PROSPETTIVE FUTURE NEL TRATTAMENTO. Cinzia Ortega Dipartimento di Oncologia Medica Fondazione del Piemonte per l Oncologia I.R.C.C.S.

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1 PROSPETTIVE FUTURE NEL TRATTAMENTO MEDICO DEL mrcc Cinzia Ortega Dipartimento di Oncologia Medica Fondazione del Piemonte per l Oncologia I.R.C.C.S. Candiolo

2 Future strategies in mrcc Improve therapeutic index of TKIs Dose intensification, different schedules Overcoming VEGFR TKI Resistance Novel targets and drugs Novel immunotherapeutic strategies Treatment selection based on tumor biology and predictive factors

3 Cabozantinib: synergistic approach of VEGF/c Met blockade Oral TKI targeting VEGFR2, MET, RET Higher c MET expression in RCC tumor specimens has been associated with higher tumor grade and clinical stage and was found to be an independent predictor of poor prognosis. In human tumor xenograft models, c MET expression appeared to induce the development of resistance to VEGFtargeted therapy through maintenance of an alternate angiogenic pathway. Hepatocyte growth factor (HGF), the ligand for c MET, is expressed in higher concentrations in VEGF pathway inhibitor resistant tumors supporting a role for the c MET/HGF pathway in the acquired resistance to antiangiogenic therapy. (Image Source: Exelixis, Inc.) Vaishampayan, Current Oncol Rep 2013

4 Cabozantinib and bone mets Both HGF and MET are expressed by osteoblasts and osteoclasts in vitro and mediate cellular responses such as proliferation, migration, and differentiation. Cabozantinib targets both MET and VEGFR2 in osteoblast/osteoclast cells. Targeting both the tumor and the bone microenvironment Choueiri, ASCO 2012; Vaishampayan, Current Oncol Rep 2013

5 Cabozantinib: ongoing studies 1 st line Target enrolment: 150 pts Study completion date: 2017 Phase III - 2 nd line Target enrolment: 650 pts Estimated study completion date: Calvo, Kidney Cancer Symposium 2014

6 Immunotherapy: PD 1 and PD L1 NIVOLUMAB Fully human PD 1 blocking antibody High affinity for PD 1 Promotes antitumour response Presented By Padmanee Sharma at 2014 ASCO Annual Meeting (modified)

7 Choueiri, ASCO GU 2015

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9 PD L1 Tumor Expression and OS: COMPARZ Study Analysis PD L1 is a prognostic marker for OS in TKI treated RCC patients Increased PD L1, or increased PD L1 plus tumor CD8+ T cell counts, were associated with shorter OS. Choueiri, ASCO GU 2014, abs 416

10 Nivolumab vs. everolimus after VEGF TKI therapy Phase III study design Advanced or metastatic RCC with clear cell histology Measurable disease 1 or 2 prior VEGF TKI therapy No prior mtor inhibitor R A N D O M IS A TI O N Nivolumab 3 mg/kg Iv Q 2 weeks Everolimus oral once daily Estimated enrolment: 822 Estimated completion: February 2016 Primary endpoint: OS Secondary endpoints: PFS, ORR, Safety Motzer, J Clin Oncol 31, 2013 (suppl; abstr TPS4592)

11 Novel Immunotherapy: Combinations Presented By Michael Atkins at 2014 ASCO Annual Meeting

12 Phase I study of nivolumab in combination with ipilimumab in mrcc Hammers, J Clin Oncol 32:5s, 2014 (suppl; abstr 4504)

13 Hammers, J Clin Oncol 32:5s, 2014 (suppl; abstr 4504)

14 Hammers, J Clin Oncol 32:5s, 2014 (suppl; abstr 4504)

15 MPDL3280A (anti PD L1) Phase 1a Efficacy Summary Cho, JCO 31, 2013 (suppl; abstr 4505)

16 MPDL3280A: Randomized Phase II study MPDL3280A: Randomized Phase II Study Presented By Michael Atkins at 2014 ASCO Annual Meeting

17 Escudier, Educational Session RCC, ESMO 2014

18 Rini, Atkins Lancet Oncology RCC pathways and targets

19 Novel PI3K/mTOR inhibitors A new generation of dual mtor inhibitors that bind directly to the ATP binding domain of mtor blocking both TORC1 and TORC2 activity including HIF 2 alpha expression. Pal, CORE meeting, 2014 (modified)

20 Novel PI3K/mTOR inhibitors Calvo, Kidney Cancer Symposium 2014

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24 Conclusions New targets are arising, and promising novel drugs are being tested Novel pure antiangiogenics (cabozantinib) Novel PI3K/Akt/mTOR inhibitors Immunotherapy: combination strategies allow to consider all patients for immunotherapy regardless the expression of certain markers (ie. PD L1) Establishment of therapies against these targets can produce more durable tumor reponses and a more personalized cure

25 ASCO GU 2015 PILLS

26 Haas, ASCO GU 2015

27 Primary endpoint: DFS Haas, ASCO GU 2015

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29 Patients with locally advanced kidney cancer should not be treated with either adjuvant sorafenib or sunitinib Haas, ASCO GU 2015

30 Upfront treatment or observation? Rini, ASCO GU 2015

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32 Rini, ASCO GU 2015

33 Treatment discontinuation: when? Albiges, ASCO GU 2015

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