Johnson, toxic epiderm. necrolysis): discontinue permanently
•
QT prolongation ECG & electrolytes (incl. Mg) must be monitored in all pts • before start of treatment • After 1 month • After dose modification Further monitoring is recommended (esp. in pts with severe hepatic impairment) • Monthly during first 3 months • At least every 3 months thereafter • See dose modification schedule
Zelboraf SPC 2012
50
Vemurafenib: special warnings and precautions for use •
Ophtalmologic reactions monitor pts routinely as serious reactions including uveitis & retinal vein occlusion have been reported
•
Cutaneous squamous cell carcinomas (CuSCC) (including kerato-acanthoma (KA) or mixed KA subtype): median time to appearance: 7-8 weeks –
–
–
Zelboraf SPC 2012
Dermato evaluation recommended prior to & routinely during treatment till 6 months after end of treatment. Any suspicious lesion should be excised, examined by dermatopathologist & treated as per local standard of care • Monthly dermato evaluation • up to 6 months after treatment for CuSCC • Continue Zelboraf treatment without dose adjustment Patients should be instructed to inform their physician of any skin change
51
Vemurafenib: special warnings and precautions •
Non-CuSCC –
•
Head & neck evaluation (at least visual inspection oral mucosa and lymph node palpation) recommended before, 3-monthly during and 6-monthly after end of treatment
–
CT scan before start and 6-monthly
–
Anal & pelvic ♀ examination before and at end of treatment
New primary melanoma –
Reported cases were managed with excision
–
Zelboraf treatment was continued without dose adjustment
–
Monitoring measures as for CuSCC
Zelboraf SPC 2012
52
Vemurafenib: special warnings and precautions •
Liver injury – –
–
•
Liver lab abnormalities may occur Liver enzymes & bilirubine should be monitored before and during treatment Lab abnormalities to be managed with dose reduction, treatment interruption or discontinuation
Photosensitivity –
–
Zelboraf SPC 2012
(mild to severe cases reported)
To help patients protect from sunburn all should be advised to : • avoid sun exposure whilst on treatment • wear protective clothing & use broad spectrum sunscreen (SPF ≥30) & lipbalm As from intolerable Grade 2 toxicity, dose modifications are recommended
53
Vemurafenib: special populations •
Elderly –
•
•
Renal impairment –
risk for ↑exposure
–
Mild/moderate: no adjustment to start dose
–
Severe: caution, closely monitor (limited data available)
Hepatic impairment – –
–
•
no dose adjustment required
Zelboraf is cleared by the liver risk for ↑ exposure Mild (e.g. due to liver mets, w/o hyperbilirubinaemia): no adjustment to start dose Moderate/severe: closely monitor especially first few weeks (!accumulation) + monthly ECG during first 3 months
Paediatric, non-caucasian use –
Zelboraf SPC 2012
no data available
54
Effect of concomitant medication on Zelboraf Zelboraf plasma concentration might be influenced by strong inducers or inhibitors of CYP3A4 and/or transport proteins •
Zelboraf should be used with caution in combo with potent inhibitors of CYP3A4, glucuronidation and/or transport proteins –
•
Concomitant use of potent inducers of P-gp, glucuronidation, and/or CYP3A4 may lead to suboptimal exposure to Zelboraf and should be avoided –
•
e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir
e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericum perforatum]
Medicines that inhibit or influence P-gp could potentially influence Zelboraf PK –
e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine
Zelboraf SPC 2012
55
BRAF inhibitie - DABRAFENIB Fase III studie (BREAK-3) Dabrafenib (3:1)
DTIC
50% (93/187 pt)
6% (4/63 pt)
Progressievrije overleving (PFS)*
6.7 maand
2.9 maand
Globale overleving (OS)
Overlevingsvoordeel (niet statistisch significant)**
150 mg PO BID Objectieve respons (OR)*
(waarvan 6 pt met complete respons (CR))
1000 mg/m² IV q3wk enkel partiële respons
* Independent review committee ** HR 0.61 (95% CI 0.-1.48); statistisch niet significant, maar te weinig ‘events’ en overschakelen van DTIC naar dabrafenib toegestaan bij progressie onder DTIC
Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25.
56
Proportion Alive Without Progression
PFS: Independent reviewer-assessed (cut-off: 19 December 2011) Hazard ratio 0.35 (95% CI 0.20, 0.61) 1.0 0.9
Dabrafenib: median PFS 6.7 m
0.8 0.7 0.6 0.5
DTIC: median PFS 2.9 m
0.4 0.3 0.2 0.1 0.0 0
1
2
3
4
5
6
7
8
9
7 2
4 0
0 0
Time from Randomization (Months) Number at risk 187 63
182 53
167 32
112 16
98 12
Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25.
39 5
28 4
Dabrafenib (BREAK-3): treatmentrelated AEs: ≥ 5% of patients Dabrafenib, n (%) AE
Skin
GI
Hematologic
Other
All
DTIC, n (%)
Grade 3
Grade 4
All
Grade 3
Grade 4
Hyperkeratosis
95 (51)
1 (<1)
1 (<1)
–
–
–
Palmar-plantar hyperkeratosis
39 (21)
4 (2)
–
1 (2)
–
–
SCC/KA
13 (7)
9 (5)
–
–
–
–
Nausea
18 (10)
–
–
21 (36)
–
–
Vomiting
8 (4)
–
–
12 (20)
–
–
Neutropenia
2 (1)
1 (<1)
–
9 (15)
3 (5)
4 (7)
Thrombocytopenia
1 (<1)
1 (<1)
–
5 (8)
1 (2)
2 (3)
Leukopenia
1 (<1)
–
–
3 (5)
1 (2)
–
Arthralgia
30 (16)
1 (<1)
–
–
–
–
Fatigue
32 (17)
2 (1)
–
13 (22)
–
–
Headache
32 (17)
–
–
2 (3)
–
–
Pyrexia
28 (15)
5 (3)
–
–
–
–
Asthenia
26 (14)
–
–
7 (12)
–
–
Photosensitivity: dabrafenib (3%), DTIC (5%)
Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25.
DABRAFENIB Hersenmetastasen Fase II gegevens • • •
N=172 pt, asymptomatische hersenmetastasen, al dan niet voorbehandeld V600E: OR=35%, OR+SD=85%, PFS 16 wk V600K: OR=7% vs. 22% (voorbehandeld vs. 1e lijn), OR+SD=33-50%
Kirkwood J, Long GV, Trefzer U, et al. BREAK-MB: A phase II study assessing overall intracranial response rate 17 (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets) (abstract #8501). J Clin Oncol 2012.
59
MEK1/MEK 2 INHIBITIE
60
TRAMETINIB Krachtige, specifieke MEK1/MEK2 inhibitor Trametinib vs. chemotherapie
Fase III METRIC studie • • • • •
N=322, 2:1 randomisatie (trametinib vs. DTIC of Taxol) Mutatiestatus: V600E (87%), V600K (13%) Vooraf chemotherapie (1/3 pt) of immunotherapie (30%) Overschakelen van chemotherapie naar trametinib toegelaten bij PD Nevenwerkingen: huiduitslag (57%), diarree (43%), oedeem (26%), troebel zicht (9%), daling ejectiefractie (7%)
Trametinib 2 mg/d PO
Chemotherapie
PFS
4.8 m
1.5 m
OS (6 m. overleving %)
81%
67%
61
BRAF + MEK inhibitie: rationale RAS
BRAFi (dabrafenib)
BRAF mut BRAF
PFS 5.1 mo; RR 53%1 Hyperproliferative skin AEs
MEKi (trametinib)
MEK
OS HR 0.54 v chemo PFS 4.8 mo; RR 22%2 Rash AE
Preclinical BRAFi +MEKi Delays BRAFi resistance Hyperproliferative skin AE pERK
Proliferation Survival Invasion Metastasis 1. Hauschild A, Lancet 2012; 2. Flaherty K, NEJM 2012
TRAMETINIB Trametinib + BRAF inhibitie Fase I/II dosis-escalatie studie • •
N=135 (n=103 maligne melanoom met BRAF mutatie) Gunstig nevenwerkingen profiel: afzwakken BRAF toxiciteit, minder SCC
Fase I - II studie* • • • • • •
Fase I (farmacokinetiek, veiligheid): n=85;D(75/150mg BID), T (1-1.5-2mg OD) Fase II: n=162; D(150mg BID) + T(1-2mg OD) vs D (150mg BID) OR=76% vs. 54% PFS=9.4 m vs. 5.8 m Minder cutane SCC met combinatietherapie (7% vs. 19%) Meer koorts met combinatietherapie (71% vs. 26%)
Fase III studies • •
Opgestart (ook in AZ KLINA !) Dabrafenib + trametinib vs. Dabrafenib mono OF vs. vemurafenib
*Flaherty et al. NEJM Sept 27, 2012
63
BRAFi and MEKi Associated Adverse Events Monotherapy D (n=53)
Combination D+T 150/1 (n=54)
Combination D+T 150/2 (n=55)
Skin papilloma
8 (15)
4 (7)
2 (4)
Hyperkeratosis
16 (30)
3 (6)
5 (9)
10 (19)
1 (2) p=0.004
4 (7) p=0.09
2 (4)
6 (11)
9 (16)
Ejection Fraction
0
2 (4)
5 (9)
Chorioretinopathy
0
0
1 (2)
Squamous cell carcinoma/ keratoacanthoma Acneiform rash
*Skin toxicities include multiple terms, no cases of RVO
Long et al., ESMO 2012
ANDERE MOLECULAIR GERICHTE THERAPIEEN Andere MEK inhibitoren MEK 162 • • • •
Specifieke MEK inhibitor Activiteit in pt met gevorderd maligne melanoom Fase II studie: n=71, V600 BRAF of NRAS mutatie Fase II resultaten: PR=20%, OR + SD = 60-68% (BRAF, NRAS resp.)
Selumetinib • • •
Specifieke MEK inhibitor Gerandomiseerde fase II studie vs. Temodal: n=200, BRAF mutatiestatus Resultaten: geen verschil in PFS; retrospectieve analyse: 11% respons in pt met BRAF mutatie
KIT inhibitie
C-kit mutaties in 15-20% van pt met acraal of mucosaal melanoom, en minder frequent in melanomen ontstaan in zones van chronische zonbeschadiging Weinig activiteit in niet-geselecteerde pt Activiteit in geselecteerde pt (c-kit mutatie of amplificatie): fase II OR=21%
65
ANDERE MOLECULAIR GERICHTE THERAPIEEN Angiogenese axitinib • • • •
Fase II studie N=32 (n=25 voorbehandeld) Resultaten: OR=19%, PFS=2.9 m, OS=6.6 m Rol in maligne melanoom ?
bevacizumab •
Fase II gegevens in monotherapie of in combinatie (chemo, IFN)
•
BEAM: gerandomiseerde fase II o Carboplatinum + Taxol, +/- bevacizumab (B) o Geplande analyse bij FU=13 m: trend tot betere resultaten met B o PFS: 5.6 m vs 4.2 m o OS: 12.3 m vs 8.6 m o Significant overlevingsvoordeel in groep M1c en hoog LDH
Apoptose oblimersen • •
Anti-sense oligonucleotide, onderdrukt expressie van Bcl-2 (anti-apoptose) Interessante gegevens van initiële fase III niet bevestigd in tweede studie
66
Ipilimumab (YERVOYTM): werkingsmechanisme T-cel aktivatie
T-cel TCR MHC-II
T-cel inaktivatie
T-cel
CD28 B7
TCR MHC-II
T-cel aktivatie
T-cel CD28 CTLA 4 B7
TCR
CD28
MHC-II B7
APC
APC
CTLA 4
YERVOYTM
APC
67
YERVOYTM pivotal MDX010-20 trial: a large multicentre, double-blind, randomised, phase 3 trial PIVOTAL PHASE 3 MDX010-20 STUDY DESIGN Screening
Pretreated metastatic melanoma patients with life expectancy ≥ 4 months at baseline
RANDOMISE
676 * PATIENTS
403 PATIENTS
137 PATIENTS
136 PATIENTS
Induction
Follow-up
YERVOY™ 3 mg/kg 1 dose every 3 weeks (x4) + gp100
≥1 Reinduction†
YERVOY™ 3 mg/kg 1 dose every 3 weeks (x4)
≥1 Reinduction†
gp100
in eligible patients
in eligible patients
≥1 Reinduction† in eligible patients
Duration of follow-up ranged up to 55 months.1 * Due to the inclusion of the gp100 peptide vaccine comparator, the study was restricted to patients with HLA-A2*0201 genotype.1,6 † Because of the minimal amount of data, re-induction is not within label. An additional four doses of treatment were offered to patients who developed progressive disease (PD) after initial clinical response (partial response [PR] or complete response [CR]) or after stable disease (SD) lasting longer than 3 months from initial tumour assessment.1,6
Ipilimumab (Yervoy
TM)
Fase II1
Fase III2 Ipi-gp100
Fase III2 Ipi
Fase III2 gp100
5.8%
5.7%
10.9%
1.5%
3.3 m
3.18 m
2.74 m
20.1%
28.5%
11%
Respons verbetering na > 6m
3 PD -> SD 3 SD -> PR 1 PR -> CR
2 SD -> PR 3 PR -> CR
Behoud van respons > 2j
17.4% (27 - +44m)
60.6% (26 - +44 m)
0
Tijd tot progressie
2.76 m
2.86 m
2.76 m
% minder kans op progressie
19% (versus gp100)
36% (versus gp100)
Beste respons Tijd tot respons Ziektecontrole
27 – 35%
1-j overleving
47%
43.6%
45.6%
25.3%
2-j overleving
32%
21.6%
23.5%
13.7%
Mediane overleving
10.2 m
10 m
10.1 m
6.4 m
1Ann
Oncol 21:1712-17, 2010
2NEJM
363:8, August 19, 2010
Immunopotentiation with YERVOYTM Potential in tumour burden withof YERVOY results in 4changes distinct patterns response8
Minority of responders
Majority of responders
TM
Conventional response Slow, steady decline in tumor burden Late response after initial progression New lesion appears and then declines along with target lesion Baseline
12 weeks First assessment
Later assessments
Adapted from Wolchok et al. 2009
70
Nood aan aangepaste respons criteria WHO* New, measurable lesions (i.e., ≥5 x 5 mm) New, nonmeasurable lesions (i.e., <5 x 5 mm) Non-index lesions
irRC**
Always represent PD
Incorporated into tumor burden
Always represent PD
Do not define progression (but preclude irCR)
Changes contribute to defining BOR of CR, PR, SD and PD
Contribute to defining irCR (complete disappearance required)
CR
Disappearance of all lesions in two consecutive observations not less than 4 weeks apart
Disappearance of all lesions in two consecutive observations not less than 4 wk aprt
PR
≥50% decrease in SPD of all index lesions compared with baseline in two observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions 50% decrease in SPD compared with baseline cannot be established nor 25% increase compared with nadir, in absence of new lesions or unequivocal progression of non-index lesions At least 25% increase in SPD compared with nadir and/or unequivocal progression of non-index lesions and/or appearance of new lesions (at any single time point)
≥50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart
SD
PD
Adapted from Wolchok et al. 2009
Designed to detect early effects of cytotoxic agents, and may not provide a complete assessment of immunotherapeutic agents.8
50% decrease in tumor burden compared with baseline cannot be established nor 25% increase compared with nadir
At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 weeks apart
Designed to better capture the response patterns observed with immunotherapeutic agents e.g. ipilimumab.8
71
Most common irARs with YERVOYTM are dermatologic or GI related Most common immune-related adverse reactions in the pivotal phase 3 MDX010-20 trial % of Patients YERVOY™ + gp100 n=380
irAR
YERVOY™ n=131
gp100 n=132
Any grade
Grade 3
Grade 4
Any grade
Grade 3
Grade 4
Any grade
Grade 3
Grade 4
Any
58.2
9.7
0.5
61.1
12.2
2.3
31.8
3.0
0
Dermatologic
40.0
2.1
0.3
43.5
1.5
0
16.7
0
0
GI
32.1
5.3
0.5
29.0
7.6
0
14.4
0.8
0
Endocrine
3.9
1.1
0
7.6
2.3
1.5
1.5
0
0
Hepatic
2.1
1.1
0
3.8
0
0
4.5
2.3
0
Other irAR
3.2
1.3
0
4.6
1.5
0.8
2.3
0.8
0
Death due to irAR
1.3
1.5
0 Adapted from Hodi et al. 2010
For more information about safety, see YERVOYTM Summary of Product Characteristics. 2NEJM
363:8, August 19, 2010
72
ipilimumab - irAE •
GASTROINTESTINAL –
•
SKIN –
•
Signs and symptoms such as: • Diarrhoea • Abdominal pain • Blood or mucus in stool • Bowel perforation • Peritoneal signs • Ileus
Symptoms such as: • Pruritus • Rash
NEUROLOGIC –
Symptoms such as: • Unilateral or bilateral weakness • Sensory alterations • Paraesthesia
• ENDOCRINE – Signs and symptoms such as: • Fatigue • Headache • Mental status changes • Abdominal pain • Unusual bowel habits • Hypotension • Abnormal thyroid function tests and/or serum chemistries • LIVER – Signs such as: • Abnormal liver function • tests (e.g. elevated AST, ALT • or total bilirubin) • OTHER ADVERSE REACTIONS – Including ocular manifestations
A more exhaustive list of adverse reactions can be found on slide 62. For more information about safety, see YERVOYTM Summary of Product Characteristics.
73
Management of irARs with YERVOYTM generally depends upon their severity and persistence1 Three-step approach1 Mild1
• Treat symptomatically
• Treat with oral corticosteroids (prednisone 1 mg/kg daily or equivalent) • Omit next dose of YERVOYTM until symptoms resolve or return to baseline. Do not replace this omitted dose
Persistent mild or moderate1
Symptoms worsen, are severe, or life-threatening1
• Treat with high-dose IV corticosteroids (methylprednisolone 2 mg/kg daily or equivalent) • If symptoms improve, then consider a gradual steroid taper over at least 4 weeks • If symptoms do not respond within 5-7 days then consider alternative immunosuppression therapies • Permanently discontinue YERVOYTM* * In skin irARs: Severe grade 3: Omit treatment; Severe grade 4 Rash or Severe grade 3 Pruritus: Discontinue YERVOYTM.1
irAR management algorithms by organ system
When to omit or discontinue YERVOYTM
For more information about safety, see YERVOYTM Summary of Product Characteristics.
Risk evaluation and mitigation strategies (REMS)
Hedgehog signaling is critical for embryonic development
Activation of SMO or functional loss of PTCH in >90 % of BCC vismodegib Cl
N
O HN
Cl
O S O
PTCH, Patched; SHH, Sonic Hedgehog; SMO, smoothened
Teh MT et al. Cancer Res 2005;65:8597–8603
75
SHH4476g (ERIVANCE BCC): Study design
Patients with advanced BCC (n=104) n=71 with locally advanced BCC
Vismodegib continuous dosing 150 mg/day
Until progression, intolerable toxicity or withdrawal from study
n=33 with metastatic BCC
• Locally advanced BCC:
Inoperable
Surgery inappropriate • 1 cm • 2 recurrences after surgery and curative resection unlikely and/or anticipated substantial morbidity and/or deformity from surgery 1. Sekulic A et al. New Engl J Med 2012;366:2171–9
SHH4476g (ERIVANCE BCC): Objective response rate in mBCC mBCC (n=33) IRF (1°endpoint) INV (2°endpoint)
INV
Primary analysis1
Primary analysis1
6 month update2
Responders, n (%)
10 (30.3)
15 (45.5)
16 (48.5)
Stable disease, n (%)
21 (63.6)
15 (45.5)
14 (42.4)
Progressive disease, n (%)
1 (3.0)
2 (6.1)
2 (6.1)
Unevaluable/missing, n (%)
1 (3.0)
1 (3.0)
1 (3.0)
(15.6–48.2)
(28.1–62.2)
(30.8–66.2)
12.9 (1.9–12.9)
12.9 (5.55–NE)
95% CI for objective response P‐value
Median duration of response, months (range)
0.0011
7.6 (2.1–11.1)
1. Sekulic A et al. New Engl J Med 2012;366:2171–9 2. Sekulic A et al. J Clin Oncol 2012; May 30: a8579
SHH4476g (ERIVANCE BCC): Objective response rate in laBCC, primary analysis laBCC1 (n = 63) IRF (1°endpoint)
INV (2°endpoint)
Responders, n (%)
27 (42.9)
38 (60.3)
Stable disease, n (%)
24 (38.1)
15 (23.8)
Progressive disease, n (%)
8 (12.7)
6 (9.5)
Unevaluable/missing, n (%)
4 (6.3)
4 (6.3)
(30.5–56.0)
(47.2–71.7)
95% CI for objective response P‐value
Median duration of response, months (range)
<0.0001
7.6 (1.0–12.9)
7.6 (1.4–16.6)
1. Sekulic A et al. New Engl J Med 2012;366:2171–9 2. Sekulic A et al. J Clin Oncol 2012; May 30: a8579
SHH4476g (ERIVANCE BCC): Secondary and exploratory efficacy endpoints mBCC (n=33) Median progression‐free survival, months [95% CI] Primary analysis, IRF1 Primary analysis, INV1 6 month update, INV2 Absence of residual BCC on biopsy (at week 24 or best response)1 Clinical benefit rate*, n (%)3
laBCC (n=63)
9.5 [7.4–NE] 9.2 [7.4–NE] 9.3 [7.4–16.6]
9.5 [84–11.9] 11.3 [9.5–16.8] 12.9 [10.22–NE]
N/A
54%
25 (76)
47 (75)
*Clinical benefit rate = response at any time (prior to or post‐PD) + stable disease lasting 24 or more weeks, as assessed by independent review 1. Sekulic A et al. New Engl J Med 2012;366:2171–9 2. Sekulic A et al. J Clin Oncol 2012; May 30: a8579 3. Dirix L. ECCO‐ESMO 2011
SHH4476g (ERIVANCE BCC): Vismodegib treatment duration All treated patients (n=104) mBCC (n=33)
laBCC (n=71)
10.0 (0.7–16.4)
9.7 (1.1–18.7)
Median duration of therapy Primary analysis, months (range)1 6‐month update, months2
12.93
Patients remaining on treatment, n (%) Primary analysis1
19 (57.6)
32 (45.1)
6‐month update2
11 (33.3)
26 (36.6)
1. Sekulic A et al. New Engl J Med 2012;366:2171–9 2. Sekulic A et al. J Clin Oncol 2012; May 30: a8579
SHH4476g (ERIVANCE BCC): Most common adverse events, primary analysis1 All treated patients (n=104)
MedDRA preferred term
All adverse events (%)
Grade 1 mild (%)
Grade 2 moderate (%)
Grade 3–4 severe (%)
Muscle spasms
68
48
16
4
Alopecia
63
49
14
0
Dysgeusia
51
28
23
0
Weight decreased
46
27
14
5
Fatigue
36
27
5
4
Nausea
29
21
7
1
Decreased appetite
23
14
6
3
Diarrhoea
22
16
5
1
1. Sekulic A et al. New Engl J Med 2012;366:2171–9
SHH4476g (ERIVANCE BCC): Serious adverse events, primary analysis1 All treated patients (n=104)
Serious events, n (%) Fatal events, n (%)
All
Possibly related to vismodegib
26 (25)
4 (4)
7 (7)
0
• The grade 3–5 adverse event profile for the 6‐month update was generally consistent with that of the primary analysis2 No additional grade 5 adverse events were reported in the 6‐month update
1. Sekulic A et al. New Engl J Med 2012;366:2171–9 2. Sekulic A et al. J Clin Oncol 2012; May 30: a8579
SHH4476g (ERIVANCE BCC): Efficacy of vismodegib in locally advanced BCC
Baseline
Week 8
Week 20
Week 16: no BCC on biopsy
1. Sekulic A et al. New Engl J Med 2012;366:2171–9