Carcinoma renale metastatico: cambia la pratica clinica? Camillo Porta Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia

New target, new agent (James Brugarolas) Atezolizumab + Bevacizumab and PD-L1 expression (Tom Powles) ctdna and mutational load under Tx selective pressure (Sumanta K. Pal)

Slide 20 Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

HIF2-I (PT2399) is active against RCC Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

HIF2-I (PT2399) has greater activity than sunitinib <br />and is better tolerated Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

HIF2-I specifically inhibits tumor VEGF production, but not systemic VEGF (and does not affect blood pressure) Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

Sensitive tumors have higher levels of HIF-2a Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

HIF2-I (PT2399) specifically inhibits HIF-2 regulated genes in sensitive tumors, but does not affect gene expression in resistant Presented By James Brugarolas at 2017 Genitourinary Cancers Symposium

Let s go back to the molecular pathogenesis of ccrcc

This is why targeting HIF-2a makes sense

New target, new agent (James Brugarolas) Atezolizumab + Bevacizumab and PD-L1 expression (Tom Powles) ctdna and mutational load under Tx selective pressure (Sumanta K. Pal)

IMmotion150 (Phase II) Trial Design Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium

IRF-Assessed PFS<br />ITT Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium

IRF-Assessed PFS<br /> 1% of IC Expressing PD-L1 Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium

Atezo + Beva: how promising is such a combo? PD-1 + CTLA-4 inhibition Checkmate214 Phase III Sunitinib 50 mg/day 4/2 PD-L1 + VEGF inhibition IMmotion151 Phase III Sunitinib 50 mg/day 4/2 Personalized vaccine + VEGFR inhibition ADAPT Phase III Sunitinib R n=1071 R n=830 Nivolumab + Ipilimumab Atezolizumab + Bevacizumab 3mg/kg IV + 1mg/kg IV every 3 weeks X4 then Nivolumab 3mg/kg IV every 2 weeks 1200 mg IV + 15 mg/kg IV every 3 weeks R n=450 AGS-003 + Sunitinib 8 injections in first year followed by quarterly boosters + sunitinib Co-Primary endpoints: PFS, OS PD-L1 + VEGFRs inhibition Javelin Renal 101 Phase III Sunitinib 50 mg/day 4/2 Co-Primary endpoints: PFS, OS PD1 + VEGFR inhibition Keynote 426 Phase III Sunitinib 50 mg/day 4/2 Primary endpoint: OS Multikinase inhibition + PD1 or mtor CLEAR E7080-G000-307 Phase III Sunitinib R n=583 n=840 R Avelumab + Axitinib 10 mg/kg IV every 2 weeks + 5 mg PO BD Primary endpoint: PFS Axitinib + Pembrolizumab 5 mg BID + 200 mg (IV) every 3 weeks Co-Primary endpoint: PFS, OS R n=735 Lenvatinib + Pembrolizumab 20 mg/day + 200 mg (IV) every 3 weeks Lenvatinib + Everolimus 18 mg/day + 5 mg/day Co-Primary endpoints: PFS,

PD-L1 expression in RCC

New target, new agent (James Brugarolas) Atezolizumab + Bevacizumab and PD-L1 expression (Tom Powles) ctdna and mutational load under Tx selective pressure (Sumanta K. Pal)

Objective Presented By Sumanta Pal at 2017 Genitourinary Cancers Symposium

Results Presented By Sumanta Pal at 2017 Genitourinary Cancers Symposium

Results ctdna Assessment of the Overall Cohort (n=224) Presented By Sumanta Pal at 2017 Genitourinary Cancers Symposium

Results ctdna Assessment of Patients with Clear Cell RCC (n=89) Presented By Sumanta Pal at 2017 Genitourinary Cancers Symposium

Results Selected GAs by Line of Therapy Presented By Sumanta Pal at 2017 Genitourinary Cancers Symposium

ctdna in mrcc across treatment lines ctdna has been detected in the majority (79%) of patients with mrcc Among a huge amount of genetic alterations, TP53, VHL, EGFR, NF1 and ARID1A were the commonest After the selective pressure of targeted agents, genetic alterations increase After 1 st line therapy, the commonest genetic alterations include TP53, NF1, EGFR and PIK3CA These alterations underscore potentially targetable mechanisms of resistance, new as well as already known

A negative trial or just a trial done with a wrong timing?

c.porta@smatteo.pv.it