Cancer du rein à cellules claires et ITK: un exemple d acharnement positif

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1 Samedi 3 décembre 2016 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

2 Liens d intérêt Honoraires pour consulting (Board) Sanofi, Pfizer, Novartis, Astellas, BMS

3 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?

4 ITK FOREVER!

5 Timeline of Development of Targeted Agents for RCC (FDA) TKI+++ Sorafenib [advanced RCC] Sunitinib (advanced RCC) Pazopanib (advanced RCC) Bevacizumab + IFN-α (metastatic RCC) Axitinib (advanced RCC after failure of 1 systemic therapy) Cabozantinib (advanced RCC after failure of 1 systemic therapy) Immunotherapy with IFN-α or IL-2 Temsirolimus (advanced RCC) Everolimus (advanced RCC after failure of sorafenib or sunitinib) Nivolumab (advanced RCC after failure of 1 systemic therapy) US Food and Drug Administration.

6 Sunitinib vs IFNa PFS OS Motzer R, NEJM 2007 Motzer R, JCO 2009

7 COMPARZ: Phase III Noninferiority Trial of Pazopanib vs Sunitinib in First-line mrcc 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 Randomized 1:1 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

8 Proportion of Pts Progression Free Primary Endpoint: PFS (Independent Review) N Median PFS, Mos (95% CI) Pazopanib ( ) Sunitinib ( ) HR: (95% CI: ) Pazopanib Sunitinib Pts at Risk, n Mos Motzer RJ, et al. NEJM 2012

9 ESMO 2014 guidelines Groupe à risque MSKCC Standard Option 1 ère 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] 2 ème ligne Post-TKI Everolimus [I,B] Axitinib [II,A] Sorafenib [II,A] TKI omniprésents Escudier B. et al., Annals of Oncology 2014

10 ITK-ITK ou ITK-mTOR?

11 Quelle séquence: ITK-ITK ou ITK-mTOR? Etude SMART européenne 241 mrcc receiving 2 nd 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

12 Quelle séquence: ITK-ITK ou ITK-mTOR? Question non résolue Elaidi R. et al., Annals of Oncology 2015

13 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

14 Dose d ITK: more is better

15 1- Corrélation AUC du sunitinib et efficacité Houk BE. et al., Cancer Chemother Pharmacol 2010

16 Schémas alternatifs sunitinib 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 Year Authors Title Journal 2009 Gyergyay et al. Decreased toxicity schedule of suni nib in renal cell cancer: 2 weeks on/1 week off J Clin Oncol 2013 Neri et al. Biweekly suni nib regimen reduces toxicity and retains efficacy in metasta c renal cell carcinoma: a single-center experience with 31 pa ents 2014 Atkinson et al. Clinical outcomes for pa ents with metasta c renal cell carcinoma treated with alterna ve suni nib schedules 2014 Bjarnason et al. Outcomes in pa ents with metasta c renal cell cancer treated with individual suni nib therapy: correla on with dynamic microbubble ultrasound data and review of the literature 2014 Cheng et al. Survival outcomes associated with different suni nib dosing regimens in metasta c renal cell carcinoma 2014 Kondo et al. Superior tolerability of altered dosing schedule of suni nib with 2-weeks-on and 1-weekoff in pa ents with metasta c renal cell carcinoma. Comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off 2014 Najjar et al. A 2 weeks on and 1 week off schedule of suni nib is associated with decreased toxicity in metasta c renal cell carcinoma 2014 Ohzeki et al. Efficacy of tradi onal and alterna ve schedule in Japanese pa ents with metasta c renal cell carcinoma 2014 Togo et al. The safety and efficacy of suni nib using a modified regimen (2 weeks on/1 week off) for treatment of metasta c renal cell carcinoma 2015 Bracarda et al. Retrospec ve observa onal study administered on schedule 2/1 in pa ents with metasta c renal cell carcinoma (mrcc): the RAINBOW study 2015 Miyake et al. Improved health-related quality of life of pa ents with metasta c renal cell carcinoma treated with a 2 weeks on and 1 week off schedule of suni nib Int J Urol J Urol Urol Oncol J Clin Oncol Jpn J Clin Oncol Eur J Cancer Int J Urol Hinkyokika Kiyo Ann Oncol Med Oncol

17 Schémas alternatifs sunitinib Etude SURF: phase 2 randomisée SCHEMA DE L ETUDE EUDRACT: Promoteur: CHRU Besançon PI: Dr Tristan MAURINA

18 2- Axitinib: augmenter la dose en l absence de toxicité Rini B et al., Lancet Oncol 2013 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

19 Re-challenge

20 Rechallenge Sunitinib! RESUME study 52 patients, Rechallenge Sunitinib 3 ème ligne et plus Oudard S et al., EJC 2016

21 QUOI DE NEUF EN 2016? Encore un ITK: CABOZANTINIB!

22 METEOR: Cabozantinib vs Everolimus Cabozantinib: TKI anti-met, VEGFR, et AXL 1 Phase 2 encourageante 2 Choueiri T., Abst.#4LBA, ECC2015; 1.Yakes FM et al., Mol Cancer Ther, 2011; 2.Choueiri TK et al., Ann Oncol, 2014 Choueiri T et al., NEJM 2015

23 Etude METEOR: PFS, critère principal Choueiri T et al., NEJM 2015 Choueiri T et al., Lancet Oncol 2016

24 Etude METEOR: amélioration OS Choueiri T et al., Lancet Oncol 2016

25 Quid des toxicités? Cabozantinib (N=331) Everolimus (N=322) Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4 Any adverse event* >99 58 Diarrhea Fatigue Nausea <1 Decreased appetite <1 PPE syndrome <1 Hypertension Vomiting <1 Weight decreased Constipation 25 <1 19 <1 Anemia Cough 18 <1 33 <1 Dyspnoea Rash 15 <1 28 <1 Events of interest Hyperglycaemia 5 < Pneumonitis 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 Presented at the European Cancer Congress, Vienna, 26 September

26 ESMO 2016 actualisées Groupe à risque MSKCC Standard Option 1 ère ligne bon ou intermédiaire Sunitinib [I,A] Pazopanib [I,A] IL-2 haute dose [III,C] Sorafenib [II,B] Bevacizumab + IFN-a [I,A] élevé Temsirolimus [II,A] Sunitinib [II,B] Sorafenib [III,B] Pazopanib [III,B] 2 ème ligne Post-TKI Nivolumab [I,A] Cabozantinib [I,A] Everolimus [II,B] Axitinib [II,B] Sorafenib [III,B] 3 ème 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

27 What next?

28 JCO 14 novembre 2016 The sooner the better? Phase 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

29 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

30 Des ITK en combo! Lancet Oncol July 2016 EMA/CHMP/480541/2016 Committee for Medicinal Products for Human Use (CHMP) Sum m a ry of opinion 1 (initial authorisation) 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.

31 Des ITK en combo avec I-O agents Rini B. et al., Journal of ImmunoTherapy of Cancer 2016

32 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

33 HOPITAL EUROPEEN GEORGES POMPIDOU Medical Oncology Stéphane Oudard, MD, PhD Constance Thibault, MD Antoine Angelergues, MD ARTIC Reza Elaidi, PhD Elena Braychenko Houda Belhouari Urology Arnaud Méjean, MD, PhD Marc-Olivier Timsit, MD, PhD 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