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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?
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  • Unpublished data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

...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.

vegf a dynamic marker of target inhibition
VEGF – a dynamic Marker of targetinhibition

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

slide14

VEGFR-TKI treatment is associated with 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 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-inhibitionisassociatedwithvesselmaturation
  • red: pericytes (SMA). green: CD31

Verheul Clin Cancer Res 2007

everolimus inhibits vessel maturation in mice
Everolimus inhibitsvesselmaturation in mice

pericytes

vessels

Lane Clin Cancer Res 2009

slide19

Follow-upafter 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%)

slide20

OSpatientswithsubsequenttherapy

(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?(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 .

slide22

TKI-resistanceis transient in TKI-responsivepatients

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

Unpublisheddata

conclusion
Conclusion
  • 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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