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Beyond the first line : mTOR inhibitors. Viktor Grünwald Clinic for Hematology , Hemostasis , Oncology and Stem cell transplantation. The optimal sequence in RCC: But what patient , which drug ?. Validated in clinical trials. Everolimus. TKI. Currently under investigation. TKI.

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Beyond the first line mtor inhibitors

Beyondthefirstline: mTORinhibitors

Viktor Grünwald

ClinicforHematology, Hemostasis, Oncology and Stemcelltransplantation


The optimal sequence in rcc but what patient which drug
The optimal sequence in RCC: Butwhatpatient, whichdrug?

Validated in clinicaltrials

Everolimus

TKI

Currentlyunderinvestigation

TKI

TKI


Pfs everolimus record 1 central review
PFS: Everolimus - RECORD-1centralreview

100

Everolimus (n=277; Median PFS: 4.90 mo)

Placebo(n=139; Median PFS: 1.87 mo)

80

HR = 0.33

(95% CI: 0.25, 0.43)

Log-rank P<0.001

60

Proportion surviving, %

40

20

0

6

12

14

0

2

4

8

10

Month

Motzer, et al. Cancer. 2010


Why do we debate about the optimal 2 nd line therapy
Why do wedebateaboutthe optimal 2ndlinetherapy?

  • Pro (mTORi):

  • Phase III evidenceforeverolimusafterfailure of VEGF-targetedagents

  • Good tolerability

  • Change of mode of action (MOA)

  • Con (mTORi):

  • Somepatients will derivebenefitfromsustainedVEGFR-inhibition

  • Onlyfewobjectiveremissionswith mTORi

  • Isthereactivityafterfailure of everolimus?


Essentials of mtor inhibition
Essentials of mTOR-inhibition


Mtor binds in two distinct comlexes
mTOR binds in two distinct comlexes

Wullschleger Cell 2006


Resistance to mtori role of akt escape during mtorc1 inhibition
Resistance to mTORi – role of AKT escapeduring mTORC1 inhibition

  • PTEN-transfected PC3 cells

  • Unpublished data

Rapamycin - - +

10%FBS - + +

pAKT

pp70s6k

Actin


Mtor inhibitors mtori 2 0
mTORInhibitors (mTORi) 2.0

Hudes NEJM 2007. MotzerLancet 2008. Desai et al. JCO 2005 23s: #3043. Wagner et al. Mol CancerTher 2009; 8(12s): #B141. Mol CancerTher 2009; 8(12s): #B141. Mallon et al. Mol CancerTher 2009; 8(12s): #B142. Jessen et al. Mol CancerTher 2009; 8(12s): #B148.


Change of moa intrisic resistance
Change of MOA: intrisicresistance

No data, butchange of MOA in intrinisicresistanttumorsseems plausible

Motzer JCO 2009 vol. 27 (22) pp. 3584-90; EscudierLancet 2007; 370: 2103–11; Sternberg JCO 2010 vol. 28 (6) pp. 1061-8; Escudier NEJM 2007 vol. 356 (2) pp. 125-34; RixeLancetOncol 2007 vol. 8 (11) pp. 975-84


How different are vegfr tki really and what is its clinical relevance
How different are VEGFR TKI really, and what is its clinical relevance?

(IC50; nM)

x50

x1.5

*includespretreatedpatients. **ccRCC, nephrectomy and firstlineonly

1Kumar Mol Cancer Ther2007;6(7):2012-21. 2Mendel DBClin Can Res. 2003;9:327-337. 3Wilhelm SM,Cancer Res. 2004; 64: 7099-7109. 4Wickmann et al. Proc. AACR Clin Cancer Res 2003: 44: A3780. 5J ClinOncol2007;25:884-896. 5Nosov ESMO 2010


Tki may aggregate tumor invasiveness
TKI may aggregate tumor-invasiveness relevance?

...angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects... [in pancreatic NEC & GBM] ... concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis.


Predictive marker urgently needed
Predictive relevance? marker – urgentlyneeded!


Vegf a dynamic marker of target inhibition
VEGF – a relevance? dynamic Marker of targetinhibition

Murukesh British Journal of Cancer (2010) 102, 8 – 18


VEGFR-TKI treatment is associated with relevance? upregulation of PlGF

Stage I-II NSCLC patients, 2-6 weekspazopanibprior to tumorresection

Nikolinakos et al. Cancer Research 70(6) 2010


Angiogenic switch a mechanism of resistence during vegf depletion
Angiogenic relevance? switch – a mechanism of resistence during VEGF-depletion

Jubb et al.Nature Reviews Cancer 13 July 2006


Vegf inhibition is associated with vessel maturation
VEGF-inhibition relevance? isassociatedwithvesselmaturation

  • red: pericytes (SMA). green: CD31

Verheul Clin Cancer Res 2007


Everolimus inhibits vessel maturation in mice
Everolimus relevance? inhibitsvesselmaturation in mice

pericytes

vessels

Lane Clin Cancer Res 2009


Is there another line of therapy after failure of mtori
Is relevance? thereanotherline of therapyafterfailure of mTORi?


Follow-up relevance? after Everolimus therapy

Everolimus continued (n = 3)

Everolimus (N = 39)

Re-exposure (40%)

BSC

(n = 21)

Sorafenib (53%)

Sunitinib (33%)

Bevacizumab (7%)

Subsequent therapy (n = 15)

Other (7%)


OS relevance? patientswithsubsequenttherapy

(at start of everolimus)

P<0.0001

OS

23.3 mo

10.9 mo

P 0.0128


Is there another set of data supporting this observation french patients from record 1
Is there another set of data supporting this observation? relevance? (french patients from RECORD-1)

  • TKI after everolimus: sunitinib 15 pts, sorafenib 11 pts, TKI258 3 pts

N=36 (29evaluable)

* At start of everolimus

Blesius et al ESMO 2010 .


TKI-resistance relevance? is transient in TKI-responsivepatients

Patientsreceived sunitinib up-front, subsequently an mTORi and immediate re-exposure to sunitinib aftermTORi-failure

Unpublisheddata


Conclusion
Conclusion relevance?

  • Sequential treatment has been adopted in the clinic

  • Everolimus is a valid option in TKI-refractory RCC

  • Resistance to TKI remains transient in responding patients and re-exposure seems suitable

  • Incorporation of the prevailing mechanisms of resistance into the process of treatment-decision may really advance the field

  • Selection of patients susceptible for either TKI or mTORi are urgently needed


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