Cancer du rein à cellules claires et ITK:

un exemple d’acharnement positif

Dr Yann-Alexandre Vano Oncologie HEGP, Paris INSERM UMRS 1138,

Cancer, Immune Control and Escape Université Paris-Descartes - UPMC

Samedi 3 décembre 2016

Liens d’intérêt

• Honoraires pour consulting (Board)

Sanofi, Pfizer, Novartis, Astellas, BMS

RCC et ITK:

Acharnement positif?

ITK

…forever!

Dose: more is better

Re-challenge…

Quoi de neuf en 2016

Encore un nouvel ITK!

Pourquoi pas un ITK en adjuvant?

ITK FOREVER!

Timeline of Development of Targeted

Agents for RCC (FDA)

US Food and Drug Administration.

Sorafenib [advanced RCC]

Sunitinib (advanced

RCC)

Pazopanib (advanced RCC)

Bevacizumab + IFN-α (metastatic RCC)

Temsirolimus (advanced RCC)

Immunotherapy with IFN-α or IL-2

2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2012 2013 2014 2016

Everolimus (advanced RCC after failure of sorafenib or

sunitinib)

Axitinib (advanced RCC after failure of 1 systemic therapy)

2015

Cabozantinib (advanced RCC

after failure of 1

systemic therapy)

Nivolumab

(advanced RCC

after failure of 1

systemic therapy)

TKI+++

Sunitinib vs IFNa

Motzer R, NEJM 2007 Motzer R, JCO 2009

PFS OS

Pazopanib 800 mg QD continuous dosing

Dose reductions to 600 mg or 400 mg

Sunitinib 50 mg QD 4 wks on/2 wks off

Dose reductions to 37.5 mg or 25 mg

Key Eligibility Criteria

Advanced/metastatic RCC

Clear-cell histology

No previous systemic therapy

Measurable disease (RECIST 1.0)

KPS ≥ 70

Adequate organ function

Stratification factors KPS 70/80 vs 90/100

Previous nephrectomy

Baseline LDH > 1.5 vs ≤ 1.5 x ULN

COMPARZ: Phase III Noninferiority Trial

of Pazopanib vs Sunitinib in First-line

mRCC

Randomized 1:1

Primary Endpoint: PFS

(Independent Review)

N Median PFS, Mos

(95% CI)

Pazopanib 557 8.4 (8.3-10.9)

Sunitinib 553 9.5 (8.3-11.1)

HR: 1.047 (95% CI: 0.898-1.220)

Motzer RJ, et al. NEJM 2012

Pts at Risk, n

557 553

361 351

245 249

136 147

105 111

61 69

46 48

19 18

13 10

1 3

Pazopanib

Sunitinib

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n o

f P

ts P

rog

ress

ion

Fre

e

0 4 8 12 16 20 24 28 32 36 40 Mos

ESMO 2014 guidelines

Groupe à risque MSKCC Standard Option

1ère ligne

bon ou intermédiaire Sunitinib [I,A]

Pazopanib [I,A]

Bevacizumab + IFN-a [I,A]

IL-2 haute dose

[III,C]

Sorafenib [II,B]

élevé Temsirolimus [II,A]

Sunitinib [II,B]

Sorafenib [III,B]

2ème ligne Post-TKI Everolimus [I,B]

Axitinib [II,A]

Sorafenib [II,A]

Escudier B. et al., Annals of Oncology 2014

TKI omniprésents

ITK-ITK ou ITK-mTOR?

Quelle séquence:

ITK-ITK ou ITK-mTOR?

Etude SMART européenne

241 mRCC receiving 2nd line of tt after >6mo of 1 TKI Primary objective was to compare TTF and PFS of TKI-TKI and TKI-mTORi sequences.

Elaidi R et al., ECC 2013, poster P315

Quelle séquence:

ITK-ITK ou ITK-mTOR?

Elaidi R. et al., Annals of Oncology 2015

Question non résolue

La réalité est là:

1.ITK 2.ITK 3.mTOR

Cohortes IMDC

TKI:

91%

TKI:

53%

TKI:

37%

Wells JC et al., European Urol 2016

Dose d’ITK: more is better…

1- Corrélation AUC du sunitinib et

efficacité

Houk BE. et al., Cancer Chemother Pharmacol 2010

Schémas alternatifs sunitinib

Year Authors Title Journal

2009 Gyergyayetal. Decreasedtoxicityscheduleofsuni nibinrenalcellcancer:2weekson/1weekoff JClinOncol

2013 Nerietal. Biweeklysuni nibregimenreducestoxicityandretainsefficacyinmetasta crenalcellcarcinoma:asingle-centerexperiencewith31pa ents

IntJUrol

2014 Atkinsonetal. Clinicaloutcomesforpa entswithmetasta crenalcellcarcinomatreatedwithalterna vesuni nibschedules

JUrol

2014 Bjarnasonetal. Outcomesinpa entswithmetasta crenalcellcancertreatedwithindividualsuni nibtherapy:correla onwithdynamicmicrobubbleultrasounddataandreviewoftheliterature

UrolOncol

2014 Chengetal. Survivaloutcomesassociatedwithdifferentsuni nibdosingregimensinmetasta crenalcellcarcinoma

JClinOncol

2014 Kondoetal. Superiortolerabilityofaltereddosingscheduleofsuni nibwith2-weeks-onand1-week-offinpa entswithmetasta crenalcellcarcinoma.Comparisontostandarddosingscheduleof4-weeks-onand2-weeks-off

JpnJClinOncol

2014 Najjaretal. A2weeksonand1weekoffscheduleofsuni nibisassociatedwithdecreasedtoxicityinmetasta crenalcellcarcinoma

EurJCancer

2014 Ohzekietal. Efficacyoftradi onalandalterna vescheduleinJapanesepa entswithmetasta crenalcellcarcinoma

IntJUrol

2014 Togoetal. Thesafetyandefficacyofsuni nibusingamodifiedregimen(2weekson/1weekoff)fortreatmentofmetasta crenalcellcarcinoma

HinkyokikaKiyo

2015 Bracardaetal. Retrospec veobserva onalstudyadministeredonschedule2/1inpa entswithmetasta crenalcellcarcinoma(mRCC):theRAINBOWstudy

AnnOncol

2015 Miyakeetal. Improvedhealth-relatedqualityoflifeofpa entswithmetasta crenalcellcarcinomatreatedwitha2weeksonand1weekoffscheduleofsuni nib

MedOncol

Ex schéma 2/1

2 semaines de traitement / 1 semaine de pause

Utilisé initialement comme alternative à la réduction de dose en cas de toxicité

Schémas alternatifs sunitinib

Etude SURF: phase 2 randomisée

SURF Ré f : P/ 2 0 1 5 / 2 5 4

N° Version : 1

Date : 08.06.2015

Page 8 sur 8

N ° 2 0 1 5 - 0 0 2 5 7 5 - 1 6

SCHEMA DE L’ETUDE

MS = maladie stabilisée, QOL = qualité de vie, ® = randomisation, SG = survie globale,

SSP = survie sans progression, TJR = temps jusqu’à randomisation, TTF = délai entre la

date de randomisation et l’arrêt du traitement.

EUDRACT: 2015-002575-16

Promoteur: CHRU Besançon

PI: Dr Tristan MAURINA

2- Axitinib: augmenter la dose en

l’absence de toxicité

Blood pressure 150/90 mm Hg or

lower, no grade 3 or 4 axitinib- related

toxic effects, no dose reduction

YES NO

ORR 52% 34%

Rini B et al., Clin Gen Cancer 2016

Rini B et al., Lancet Oncol 2013

Re-challenge

Rechallenge Sunitinib! RESUME study

52 patients, Rechallenge Sunitinib 3ème ligne et plus

Oudard S et al., EJC 2016

QUOI DE NEUF EN 2016?

Encore un ITK: CABOZANTINIB!

• Cabozantinib: TKI anti-MET, VEGFR, et AXL1

• Phase 2 encourageante2

Choueiri T., Abst.#4LBA, ECC2015; 1.Yakes FM et al., Mol Cancer Ther, 2011; 2.Choueiri TK et al., Ann Oncol, 2014

METEOR:

Cabozantinib vs Everolimus

Choueiri T et al., NEJM 2015

Etude METEOR:

PFS, critère principal

Choueiri T et al., NEJM 2015

Choueiri T et al., Lancet Oncol 2016

Etude METEOR:

amélioration OS

Choueiri T et al., Lancet Oncol 2016

Quid des toxicités?

Cabozantinib (N=331) Everolimus (N=322)

Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4

Any adverse event* 100 68 >99 58

Diarrhea 74 11 27 2

Fatigue 56 9 46 7

Nausea 50 4 28 <1

Decreased appetite 46 2 34 <1

PPE syndrome 42 8 6 <1

Hypertension 37 15 7 3

Vomiting 32 2 14 <1

Weight decreased 31 2 12 0

Constipation 25 <1 19 <1

Anemia 17 5 38 16

Cough 18 <1 33 <1

Dyspnoea 19 3 28 4

Rash 15 <1 28 <1

Events of interest

Hyperglycaemia 5 <1 19 5

Pneumonitis 0 0 10 2

GI Perforation <1 <1 <1 <1

Fistula <1 <1 0 0

* Events reported in at least 25% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 26

Presented at the European Cancer Congress, Vienna, 26 September 2015

ESMO 2016 actualisées

Groupe à risque MSKCC Standard Option

1ère ligne

bon ou intermédiaire Sunitinib [I,A]

Pazopanib [I,A]

Bevacizumab + IFN-a [I,A]

IL-2 haute dose [III,C]

Sorafenib [II,B]

élevé Temsirolimus [II,A]

Sunitinib [II,B]

Sorafenib [III,B]

Pazopanib [III,B]

2ème ligne Post-TKI Nivolumab [I,A]

Cabozantinib [I,A]

Everolimus [II,B]

Axitinib [II,B]

Sorafenib [III,B]

3ème ligne Post-TKI / Nivolumab

Post-TKI / Cabozantinib

Cabozantinib [V,A]

Nivolumab [V,A]

Everolimus [V,B]

Axitinib [V,B]

Escudier B. et al., Annals of Oncology 2016

What next?

Phase 2

157 patients mRCC groupes intermédiaires et haut risque

Randomisés: Sunitinib vs Cabozantinib

Critère principal: PFS

mPFS: 8,2 vs 5,6 mois

HR=0,66; p=0,012

JCO 14 novembre 2016

The sooner the better?

615 patients opérés pour un RCC « high risk » UISS

Rando: sunitinib vs placébo pendant 1 an

FU médian de 5,4 ans

Critère principal: PFS avec revue centralisée

The sooner the better?

Des ITK en combo!

Lancet Oncol 2015

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21 July 2016

EMA/CHMP/480541/2016 Committee for Medicinal Products for Human Use (CHMP)

Sum m ary of opinion 1 ( init ia l authorisat ion)

Kisplyx lenvatinib

On 21 July 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive

opinion, recommending the granting of a marketing authorisation for the medicinal product Kisplyx,

intended for the treatment of patients with unresectable advanced or metastatic renal cell carcinoma

(RCC). The applicant for this medicinal product is Eisai Europe Ltd.

Kisplyx will be available as 4 mg and 10 mg hard capsules. The active substance of Kisplyx is lenvatinib, a

tyrosine kinase inhibitor (ATC code: L01XE29) that selectively inhibits the kinase activities of vascular

endothelial growth factor (VEGF) receptors, in addition to other proangiogenic and oncogenic pathway-

related receptor tyrosine kinases.

Kisplyx was shown to improve progression-free survival (PFS) in a randomized part of a Phase Ib/II study

when used with everolimus (median 14.6 [95% CI: 5.9-20.1] months) compared with everolimus used

alone (median 5.5 [95% CI: 3.5-7.1] months) with a HR of 0.40 (95% CI: 0.24, 0.68; p<0.001). The

treatment effect of the combination was also supported by a post-hoc retrospective independent blinded

review of scans with median PFS of 12.8 [95% CI: 7.4-17.5] months compared with everolimus used

alone (median 5.6 [95% CI: 3.6-9.3] months) with a HR of 0.45 (95% CI: 0.26, 0.79; p=0.003).

The most common side effects are diarrhoea, fatigue, decreased appetite, vomiting, nausea and

hypertension. Severe diarrhoea occurred at a higher frequency in the combination group than in the

everolimus group.

The full indication is: "Kisplyx is indicated in combination with everolimus for the treatment of adult

patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor

(VEGF)-targeted therapy." It is proposed that Kisplyx treatment should be initiated and supervised by a

healthcare professional experienced in the use of anticancer therapies.

Detailed recommendations for the use of this product will be described in the summary of product

characteristics (SmPC), which will be published in the European public assessment report (EPAR) and

made available in all official European Union languages after the marketing authorisation has been

granted by the European Commission.

1 Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67

days from adoption of the opinion

Des ITK en combo avec I-O

agents

Rini B. et al., Journal of ImmunoTherapy of Cancer 2016

Conclusion

ITK ciblant le VEGFR est au cœur d’une stratégie efficace dans le RCC

• On les utilise successivement

• On optimise leur dose

• On en découvre de nouveaux encore plus efficace

• Bientôt peut-être en adjuvant

• Prochainement sûrement en combinaison avec I-O

HOPITAL EUROPEEN GEORGES POMPIDOU

Medical Oncology Stéphane Oudard, MD, PhD

Constance Thibault, MD

Antoine Angelergues, MD

Urology Arnaud Méjean, MD, PhD

Marc-Olivier Timsit, MD, PhD

ARTIC Reza Elaidi, PhD

Elena Braychenko

Houda Belhouari

Pathology Virginie Verkarre, MD, PhD

Immunology Eric Tartour, MD, PhD

CORDELIERS RESEARCH CENTER

INSERM1138, team 13 Hervé Fridman, MD, PhD

Catherine Fridman, PhD

Nicolas Giraldo, MD, PhD

Etienne Becht, PhD

Florent Petitprez, PhD

Laetitia Lacroix