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Otranto 27 gennaio 2012



MECCANISMI DI RESISTENZA AI FARMACI
            NEL mRCC


             Michele Guida
     Dipartimento di Oncologia Medica
          Istituto dei Tumori Bari
Drugs Resistance in mRCC



1. Definition of resistance

2. The resistance mechanisms

3. How can we overcome the resistance
   mechanisms?
Drugs Resistance in mRCC



1. Definition of resistance

2. The resistance mechanisms

3. How can we overcome the resistance
   mechanisms?
Drugs Resistance: Definition


PRIMARY
(also “refractoriness” or “intrinsic responsiveness”):

Lack of efficacy to TKI from the start of therapy


SECONDARY
(also “acquired” or “adaptive” or “evasive” or
“angiogenesis escape”):

Arises upon the initial response to TKI lasting
for a period of time of variable length
Primary and Secondary Resistance


     Adaptive (evasive) resistance




     Intrinsic non-responsiveness



                                     2008
Pattern of Response to Available Therapy in mRCC

                         about 6 months    about 12 months




           30% of pts      10-15% of pts     50-60% of pts



                        Rini, Urologic Oncology 2008
                        Rini, Lancet Oncol 2009
Drugs Resistence in mRCC:
 Influence of patient risk score and prior therapy

                                                            % primary
Setting                       Author            Drug
                                                            resistance
                         Motzer, 2007
                         Ranpura, 2010
                                         Sunitinib             22.4
1a line
Pts with good-
intermediate prognosis
                         Su, 2010        Sorafenib             22.6


1a line
Pts with poor            Hudes, 2007     Temsirolimus           33
prognosis

                                         Everolimus after
                         Motzer, 2008                           20
                                         TKI
2a line
                                         Sunitinib after
                         Su, 2010                              52.2
                                         Sorafenib
Percentage of pts who receives a 2d line therapy

                                                                   Predictive
                   First line                    Second line
                                                                    factors
                                                          N. Pts
Drug/Author                     N. Pts      Terapia
                                                           (%)

Sunitinib                       375         Anti-VEGF/     182
Motzer et al,                                                          -
JCO 2009
                          (sunitinib arm)   anti-mTOR      (56)


Beva + IFN                     325                         180
Escudier et al, JCO                            TKI                     -
2010
                          (beva-IFN arm)                   (55)


TKI (vari studi)                            Anti-VEGF/     216
Vikers et al,                    645                                Basal PS
Urology 2010
                                            anti-mTOR      (30)
Drugs Resistance in mRCC

             Conclusive Considerations

About 30% of mRCC has an innate resistance to all available
treatments

Resistance to TKi seems to be independent from the type of
TKi used

Prior treatment with Sunitinib significantly increased the risk
of resistance to Sorafenib

Resistance is present also in mTORi treated pts

Resistance is correlated to the pts characteristics (histology,
risk score) and to the type of prior therapy
Resistance to TKI in mRCC



1. Definition of resistance


2. The resistance mechanisms

3. How can we overcome the resistance
   mechanisms?
Resistance Mechanisms in mRCC

  General considerations

1. The “angiogenic escape” to anti‑VEGF treatment is dependent
   both on cancer cell phenomena or endothelial cell phenomena




                                ?
2. Hypoxia is a known inducer of angiogenic response in a wide
   variety of tumors

3. Nevertheless, it is strongly believed that hypoxia is also the key
   mechanism of angiogenic escape

4. When angiogenesis is inhibited, tumors are in a hypoxic state
   and develop new alternative pathways to guarantee their further
   growth
Drugs Resistance: Mechanisms


PRIMARY
(also “refractoriness” or “intrinsic responsiveness”):

Lack of efficacy to TKI from the start of therapy


SECONDARY
(also “acquired” or “adaptive” or “evasive” or
“angiogenesis escape”):

Arises upon the initial response to TKI lasting
for a period of time of variable length
Which mechanisms?

Primary Resistance to TKI in mRCC

1. These cases have already activated one or more
   mechanisms of resistance not in response to
   therapy but in response to the selective pressure
   of their microenvironment

2. Probably these cases of mRCC are not sustained
   (not only) by angiogenesis mechanisms




                                                       2008
Drugs Resistence in mRCC: Which mechanisms?

                 Primary Resistance
   • Upregulation of alternate proangiogenic pathways
     (FGFR, IL-8, insulin-like GFR, ephrins, and
     angiopoietins)

   • Pre-existing inflammatory cell-mediated vascular
     protection (myeloid cell)

   • Hypovascularity and indifference toward angiogenesis
     inhibitors (desmoplastic stroma)

   • Co-option of normal vessels without requisite
     angiogenesis
                                  Sleijfer et al. Oncologist. 2007
                                  Blanke et al. J Clin Oncol. 2008
                                  Huang et al. Cancer Res 2010
Drugs Resistance: Mechanisms


PRIMARY
(also “refractoriness” or “intrinsic responsiveness”):

Lack of efficacy to TKI from the start of therapy


SECONDARY
(also “acquired” or “adaptive” or “evasive” or
“angiogenesis escape”):

Arises upon the initial response to TKI lasting
for a period of time of variable length
Secondary resistance to anti-angiogenic
               therapies




    Hypoxia: the key of the escape




              Casanovas et al, Cancer Cell 2005;8:299-309
Angiogenic Escape (II)


Experimental
     “Accelerated metastasis after short-term treatment
       with a potent inhibitor of tumor angiogenesis”
                                    Ebos et al, Cancer Cell 2009




         “Antiangiogenic therapy elicits malignant
    progression of tumors to increased local invasion and
                     distant metastasis”
                                   Paez-Ribes et al, Cancer Cell 2009
Neoplastic Evolution and Mechanisms
       of Angiogenic Escape
Angiogenic Escape in mRCC



It has been reported that the endothelial cell inhibition
mediated by TKi can be rescued by 19 pro-angiogenic factors
secreted by the tumoral vasculature


In particular, FGF2 and IL-8 support endothelial proliferation
and de novo tubule formation in the presence of sunitinib



               Faivre et al, Nat Rev Drug Discov. 2007; 6(9):734-745. Review.
Development of Resistance:
                       Angiogenic Escape (I)
 Early Phase: Response to Anti-VEGF Treatment        Late Phase: Escape to Anti-VEGF Treatment
                      Cancer cells
                                                                         Cancer cells
VEGF inhibitors                                     VEGF inhibitors
                      VEGF                                              VEGF
                      PIGF                                              PIGF

                                                                 FGF/IL-8
                                                                and other
                          HIF                                     factors
    No angiogenesis                                                           HIF
                                                        Second wave of
                                                        angiogenesis
            Hypoxia




                        Endothelial Cell                                    Endothelial Cell
 FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor;
 VEGF, vascular endothelial growth factor

                                           Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
Development of Resistance:
                       Angiogenic Escape (I)
 Early Phase: Response to Anti-VEGF Treatment        Late Phase: Escape to Anti-VEGF Treatment
                      Cancer cells
                                                                         Cancer cells
VEGF inhibitors                                     VEGF inhibitors
                      VEGF                                              VEGF
                      PIGF                                              PIGF

                                                                 FGF/IL-8
                                                                and other
                          HIF                                     factors
    No angiogenesis                                                           HIF
                                                        Second wave of
                                                        angiogenesis
            Hypoxia




                        Endothelial Cell                                    Endothelial Cell
 FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor;
 VEGF, vascular endothelial growth factor

                                           Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
In
                                                                              hu
                                                                                 ma
                                                                                   n
• FGFR is highly expressed in RCC (80% of pts)

• High levels of bFGF are reported in patients with
  disease progression

• Increased expression of FGFR1 is associated with a
  shorter progression free survival

           Welti et al. Oncogene 2011; 30(10):1183-1193.
           Tsimafeyeu Iet al. J Clin Oncol 28:15s, 2010 (suppl; abstr 4621).
           Ho Th et al. ASCO meeting 2011. J Clin Oncol 29: 2011 (suppl; abstr e15015).
Angiogenic Escape
         IL-8 mediates resistance to Sunitinib
In Xenograft models
The resistance to sunitinib is associated to a higher microvessel
density, indicating an escape from antiangiogenesis, and IL-8 levels

Sunitinib                               IL-8
resistent/
refractory                                + Ac anti IL-8

                                                             Resensitized tumor
                                        IL-8
Sunitinib
responsive


 Conclusions:
 IL-8 mediates resistance to sunitinib and could represent a
 candidate target to reverse acquired or intrinsic resistance to sunitinib
                                                            Huang et al, Cancer Res 2010
In
                                                            hu
                                                               ma
                                                                 n
• Higher expression of IL-8 on the tumor tisuue
  (IIC) is associated with resistance to sunitinib

                                      Huang et al, Cancer Res 2010.



• Higher levels of IL-8 were associated with shorter
  progression free survival in mRCC patients treated
  in phase III trials of pazopanib

                                              Liu et al, ASCO 2011.
Secondary resistance to anti-angiogenic
               therapies



The epithelial-to-mesenchymal transition
                 process
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process




   Mechanisms of Disease: epithelial–mesenchymal transition—does cellular
   plasticity fuel neoplastic progression?
   Eva A Turley, Mandana Veiseh, Derek C Radisky and Mina J Bissell
   Nature Clinical Practice Oncology 2008
Secondary resistance to anti-angiogenic therapies


   The epithelial to mesenchymal transition process:
   What significance?
   •   Sarcomatoid phenotype is observed across all histological
       subtypes, and associated with a poorer prognosis
   •   It is a potentially transient/reversible phenotype of epithelial
       cancers
   •   Epithelial-mesenchymal transition process acquires
       resistance to anti-angiogenic inhibitors in pts with renal cell
       carcinoma

       Hugo H, Ackland ML, Blick T, et al: Epithelial-mesenchymal and mesenchymal-epithelial transitions in
       carcinoma progression. J Cell Physiol 2007; 213:374–383.
       Hammers HJ, Verheul HM, Salumbides B, et al: Reversible epithelial to mesenchymal transition and acquired
       resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther
       2010; 9:1525-1535.
       Klymkowsky MW, Savagner P: Epithelial-mesenchymal transition: A cancer researcher's conceptual friend and
       foe. Am J Pathol 2009; 174:1588–1593.
Secondary resistance to anti-angiogenic therapies

  The epithelial to mesenchymal transition process:
  Main characteristics
     • Higher proliferative index
     • Transforming growth factor β1 exposure of in vitro
       cultured primary ccRCC cells resulted in cells adopting a
       mesenchymal morphology similar to sarcomatoid
       phenotype
     • IL-15 is a major regulator of epithelial homeostasis of the
       cell-microenvironment interactions in human renal
       cancer
     • Loss of the epithelial markers E-cadherin and ZO-1

                                     Bostrom et al, Hum Pat 2011
                                     Giron-Michel et al, Bull Cancer 2011
                                     Khawam et al, Cancer Res 2009
Secondary resistance to anti-angiogenic
               therapies



The intratumoral heterogeneity and gene
              mutations
A specific gene expression signature characterizes
           metastatic potential in ccRCC


 •   Transcriptional profiling of 16 primary metastatic and 18 non-
     metastatic clear cell renal cell carcinomas with microarrays

 •   Possibility of defining the metastatic potential of primary clear
     cell renal cell carcinoma based on a select number of genes
     even

 •   Potential biomarkers for metastatic clear cell renal cell
     carcinoma by gene expression analysis



                                          Sanimyatav et al, J Urol 2011
Secondary resistance to anti-angiogenic therapies
     The intratumoral heterogeneity and gene mutations

 •   Due to this genomic instability, it is strongly believed that resistance
     is a dynamic mechanism changing in different conditions (treatment
     pressure, hypoxia pressure, etc) and during the tumor growth

 •   Some genes are hyperexpressed when there is resistance (gene
     encoding sphingosine kinase, calvasculin, chemokine receptor 4
     (CXCR4), NNP1, arginase II, hypoxia-inducible protein-2 (HIG2) and
     VEGF)

 •   Other anti-angiogenic genes show reduced expression in resistant
     tumors (genes encoding cytokines associated with interferon-gamma,
     in particular IP10 (CXCL10) and Mig (CXCL9))

           Lee AJ, Endesfelder D, Rowan AJ, Walther A, et al: Chromosomal instability confers intrinsic
           multidrug resistance. Cancer Res. 2011; 71(5):1858-70.
           Navin N, Kendall J, Troge J, et al: Tumour evolution inferred by single-cell sequencing.
           Nature 2011; 472(7341):90-94.
Working Model:
  Factors Associated With Resistance

                                      -VEGF
                                      -Ang2
                                      -IL8
                                      -MMP1
                                      -uPAR
                                      -Calvasculin
  -IL10                               -Arginase
  -IFNγ                               -?TSP

Antiangiogenic                Proangiogenic
                              Progrowth
                  Atkins M, et al. ASCO GU Symposium 2008. Abstract.
Factors Associated With Resistance in mRCC
Clinical:
  - Poor risk pts
  - Histology non clear
  - Prior TKi


                 Laboratory:
                   -   levels of IL-8; IL-15 (proangiogenic)
                   -   level of HIF
                   -   Level of FGF
                   -   level of CA IX (?)


                                   Bio-molecular:
                                      - Specific mutation?
                                      - Gene profiling?
                                      - …???


                                           Huang et al, Cancer Res 2010
Main mechanisms of primary and secondary
                 resistance in mRCC

                       -   Alternative pro-angiogenic pathways mediated by FGFR, interleukin-8 (IL-8),
                           insulin-like GFR, ephrins, and angiopoietins;
                       -   Non angiogenic mechanisms
                       -   Pre-existing inflammatory cell-mediated vascular protection (myeloid cell);
Primary resistance
                       -   Hypovascularity status with consequent indifference toward angiogenesis
                           inhibitors (desmoplastic stroma);
                       -   Co-option of normal vessels without requisite angiogenesis
                       -   Non clear cell histology


                       -   New angiogenic wave induced by hypoxia determined by anti-angiogenic
                           drugs
                       -   Epithelial to mesenchymal transition
                       -   Intra-tumoral heterogeneity
                       -   Gene instability and gene iperexpression
                       -   Secondary mutations in tyrosine kinase receptors
Secondary resistance
                       -   Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
                           VEGF signalling;
                       -   Increasing of pericyte coverage of the tumour vasculature, serving to support
                           its integrity and attenuate the necessity for VEGF-mediated survival;
                       -   Access to normal tissue vasculature without obligate neovascularisation
Resistance to TKI in mRCC



1. Definition of resistance

2. The resistance mechanisms


3. How can we overcome the resistance
   mechanisms?
How can we overcome the resistance to TKI?



     • Using non cross-resistant drugs

     • New drugs (denosumab, …)

     • Re-challenge with TKi/Sequential therapies

     • Integrating the current treatment

        – Combined therapies (?)
Resistance to anti-angiogenic therapies in mRCC


   •Re-challenge with anti-angiogenic agents could be a
   valid option for some pts

   •It is thought that a “holiday” period from anti-VEGF
   therapies is able to determine a reacquired drug-
   sensitivity by clones become resistant to TKi drugs


          Zama IN, Hutson TE, Elson P, et al: Sunitinib rechallenge in metastatic renal cell
          carcinoma patients. Cancer 2010; 116(23):5400-5406.
          Rini BI, Hutson HE, Elson P et al: Clinical activity of sunitinib rechallenge in
          metastatic renal cell carcinoma. GU ASCO 2010, J Clin Oncol 2010, Abst 396.
Michele Guida and Giuseppe Colucci
Mechanism of resistance to target therapy
Adaptive mechanisms of secondary resistance
         to anti-angiogenic therapies

                      1.Activation/upregulation of alternative
                        pro-angiogenic signalling pathways


                     2.Recruitment of bone marrow-derived pro-
                       angiogenic cells, which can obviate the
                       necessity of VEGF signalling, thereby
                       effecting re-initiaton and continuance of
                       tumour angiogenesis

                      3. Incrising pericyte coverage of the tumour
                        vasculature, serving to support its
                        integrity and attenuate the necessity for
                        VEGF-mediated survival signalling

                      4.Activation and enhancement of invasion
                        and metastasis to provide access to
                        normal tissue vasculature without
                        obligate neovascularization
Adaptive mechanisms of secondary resistance
         to anti-angiogenic therapies

                      1.Activation/upregulation of alternative
                        pro-angiogenic signalling pathways



                     2.Recruitment of bone marrow-derived pro-
                       angiogenic cells, which can obviate the
                       necessity of VEGF signalling (circulating
                       endotelial cells; myeloid cell)


                      3. Incrising pericyte coverage of the tumour
                        vasculature, serving to support its
                        integrity and attenuate the necessity for
                        VEGF-mediated survival signalling

                      4.Activation and enhancement of invasion
                        and metastasis to provide access to
                        normal tissue vasculature without
                        obligate neovascularization
Potential Mechanisms of Treatment Resistance
                  In mRCC




                               Rini and Atkins 2010
Potential mechanisms of VEGFR TKI
            Resistance
How can we overcome the resistance to TKI?



     • Using non cross-resistant drugs
     • Re-challenge with TKI/Sequential therapies

     • Integrating the current treatment

        – Combined therapies

     • Using revertant drugs (IFN, …)
Everolimus vs Placebo After Progression on a VEGFR-TKI
                             in mRCC (RECORD-1 study)
                               Phase III Study Design

                                                                            Prim Endpt:
                                                                             PFS
                              RAD001 (everolimus) 10 mg/d + BSC             Sec Endpts:
 S       Randomize
 C                                                                           Response
 R
             N = 362                             Upon Disease Progression    Response
 E
               2:1
 E        RAD001 : Placebo                                                    duration
 N
                              Placebo + BSC                                  Survival
        Stratification
                                                                             Safety
  Previous VEGFR-TKI:                                                       QoL
   1 or 2
  MSKCC risk group
     – Favorable (29%)
     – Intermediate (56%)
     – Poor (15%)
          (N = 410)


                                                 Motzer et al, The Lancet 2008
Everolimus in mRCC (RECORD 1 study)

Final results and analysis of prognostic factors

  • OR: 2%
  • SD: 67%
  • PFS: 4.9 vs 1.9
  • OS: 14.4 vs 14.4 (cross-over 80% of pts)

   Independent prognostic factors for shorter OS
      – low performance status
      – high corrected calcium
      – low hemoglobin
      – prior sunitinib (P < .01)
                                    Motzer, Escudier, et al, Cancer 2010
Benefit of everolimus after multiple lines
               of treatment




             Escudier B et al. ESMO 2008; abstr 720
mRCC: about mTOR inhibition

What is the optimal time to use mTOR inhibitors in the
                treatment sequence?
Beta Fibroblast Growth Factor (FGFR) as a new Target for
                 Anti-angiogenic Therapy

                              Late Phase: Escape to Anti-VEGF Treatment
                                                   Cancer cells
                              VEGF inhibitors   VEGF
                                                PIGF
                                           FGF
                                          and other
                                           factors
                                  Second wave of        HIF
                                  angiogenesis



                                                      Endothelial Cell




    FGF/FGFR has been reported as one of the most
   important escape pathway of anti-VEGFR therapies
Dofitinib: a new multitarget agent

A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in
patients with advanced melanoma
K. B. Kim, J. Saro, S. S. Moschos, P. Hwu, A. A. Tarhini, W. Hwu, G. Jones, Y. Wang, H. Rupani
and J. M. Kirkwood (ASCO 2008)

TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC)
patients refractory to approved targeted therapies: A phase I/II dose finding
and biomarker study
E. Angevin, J. A. Lopez, A. Pande, C. Moldovan, M. Shi, J. C. Soria, X. Wang, A. Harzstark, J.
Saro, B. Escudier ASCO 2009 Abst 3563



Study CTKI258A2202: A multicenter, open-label phase II trial of dovitinib
(TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic
breast cancer
F. Andre, J. Baselga, M. J. Ellis, S. A. Hurvitz, H. S. Rugo, N. C. Turner, E. Argonza-Aviles, S.
Lake, M. M. Shi and O. Anak (ASCO 2009)
TKI 258 (Dovitinib) in mRCC
              Phase III Study Design


third line therapy

  S
  C
                     Dovitinib + BSC
  R
  E   Randomize
  E
  N

                  Sorafenib + BSC
How can we overcome the resistance to TKI?



  • Using non cross-resistant drugs

  • Re-challenge with TKI/Sequential therapies

  • Integrating the current treatment

     – Combined therapies
Selected Trials of Second-Line Agents
                          After TKI/Beva

Agent                                       Study   N         %     PFS     OS
                            Population
Author                                      phase   pts     OR/SD   (Mo)   (Mo)

Everolimus                                                          4.9
                                                     416                    14
vs placebo                 TKI refractory    III
                                                    (2:1)
                                                             2/67   vs
                                                                           vs 14*
Motzer et al Lancet ‘08                                             1.8
Axitinib                   Sorafenib
                                              II     62     23/55   7.4     na
Rini et al, JCO ‘09        refractory

Sunitinib                  Bev
                                              II     62     23/75   7.1    10.2
Rini et al, JCO ‘08        refractory

Sorafenib                  Bev/sunitinib             26
                           refractory
                                              II
                                                    each
                                                             3/38   3.8
Shepard et al, ASCO ‘08



            *cross-over 80% of pts
Second line therapy in mRCC:
                       For how many pts?


                      First line                             Second line

Therapy/Authors                       N. Pts            Therapy        N. Pts (%)

Sunitinib                               375          Anti-VEGF/anti-
                                                          mTOR          182 (56)
Motzer et al, JCO 2009             (sunitinib arm)


Beva + IFN (AVOREN study)               325
                                                          TKI           180 (55)
Escudier et al, JCO 2010           (beva-IFN arm)


TKI (various studies; 7 centers)                     Anti-VEGF/anti-
                                        645
                                                          mTOR          216 (30)
Vikers et al, Urology 2010
Estimated PFS of pts receiving
     sequential therapies

   30-50% of pts   10% of pts        5%pts
   2a line          3a line         4a line




                      Escudier et al, Cancer 2009
Optimal Sequence May Depend on Response
           to First Line Therapy
Sequential therapy: ongoing studies


                                                 Pts          N
Agent                     Sponsor   phase
                                              population      pts
Sunitinib - sorafenib
vs                                          Sequential
                         Bayer       III                      540
Sorafenib - sunitinib                       (I and II line)
(SWITCH trial)
Pazopanib - Sunitinib
                                            Sequential
vs                       GSK         III                      160
                                            (I and II line)
Sunitinib - Pazopanib
Sunitinib - Everolimus
vs                                          Sequential
                         Novartis     II                      390
Everolimus - Sunitinib                      (I and II line)
(RECORD III trial)
How can we overcome the resistance to TKI?



     • Using non cross-resistant drugs

     • Re-challenge with TKI/Sequential therapies

     • Integrating the current treatment
        – Combined therapies
Is Combination Therapy Better?

VEGF inhibitors:                       EGFR inhibitors:
-sunitinib                             -   erlotinib
-sorafenib                             -   gefitinib
-axitinib                              -   lapatinib
-pazopanib                             -   cetuximab
-bevacizumab
                              IFN



               Angiogenesis          Tumor cell proliferation



Inhibitors of
angiogenic escape                   mTOR/akt inhibitors:
mechanisms:                         - temsirolimus
-dovitinib                          - everolimus
-AMG 386                            - perifosine
-M200
Combination Drug Therapy:
                 Selected Adverse Events

                 Rash or
                                                                      GI or
Agent           Hand-Foot   Hypertension   Cytopenia   Proteinuria
                                                                     Mucosal
                 Reaction

Sunitinib         Yes           Yes          Yes          Yes         Yes

Sorafenib         Yes           Yes                       Yes         Yes

Bevacizumab                     Yes                       Yes

Temsirolimus/
                  Yes                        Yes                      Yes
Everolimus
Combined therapies in mRCC: the future?



       •Beva + TK inhibitors


       •TK inhibitors + mTOR inhibitors


       •Beva + mTOR inhibitors
Is Combination Therapy Better?

VEGF inhibitors:                       EGFR inhibitors:
-sunitinib                             -   erlotinib
-sorafenib                             -   gefitinib
-axitinib                              -   lapatinib
-pazopanib                             -   cetuximab
-bevacizumab
                              IFN



               Angiogenesis          Tumor cell proliferation



Inhibitors of
angiogenic escape                   mTOR/akt inhibitors:
mechanisms:                         - temsirolimus
-dovitinib                          - everolimus
-AMG 386                            - perifosine
-M200
Bevacizumab + TKI in mRCC:


Drug                      Study/     PFS
                                                 OR      Toxicity        Comments
combinations               Pts       (Mo)

              An
Beva +
Sunitinib*       ega      Phase I
                            31         -
                                             3/7 RCC
                                            1/3 Mela     Mild (?)
                                                                           Good

                    tive
Garcia et al, ASCO ‘08   (various)          1 adrenal                     activity

                         exp
Beva +
                            erie                           High
                                                        (hypertension,

                                nce
Sunitinib                   16                           microangiop.
Feldman,. Motzer,                                          Transient
Asco ‘08                                                ischemic CNS)


                                                           High
Beva +                                          0 CR    (hypertension,       No
                       Phase I-II
Sorafenib**
                          48
                                      14        25 PR     stomatitis,     full doses
Sosman et al, ASCO ‘08                          18 SD   hand-foot skin     together
                                                           reaction)


* Escalating doses
** Full dose Sorafenib + 50% Beva and reverse
Is Combination Therapy Better?

VEGF inhibitors:                       EGFR inhibitors:
                                       -   erlotinib
-sunitinib
-sorafenib                             -   gefitinib
-axitinib                              -   lapatinib
-pazopanib                             -   cetuximab
-bevacizumab
                              IFN



               Angiogenesis          Tumor cell proliferation



Inhibitors of
angiogenic escape                   mTOR/akt inhibitors:
mechanisms:                         - temsirolimus
-dovitinib                          - everolimus
-AMG 386                            - perifosine
-M200
EGFR EXPRESSION IN SELECTED HUMAN TUMORS

Tumor Type              Percentage of Tumors                  References
                          Expressing EGFR

Colorectal                     25-77%          Salomon (1995); Messa (1998)
Advanced Colorectal             75%            Goldstein (2001)

Head and Neck                  80-100%         Salomon (1995); Grandis (1996)

Pancreatic                     30-95%          Salomon (1995); Uegaki (1997)
Advanced Stage                  95%            Abbruzzese (2001)

                                               Fujino (1996); Rusch (1997);
NSCLC                          40-80%
                                               Fontanini (1998)

Renal Carcinoma               50-90%           Salomon (1995); Yoshida (1997)

                                               Klijn (1992); Beckman (1996);
Breast                         14-91%
                                               Bucci (1997); Walker (1999)
                                               Bartlett (1996);
Ovarian                        35-70%
                                               Fischer-Colbrie (1997)
                                               Salomon (1995); Watanabe (1996);
Glioma                         40-63%
                                               Rieske (1998)

Bladder                        31-48%          Salomon (1995); Chow (1997)
Phase I/II trial of sunitinib plus gefitinib
         in patients with mRCC (first line)



       A
 42 pts d
                isa
- Sunitinib 37.5 or 50 mg/d oral (4 weeks on, 2 off)
                      pp
- Gefitinib 250 mg/d oral
                            oin
   Results                        tin
   - OR: 37%                           ge
   - SD: 34%                                 xp
   - Median PFS: 11 moths                      eri
                                                  en
   - Accettable toxicity (diarrea G3-4 in 14%)      ce
   - No pharmacokinetic drug-drug interaction


Conclusions: “Sunitinib plus gefitinib demonstrated comparable
                 efficacy to sunitinib monotherapy”
                                               Motzer RJ, et al, Am J Clin Oncol 2010
Is Combination Therapy Better?

VEGF inhibitors:                       EGFR inhibitors:
-sunitinib                             -    erlotinib
-sorafenib                             -    gefitinib
-axitinib                              -    lapatinib
-pazopanib                             -    cetuximab
-bevacizumab
                              IFN



               Angiogenesis          Tumor cell proliferation



Inhibitors of
angiogenic escape                   mTOR/akt inhibitors:
mechanisms:                         - temsirolimus
-dovitinib                          - everolimus
-AMG 386                            - perifosine
-M200
Bevacizumab + mTOR inhibitor




  A questionable experience
Bevacizumab + mTORI in mRCC
                    A questionable experience

First and Second line


Drug                     Study/               PFS                            OS
                                                                    OR              Toxicity
combinations              Pts                 (Mo)                          (Mo)
                         Phase II
Beva + Everolimus                       11              12         23% PR
Whorf et al, ASCO ‘08               (in 29 pretr.
                                                                   53% SD
                                                                             -        mild
                           59         with TKI)     (first line)



Beva + Temsirolimus
Merchan et al, JCO ’09
                           45           5.3             18          14.5     -     acceptable
Bevacizumab + mTOR inhibitor
               Phase III randomized first-line study
                        Temsirolimus + Bevacizumab
                                                            1° Endpoint:
Screen      R 1:1
                                                             PFS
                        Interferon alfa-2a + Bevacizumab
           822 pts



          RECORD-2: randomized phase II first-line study

                         Everolimus + Bevacizumab
                                                            1° Endpoint:
Screen       R 1:1
                                                             PFS
                         Interferon alfa-2a + Bevacizumab


         Randomized phase III second line study (CALG study)
                        Everolimus + Bevacizumab
Screen                                                      1° Endpoint:
            R 1:1
                                                             PFS
                        Placebo
Bevacizumab + mTOR inhibitor


 First line therapy


Can the combination of Temsirolimus and Bevacizumab
          improve the treatment of mRCC?

       Results of the randomized TORAVA phase II trial



           Escudier BJ, Negrier S, Gravis G, et al.

                 ASCO 2010. Abstract 4516   .
TORAVA Frontline Combination of Temsirolimus and
             Bevacizumab in mRCC




    • Primary endpoint: non-progression rate at week 48 > 50% (42% to 46% previous studies)
    • 160 patients required for 2:1:1 randomization
TORAVA Frontline Combination of Temsirolimus and
            Bevacizumab in mRCC

                           RESULTS

                  Temsirolimus/Beva   Sunitinib   Beva/Interferon
    Outcome
                       (n = 88)        (n = 42)      (n = 41)
    48 ww
                        30.7            40.5           65.9
    non PD>50%

    PFS (Mo)             8.2             8.2           16.8


    Best OR /%)         27.3            23.8            39


    SD (%)              47.7             50            34.1
TORAVA Frontline Combination of Temsirolimus and
            Bevacizumab in mRCC

                               Toxicity

Serious Adverse     Temsirolimus/Beva         Sunitinib     Beva/Interferon
Events, %                (n = 88)              (n = 42)        (n = 40)



Grade 3                     26.1                11.9              20.0

Grade 4                     12.5                 2.4               7.5

Death                        3.4                  0                 0



Note:
50% of pts in temsirolimus/beva arm ceased therapy before Week 48 for reasons not
related to progressive disease, primarily toxicity (41%)
Conclusions of the Authors:




TORAVA Study Do Not Support Frontline Combination of
       Temsirolimus and Bevacizumab in mRCC


                     Escudier BJ, Negrier S, Gravis G, et al.
                     ASCO 2010. Abstract 4516.
Bevacizumab + Everolimus


First an second line therapy



   Phase II trial of Bevacizumab + Everolimus in pts
                   with advanced RCC


        J.D. Hainsworth,…. Whorf, J Clin Oncol 2010
Bevacizumab + mTOR inhibitor
                      Bevacizumab + Everolimus
                            phase II study

                                  Naïve pts        Pre-treated pts*
Outcomes
                                   (N = 50)            (N = 30)

OR (%)                               30                    23

SD                                   50                    64

N. with tumor shrinkage              78                    73

PFS (mo)                             9.1                   7.1

Survival (mo)                       21.3                  14.5

 *Sunitinib or Sorafenib
                                           Hainsworth et al, JCO 2010
Bevacizumab + Everolimus


   Bernard Escudier, Editorial JCO 2010

• The final PFS differs 3 and 4 months fewer than in the
  preliminary report (12 vs 9,1 for untreated and 11 vs 7.1
  for pre-treated pts)

• PFS has became the same that of control arm (8.5-12.2
  months) and less than other standards of care (sunitinib
  or pazopanib monotherapy -11 months)

• The rationale for the two large randomized studies is
  much weaker and questionable

• Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI?


      Using old and new drugs (IFN, …)


      “Redefining the role of Interferon in the treatment of
       malignant diseases”


                         Bracarda, Eggermont, Samuelsson

                                Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
     First- or Second-Line* Therapy in mRCC

                          Gollob et al, JCO 2007




 •Sorafenib 400 mg orally bid for 8 weeks
 •IFN alpha-2b: 10 mil. IU subcutaneously three times a week

 followed by a 2-week break



  *IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
             or Second-Line Therapy in mRCC


                                           All pts          First line       Second line
                                          (40 pts)           (20 pts)          (20 pts)

    Response, n (%)                        13 (33)              10                  3

     CR                                      2 (5)

     PR                                    11 (28)

     SD                                    12 (29)


    PFS (mo)                                 10

    Dose reduction (% of pts*)               65

 *Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss

                                                                         Gollob et al, JCO 2007
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
        STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO


                    Studio G.O.I.M. 2901


 PIANO DI TRATTAMENTO


 •Braccio A
    Everolimus 10 mg/die per via orale


 •Braccio B

    Everolimus stesse dosi + Interferone alpha-2a, basse
    dosi s.c. (3 Mil U.I. x 3 volte/settimana)

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Mechanism of resistance to target therapy

  • 1. Otranto 27 gennaio 2012 MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC Michele Guida Dipartimento di Oncologia Medica Istituto dei Tumori Bari
  • 2. Drugs Resistance in mRCC 1. Definition of resistance 2. The resistance mechanisms 3. How can we overcome the resistance mechanisms?
  • 3. Drugs Resistance in mRCC 1. Definition of resistance 2. The resistance mechanisms 3. How can we overcome the resistance mechanisms?
  • 4. Drugs Resistance: Definition PRIMARY (also “refractoriness” or “intrinsic responsiveness”): Lack of efficacy to TKI from the start of therapy SECONDARY (also “acquired” or “adaptive” or “evasive” or “angiogenesis escape”): Arises upon the initial response to TKI lasting for a period of time of variable length
  • 5. Primary and Secondary Resistance Adaptive (evasive) resistance Intrinsic non-responsiveness 2008
  • 6. Pattern of Response to Available Therapy in mRCC about 6 months about 12 months 30% of pts 10-15% of pts 50-60% of pts Rini, Urologic Oncology 2008 Rini, Lancet Oncol 2009
  • 7. Drugs Resistence in mRCC: Influence of patient risk score and prior therapy % primary Setting Author Drug resistance Motzer, 2007 Ranpura, 2010 Sunitinib 22.4 1a line Pts with good- intermediate prognosis Su, 2010 Sorafenib 22.6 1a line Pts with poor Hudes, 2007 Temsirolimus 33 prognosis Everolimus after Motzer, 2008 20 TKI 2a line Sunitinib after Su, 2010 52.2 Sorafenib
  • 8. Percentage of pts who receives a 2d line therapy Predictive First line Second line factors N. Pts Drug/Author N. Pts Terapia (%) Sunitinib 375 Anti-VEGF/ 182 Motzer et al, - JCO 2009 (sunitinib arm) anti-mTOR (56) Beva + IFN 325 180 Escudier et al, JCO TKI - 2010 (beva-IFN arm) (55) TKI (vari studi) Anti-VEGF/ 216 Vikers et al, 645 Basal PS Urology 2010 anti-mTOR (30)
  • 9. Drugs Resistance in mRCC Conclusive Considerations About 30% of mRCC has an innate resistance to all available treatments Resistance to TKi seems to be independent from the type of TKi used Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib Resistance is present also in mTORi treated pts Resistance is correlated to the pts characteristics (histology, risk score) and to the type of prior therapy
  • 10. Resistance to TKI in mRCC 1. Definition of resistance 2. The resistance mechanisms 3. How can we overcome the resistance mechanisms?
  • 11. Resistance Mechanisms in mRCC General considerations 1. The “angiogenic escape” to anti‑VEGF treatment is dependent both on cancer cell phenomena or endothelial cell phenomena ? 2. Hypoxia is a known inducer of angiogenic response in a wide variety of tumors 3. Nevertheless, it is strongly believed that hypoxia is also the key mechanism of angiogenic escape 4. When angiogenesis is inhibited, tumors are in a hypoxic state and develop new alternative pathways to guarantee their further growth
  • 12. Drugs Resistance: Mechanisms PRIMARY (also “refractoriness” or “intrinsic responsiveness”): Lack of efficacy to TKI from the start of therapy SECONDARY (also “acquired” or “adaptive” or “evasive” or “angiogenesis escape”): Arises upon the initial response to TKI lasting for a period of time of variable length
  • 13. Which mechanisms? Primary Resistance to TKI in mRCC 1. These cases have already activated one or more mechanisms of resistance not in response to therapy but in response to the selective pressure of their microenvironment 2. Probably these cases of mRCC are not sustained (not only) by angiogenesis mechanisms 2008
  • 14. Drugs Resistence in mRCC: Which mechanisms? Primary Resistance • Upregulation of alternate proangiogenic pathways (FGFR, IL-8, insulin-like GFR, ephrins, and angiopoietins) • Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) • Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma) • Co-option of normal vessels without requisite angiogenesis Sleijfer et al. Oncologist. 2007 Blanke et al. J Clin Oncol. 2008 Huang et al. Cancer Res 2010
  • 15. Drugs Resistance: Mechanisms PRIMARY (also “refractoriness” or “intrinsic responsiveness”): Lack of efficacy to TKI from the start of therapy SECONDARY (also “acquired” or “adaptive” or “evasive” or “angiogenesis escape”): Arises upon the initial response to TKI lasting for a period of time of variable length
  • 16. Secondary resistance to anti-angiogenic therapies Hypoxia: the key of the escape Casanovas et al, Cancer Cell 2005;8:299-309
  • 17. Angiogenic Escape (II) Experimental “Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis” Ebos et al, Cancer Cell 2009 “Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis” Paez-Ribes et al, Cancer Cell 2009
  • 18. Neoplastic Evolution and Mechanisms of Angiogenic Escape
  • 19. Angiogenic Escape in mRCC It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature In particular, FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib Faivre et al, Nat Rev Drug Discov. 2007; 6(9):734-745. Review.
  • 20. Development of Resistance: Angiogenic Escape (I) Early Phase: Response to Anti-VEGF Treatment Late Phase: Escape to Anti-VEGF Treatment Cancer cells Cancer cells VEGF inhibitors VEGF inhibitors VEGF VEGF PIGF PIGF FGF/IL-8 and other HIF factors No angiogenesis HIF Second wave of angiogenesis Hypoxia Endothelial Cell Endothelial Cell FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
  • 21. Development of Resistance: Angiogenic Escape (I) Early Phase: Response to Anti-VEGF Treatment Late Phase: Escape to Anti-VEGF Treatment Cancer cells Cancer cells VEGF inhibitors VEGF inhibitors VEGF VEGF PIGF PIGF FGF/IL-8 and other HIF factors No angiogenesis HIF Second wave of angiogenesis Hypoxia Endothelial Cell Endothelial Cell FGF, fibroblast growth factor; HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor Adapted from Casanovas et al, Cancer Cell 2005;8:299-309.
  • 22. In hu ma n • FGFR is highly expressed in RCC (80% of pts) • High levels of bFGF are reported in patients with disease progression • Increased expression of FGFR1 is associated with a shorter progression free survival Welti et al. Oncogene 2011; 30(10):1183-1193. Tsimafeyeu Iet al. J Clin Oncol 28:15s, 2010 (suppl; abstr 4621). Ho Th et al. ASCO meeting 2011. J Clin Oncol 29: 2011 (suppl; abstr e15015).
  • 23. Angiogenic Escape IL-8 mediates resistance to Sunitinib In Xenograft models The resistance to sunitinib is associated to a higher microvessel density, indicating an escape from antiangiogenesis, and IL-8 levels Sunitinib IL-8 resistent/ refractory + Ac anti IL-8 Resensitized tumor IL-8 Sunitinib responsive Conclusions: IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib Huang et al, Cancer Res 2010
  • 24. In hu ma n • Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib Huang et al, Cancer Res 2010. • Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib Liu et al, ASCO 2011.
  • 25. Secondary resistance to anti-angiogenic therapies The epithelial-to-mesenchymal transition process
  • 27. The epithelial-to-mesenchymal transition process Mechanisms of Disease: epithelial–mesenchymal transition—does cellular plasticity fuel neoplastic progression? Eva A Turley, Mandana Veiseh, Derek C Radisky and Mina J Bissell Nature Clinical Practice Oncology 2008
  • 28. Secondary resistance to anti-angiogenic therapies The epithelial to mesenchymal transition process: What significance? • Sarcomatoid phenotype is observed across all histological subtypes, and associated with a poorer prognosis • It is a potentially transient/reversible phenotype of epithelial cancers • Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma Hugo H, Ackland ML, Blick T, et al: Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 2007; 213:374–383. Hammers HJ, Verheul HM, Salumbides B, et al: Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 2010; 9:1525-1535. Klymkowsky MW, Savagner P: Epithelial-mesenchymal transition: A cancer researcher's conceptual friend and foe. Am J Pathol 2009; 174:1588–1593.
  • 29. Secondary resistance to anti-angiogenic therapies The epithelial to mesenchymal transition process: Main characteristics • Higher proliferative index • Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype • IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer • Loss of the epithelial markers E-cadherin and ZO-1 Bostrom et al, Hum Pat 2011 Giron-Michel et al, Bull Cancer 2011 Khawam et al, Cancer Res 2009
  • 30. Secondary resistance to anti-angiogenic therapies The intratumoral heterogeneity and gene mutations
  • 31. A specific gene expression signature characterizes metastatic potential in ccRCC • Transcriptional profiling of 16 primary metastatic and 18 non- metastatic clear cell renal cell carcinomas with microarrays • Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even • Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis Sanimyatav et al, J Urol 2011
  • 32. Secondary resistance to anti-angiogenic therapies The intratumoral heterogeneity and gene mutations • Due to this genomic instability, it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure, hypoxia pressure, etc) and during the tumor growth • Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase, calvasculin, chemokine receptor 4 (CXCR4), NNP1, arginase II, hypoxia-inducible protein-2 (HIG2) and VEGF) • Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma, in particular IP10 (CXCL10) and Mig (CXCL9)) Lee AJ, Endesfelder D, Rowan AJ, Walther A, et al: Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 2011; 71(5):1858-70. Navin N, Kendall J, Troge J, et al: Tumour evolution inferred by single-cell sequencing. Nature 2011; 472(7341):90-94.
  • 33. Working Model: Factors Associated With Resistance -VEGF -Ang2 -IL8 -MMP1 -uPAR -Calvasculin -IL10 -Arginase -IFNγ -?TSP Antiangiogenic Proangiogenic Progrowth Atkins M, et al. ASCO GU Symposium 2008. Abstract.
  • 34. Factors Associated With Resistance in mRCC Clinical: - Poor risk pts - Histology non clear - Prior TKi Laboratory: - levels of IL-8; IL-15 (proangiogenic) - level of HIF - Level of FGF - level of CA IX (?) Bio-molecular: - Specific mutation? - Gene profiling? - …??? Huang et al, Cancer Res 2010
  • 35. Main mechanisms of primary and secondary resistance in mRCC - Alternative pro-angiogenic pathways mediated by FGFR, interleukin-8 (IL-8), insulin-like GFR, ephrins, and angiopoietins; - Non angiogenic mechanisms - Pre-existing inflammatory cell-mediated vascular protection (myeloid cell); Primary resistance - Hypovascularity status with consequent indifference toward angiogenesis inhibitors (desmoplastic stroma); - Co-option of normal vessels without requisite angiogenesis - Non clear cell histology - New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs - Epithelial to mesenchymal transition - Intra-tumoral heterogeneity - Gene instability and gene iperexpression - Secondary mutations in tyrosine kinase receptors Secondary resistance - Bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling; - Increasing of pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival; - Access to normal tissue vasculature without obligate neovascularisation
  • 36. Resistance to TKI in mRCC 1. Definition of resistance 2. The resistance mechanisms 3. How can we overcome the resistance mechanisms?
  • 37. How can we overcome the resistance to TKI? • Using non cross-resistant drugs • New drugs (denosumab, …) • Re-challenge with TKi/Sequential therapies • Integrating the current treatment – Combined therapies (?)
  • 38. Resistance to anti-angiogenic therapies in mRCC •Re-challenge with anti-angiogenic agents could be a valid option for some pts •It is thought that a “holiday” period from anti-VEGF therapies is able to determine a reacquired drug- sensitivity by clones become resistant to TKi drugs Zama IN, Hutson TE, Elson P, et al: Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010; 116(23):5400-5406. Rini BI, Hutson HE, Elson P et al: Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma. GU ASCO 2010, J Clin Oncol 2010, Abst 396.
  • 39. Michele Guida and Giuseppe Colucci
  • 41. Adaptive mechanisms of secondary resistance to anti-angiogenic therapies 1.Activation/upregulation of alternative pro-angiogenic signalling pathways 2.Recruitment of bone marrow-derived pro- angiogenic cells, which can obviate the necessity of VEGF signalling, thereby effecting re-initiaton and continuance of tumour angiogenesis 3. Incrising pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling 4.Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
  • 42. Adaptive mechanisms of secondary resistance to anti-angiogenic therapies 1.Activation/upregulation of alternative pro-angiogenic signalling pathways 2.Recruitment of bone marrow-derived pro- angiogenic cells, which can obviate the necessity of VEGF signalling (circulating endotelial cells; myeloid cell) 3. Incrising pericyte coverage of the tumour vasculature, serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling 4.Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
  • 43. Potential Mechanisms of Treatment Resistance In mRCC Rini and Atkins 2010
  • 44. Potential mechanisms of VEGFR TKI Resistance
  • 45. How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies • Using revertant drugs (IFN, …)
  • 46. Everolimus vs Placebo After Progression on a VEGFR-TKI in mRCC (RECORD-1 study) Phase III Study Design Prim Endpt:  PFS RAD001 (everolimus) 10 mg/d + BSC Sec Endpts: S Randomize C  Response R N = 362 Upon Disease Progression  Response E 2:1 E RAD001 : Placebo duration N Placebo + BSC  Survival Stratification  Safety  Previous VEGFR-TKI:  QoL 1 or 2  MSKCC risk group – Favorable (29%) – Intermediate (56%) – Poor (15%) (N = 410) Motzer et al, The Lancet 2008
  • 47. Everolimus in mRCC (RECORD 1 study) Final results and analysis of prognostic factors • OR: 2% • SD: 67% • PFS: 4.9 vs 1.9 • OS: 14.4 vs 14.4 (cross-over 80% of pts) Independent prognostic factors for shorter OS – low performance status – high corrected calcium – low hemoglobin – prior sunitinib (P < .01) Motzer, Escudier, et al, Cancer 2010
  • 48. Benefit of everolimus after multiple lines of treatment Escudier B et al. ESMO 2008; abstr 720
  • 49. mRCC: about mTOR inhibition What is the optimal time to use mTOR inhibitors in the treatment sequence?
  • 50. Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy Late Phase: Escape to Anti-VEGF Treatment Cancer cells VEGF inhibitors VEGF PIGF FGF and other factors Second wave of HIF angiogenesis Endothelial Cell FGF/FGFR has been reported as one of the most important escape pathway of anti-VEGFR therapies
  • 51. Dofitinib: a new multitarget agent A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma K. B. Kim, J. Saro, S. S. Moschos, P. Hwu, A. A. Tarhini, W. Hwu, G. Jones, Y. Wang, H. Rupani and J. M. Kirkwood (ASCO 2008) TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study E. Angevin, J. A. Lopez, A. Pande, C. Moldovan, M. Shi, J. C. Soria, X. Wang, A. Harzstark, J. Saro, B. Escudier ASCO 2009 Abst 3563 Study CTKI258A2202: A multicenter, open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancer F. Andre, J. Baselga, M. J. Ellis, S. A. Hurvitz, H. S. Rugo, N. C. Turner, E. Argonza-Aviles, S. Lake, M. M. Shi and O. Anak (ASCO 2009)
  • 52. TKI 258 (Dovitinib) in mRCC Phase III Study Design third line therapy S C Dovitinib + BSC R E Randomize E N Sorafenib + BSC
  • 53. How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies
  • 54. Selected Trials of Second-Line Agents After TKI/Beva Agent Study N % PFS OS Population Author phase pts OR/SD (Mo) (Mo) Everolimus 4.9 416 14 vs placebo TKI refractory III (2:1) 2/67 vs vs 14* Motzer et al Lancet ‘08 1.8 Axitinib Sorafenib II 62 23/55 7.4 na Rini et al, JCO ‘09 refractory Sunitinib Bev II 62 23/75 7.1 10.2 Rini et al, JCO ‘08 refractory Sorafenib Bev/sunitinib 26 refractory II each 3/38 3.8 Shepard et al, ASCO ‘08 *cross-over 80% of pts
  • 55. Second line therapy in mRCC: For how many pts? First line Second line Therapy/Authors N. Pts Therapy N. Pts (%) Sunitinib 375 Anti-VEGF/anti- mTOR 182 (56) Motzer et al, JCO 2009 (sunitinib arm) Beva + IFN (AVOREN study) 325 TKI 180 (55) Escudier et al, JCO 2010 (beva-IFN arm) TKI (various studies; 7 centers) Anti-VEGF/anti- 645 mTOR 216 (30) Vikers et al, Urology 2010
  • 56. Estimated PFS of pts receiving sequential therapies 30-50% of pts 10% of pts 5%pts 2a line 3a line 4a line Escudier et al, Cancer 2009
  • 57. Optimal Sequence May Depend on Response to First Line Therapy
  • 58. Sequential therapy: ongoing studies Pts N Agent Sponsor phase population pts Sunitinib - sorafenib vs Sequential Bayer III 540 Sorafenib - sunitinib (I and II line) (SWITCH trial) Pazopanib - Sunitinib Sequential vs GSK III 160 (I and II line) Sunitinib - Pazopanib Sunitinib - Everolimus vs Sequential Novartis II 390 Everolimus - Sunitinib (I and II line) (RECORD III trial)
  • 59. How can we overcome the resistance to TKI? • Using non cross-resistant drugs • Re-challenge with TKI/Sequential therapies • Integrating the current treatment – Combined therapies
  • 60. Is Combination Therapy Better? VEGF inhibitors: EGFR inhibitors: -sunitinib - erlotinib -sorafenib - gefitinib -axitinib - lapatinib -pazopanib - cetuximab -bevacizumab IFN Angiogenesis Tumor cell proliferation Inhibitors of angiogenic escape mTOR/akt inhibitors: mechanisms: - temsirolimus -dovitinib - everolimus -AMG 386 - perifosine -M200
  • 61. Combination Drug Therapy: Selected Adverse Events Rash or GI or Agent Hand-Foot Hypertension Cytopenia Proteinuria Mucosal Reaction Sunitinib Yes Yes Yes Yes Yes Sorafenib Yes Yes Yes Yes Bevacizumab Yes Yes Temsirolimus/ Yes Yes Yes Everolimus
  • 62. Combined therapies in mRCC: the future? •Beva + TK inhibitors •TK inhibitors + mTOR inhibitors •Beva + mTOR inhibitors
  • 63. Is Combination Therapy Better? VEGF inhibitors: EGFR inhibitors: -sunitinib - erlotinib -sorafenib - gefitinib -axitinib - lapatinib -pazopanib - cetuximab -bevacizumab IFN Angiogenesis Tumor cell proliferation Inhibitors of angiogenic escape mTOR/akt inhibitors: mechanisms: - temsirolimus -dovitinib - everolimus -AMG 386 - perifosine -M200
  • 64. Bevacizumab + TKI in mRCC: Drug Study/ PFS OR Toxicity Comments combinations Pts (Mo) An Beva + Sunitinib* ega Phase I 31 - 3/7 RCC 1/3 Mela Mild (?) Good tive Garcia et al, ASCO ‘08 (various) 1 adrenal activity exp Beva + erie High (hypertension, nce Sunitinib 16 microangiop. Feldman,. Motzer, Transient Asco ‘08 ischemic CNS) High Beva + 0 CR (hypertension, No Phase I-II Sorafenib** 48 14 25 PR stomatitis, full doses Sosman et al, ASCO ‘08 18 SD hand-foot skin together reaction) * Escalating doses ** Full dose Sorafenib + 50% Beva and reverse
  • 65. Is Combination Therapy Better? VEGF inhibitors: EGFR inhibitors: - erlotinib -sunitinib -sorafenib - gefitinib -axitinib - lapatinib -pazopanib - cetuximab -bevacizumab IFN Angiogenesis Tumor cell proliferation Inhibitors of angiogenic escape mTOR/akt inhibitors: mechanisms: - temsirolimus -dovitinib - everolimus -AMG 386 - perifosine -M200
  • 66. EGFR EXPRESSION IN SELECTED HUMAN TUMORS Tumor Type Percentage of Tumors References Expressing EGFR Colorectal 25-77% Salomon (1995); Messa (1998) Advanced Colorectal 75% Goldstein (2001) Head and Neck 80-100% Salomon (1995); Grandis (1996) Pancreatic 30-95% Salomon (1995); Uegaki (1997) Advanced Stage 95% Abbruzzese (2001) Fujino (1996); Rusch (1997); NSCLC 40-80% Fontanini (1998) Renal Carcinoma 50-90% Salomon (1995); Yoshida (1997) Klijn (1992); Beckman (1996); Breast 14-91% Bucci (1997); Walker (1999) Bartlett (1996); Ovarian 35-70% Fischer-Colbrie (1997) Salomon (1995); Watanabe (1996); Glioma 40-63% Rieske (1998) Bladder 31-48% Salomon (1995); Chow (1997)
  • 67. Phase I/II trial of sunitinib plus gefitinib in patients with mRCC (first line) A 42 pts d isa - Sunitinib 37.5 or 50 mg/d oral (4 weeks on, 2 off) pp - Gefitinib 250 mg/d oral oin Results tin - OR: 37% ge - SD: 34% xp - Median PFS: 11 moths eri en - Accettable toxicity (diarrea G3-4 in 14%) ce - No pharmacokinetic drug-drug interaction Conclusions: “Sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy” Motzer RJ, et al, Am J Clin Oncol 2010
  • 68. Is Combination Therapy Better? VEGF inhibitors: EGFR inhibitors: -sunitinib - erlotinib -sorafenib - gefitinib -axitinib - lapatinib -pazopanib - cetuximab -bevacizumab IFN Angiogenesis Tumor cell proliferation Inhibitors of angiogenic escape mTOR/akt inhibitors: mechanisms: - temsirolimus -dovitinib - everolimus -AMG 386 - perifosine -M200
  • 69. Bevacizumab + mTOR inhibitor A questionable experience
  • 70. Bevacizumab + mTORI in mRCC A questionable experience First and Second line Drug Study/ PFS OS OR Toxicity combinations Pts (Mo) (Mo) Phase II Beva + Everolimus 11 12 23% PR Whorf et al, ASCO ‘08 (in 29 pretr. 53% SD - mild 59 with TKI) (first line) Beva + Temsirolimus Merchan et al, JCO ’09 45 5.3 18 14.5 - acceptable
  • 71. Bevacizumab + mTOR inhibitor Phase III randomized first-line study Temsirolimus + Bevacizumab 1° Endpoint: Screen R 1:1  PFS Interferon alfa-2a + Bevacizumab 822 pts RECORD-2: randomized phase II first-line study Everolimus + Bevacizumab 1° Endpoint: Screen R 1:1  PFS Interferon alfa-2a + Bevacizumab Randomized phase III second line study (CALG study) Everolimus + Bevacizumab Screen 1° Endpoint: R 1:1  PFS Placebo
  • 72. Bevacizumab + mTOR inhibitor First line therapy Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC? Results of the randomized TORAVA phase II trial Escudier BJ, Negrier S, Gravis G, et al. ASCO 2010. Abstract 4516 .
  • 73. TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC • Primary endpoint: non-progression rate at week 48 > 50% (42% to 46% previous studies) • 160 patients required for 2:1:1 randomization
  • 74. TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS Temsirolimus/Beva Sunitinib Beva/Interferon Outcome (n = 88) (n = 42) (n = 41) 48 ww 30.7 40.5 65.9 non PD>50% PFS (Mo) 8.2 8.2 16.8 Best OR /%) 27.3 23.8 39 SD (%) 47.7 50 34.1
  • 75. TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity Serious Adverse Temsirolimus/Beva Sunitinib Beva/Interferon Events, % (n = 88) (n = 42) (n = 40) Grade 3 26.1 11.9 20.0 Grade 4 12.5 2.4 7.5 Death 3.4 0 0 Note: 50% of pts in temsirolimus/beva arm ceased therapy before Week 48 for reasons not related to progressive disease, primarily toxicity (41%)
  • 76. Conclusions of the Authors: TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC Escudier BJ, Negrier S, Gravis G, et al. ASCO 2010. Abstract 4516.
  • 77. Bevacizumab + Everolimus First an second line therapy Phase II trial of Bevacizumab + Everolimus in pts with advanced RCC J.D. Hainsworth,…. Whorf, J Clin Oncol 2010
  • 78. Bevacizumab + mTOR inhibitor Bevacizumab + Everolimus phase II study Naïve pts Pre-treated pts* Outcomes (N = 50) (N = 30) OR (%) 30 23 SD 50 64 N. with tumor shrinkage 78 73 PFS (mo) 9.1 7.1 Survival (mo) 21.3 14.5 *Sunitinib or Sorafenib Hainsworth et al, JCO 2010
  • 79. Bevacizumab + Everolimus Bernard Escudier, Editorial JCO 2010 • The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 9,1 for untreated and 11 vs 7.1 for pre-treated pts) • PFS has became the same that of control arm (8.5-12.2 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months) • The rationale for the two large randomized studies is much weaker and questionable • Usefulness of phase II non randomized small study
  • 80. How can we overcome the resistance to TKI? Using old and new drugs (IFN, …) “Redefining the role of Interferon in the treatment of malignant diseases” Bracarda, Eggermont, Samuelsson Eur J Cancer 2010
  • 81. Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line* Therapy in mRCC Gollob et al, JCO 2007 •Sorafenib 400 mg orally bid for 8 weeks •IFN alpha-2b: 10 mil. IU subcutaneously three times a week followed by a 2-week break *IL-2 pre-treated pts
  • 82. Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in mRCC All pts First line Second line (40 pts) (20 pts) (20 pts) Response, n (%) 13 (33) 10 3 CR 2 (5) PR 11 (28) SD 12 (29) PFS (mo) 10 Dose reduction (% of pts*) 65 *Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss Gollob et al, JCO 2007
  • 83. CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO Studio G.O.I.M. 2901 PIANO DI TRATTAMENTO •Braccio A Everolimus 10 mg/die per via orale •Braccio B Everolimus stesse dosi + Interferone alpha-2a, basse dosi s.c. (3 Mil U.I. x 3 volte/settimana)

Notas del editor

  1. Questi i farmaci ed i loro target. Si suppone che quanto più queste vie siano importanti nel singolo pz e nella singola neoplasia, tanto più il farmaco è efficace. Ma evidentemente ci sono pts la cui neoplasia non è dipendente (o almeno non è strettamente dipendente da questi path ways) tant’è che non rispondono affatto (R 1°) o progrediscono più o meno rapidamente
  2. Ensues: si manifesta
  3. R. 2°: o adattativa o evasiva: dopo un periodo di sensibilità al farmaco, il T si ADATTA e mette in atto meccanismi di escape -Netta contrazione della angiogenesi; poche mitosi; molte cell in apoptosi In seguito ripresa della NEOANGIOGENESI ma sempre meno dipendenza dalla N. B.:Resistenza 1a Modificazione del Pattern cellulare (molte cell. Tumorali a svantaggio di quelle non t.; molte mitosi) processo di NEOANGIOVENESI è inesorabile e inarrestabile
  4. NB: i “poor risk” sono circa il 20-25%!!! Gli Early progressors calcolati ARBITRARIAMENTE fino a &lt; di 6 mesi di PFS
  5. Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  6. Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  7. Ensues: si manifesta
  8. Ma sono gli stessi pts della prima linea??? Non dati disponibili. NB: In everolimus solo 40 pts su 274 del braccio Ever. Erano poor risk
  9. Ensues: si manifesta
  10. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Pàez-Ribes M , Allen E , Hudock J , Takeda T , Okuyama H , Viñals F , Inoue M , Bergers G , Hanahan D , Casanovas O . Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, 08907 L&apos;Hospitalet de Llobregat, Spain. Comment in: Abstract Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
  11. Modello in Breast cancer. VEGF è sempre presente durante il corso vitale del tumore, pertanto una sua inibizione (se pure non sufficiente) avrebbe senso anche quando la malattia non è più responsiva. Tuttavia, man mano che il T. cresce, altri fattori pro-angiogenetici vengono prodotti a sostituzione/integrazione del VEGF. Quindi se nelle fasi iniziali può essere sufficiente bloccare il VEGF, nelle fasi più avanzate ciò non è più sufficiente. Infatti ……
  12. FGF, fibroblast growth factor;    HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor.   This schematic shows “angiogenic escape” to anti‑VEGF treatment, which may be dependent on cancer cell phenomena or endothelial cell phenomena. It may be that other growth factors, such as basic fibroblast growth factor, are responsible.   Cancer Cell. 2005 Oct;8(4):299-309. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Casanovas O , Hicklin DJ , Bergers G , Hanahan D . Department of Biochemistry and Biophysics, Comprehensive Cancer Center, and Diabetes Center, University of California, San Francisco, San Francisco, California 94143, USA. Abstract Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family . These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition. FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib
  13. FGF, fibroblast growth factor;    HIF, hypoxia-inducible factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor.   This schematic shows “angiogenic escape” to anti‑VEGF treatment, which may be dependent on cancer cell phenomena or endothelial cell phenomena. It may be that other growth factors, such as basic fibroblast growth factor, are responsible.   Cancer Cell. 2005 Oct;8(4):299-309. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Casanovas O , Hicklin DJ , Bergers G , Hanahan D . Department of Biochemistry and Biophysics, Comprehensive Cancer Center, and Diabetes Center, University of California, San Francisco, San Francisco, California 94143, USA. Abstract Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family . These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition. FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib
  14. NB: IL-8 elevata anche in pts resistenti/refrattari
  15. : 4 1. Hum Pathol. 2011 Oct 10. [Epub ahead of print] Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition. Boström AK , Möller C , Nilsson E , Elfving P, Axelson H, Johansson ME. Source Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, SE-205 02 Malmö, Sweden. Abstract Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma. Copyright © 2011 Elsevier Inc. All rights reserved. Bull Cancer. 2011 May;98(5):32-9. Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer. Giron-Michel J, Azzi S, Khawam K, Caignard A, Devocelle A, Perrier A, Chouaib S, Eid P, Azzarone B. Source Hôpital Paul-Brousse, université de Paris-Sud, Inserm UMR 1014, 14, avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France. Abstract Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the γc chain leading to the assembly of a IL-15Rαβ heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial-mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL-15Rαβγc heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane-bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Rα chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) &quot;apparently normal&quot; pTEC cells, could contribute to organize a generalized &quot;pre-neoplastic&quot; environment committed to favour tumour progression Cancer Res. 2009 Feb 15;69(4):1561-9. Epub 2009 Feb 3. Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition. Khawam K, Giron-Michel J, Gu Y, Perier A, Giuliani M, Caignard A, Devocelle A, Ferrini S, Fabbi M, Charpentier B, Ludwig A, Chouaib S, Azzarone B, Eid P. Institut National de la Sante et de la Recherche Medicale UMR 542, Université de Paris-Sud, Hôpital Paul Brousse, Villejuif Cedex, France. Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.
  16. J Urol. 2011 Jul;186(1):289-94. Epub 2011 May 20. A specific gene expression signature characterizes metastatic potential in clear cell renal cell carcinoma. Sanjmyatav J, Steiner T, Wunderlich H, Diegmann J, Gajda M, Junker K. Source Department of Urology, Jena University Hospital, Jena, Germany. Abstract PURPOSE: The discovery of metastasis markers in clear cell renal cell carcinoma is of critical importance to define individual metastatic risk and select patients for new targeted therapies. We identified potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis. MATERIALS AND METHODS: We performed transcriptional profiling of 16 primary metastatic and 18 nonmetastatic clear cell renal cell carcinomas with PIQOR™ microarrays. Differentially expressed genes were validated by quantitative real-time polymerase chain reaction. RESULTS: the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation.. The metastatic signature contained 127 transcripts. In metastatic samples a greater than 4-fold decrease in expression was detected for the genes CD151 and IKBA (t/F statistic p &lt;0.0001) while the genes MMP16, B7-H1, BCL2L2 and FRA2 showed greater than 4-fold increase of expression in metastatic primary tumors (p &lt;0.0001). Quantitative real-time polymerase chain reaction revealed significant differences in expression among all metastatic tumors, including synchronously and metachronously metastasized tumors, and nonmetastatic tumors for FRA2 (p = 0.032) and CD151 (p = 0.005). In addition, the genes B7-H1 (p = 0.040), FRA2 (p = 0.035), CD151 (p = 0.004) and BCL2L2 (p = 0.035) showed significantly higher expression in early metastasized than in nonmetastatic tumor samples. Different B7-H1 (p = 0.002) and BCL2L2 (p = 0.007) expression levels were found in samples with late metastasis compared to those in synchronously metastasized tumors. CONCLUSIONS: We determined a metastatic signature of clear cell renal cell carcinoma by microarray analysis. Our data provide the possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even in a localized situation.
  17. IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; uPAR, urokinase-type plasminogen activator receptor; TSP, thrombospondin; VEGF, vascular endothelial growth factor.   Multiple factors affect resistance. These include factors that decrease angiogenesis and factors that increase angiogenesis, both in a single patient or a single model. Several of these factors need to be accounted for when developing a comprehensive treatment approach and in understanding why a patient may be resistant to any one approach.
  18. IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; uPAR, urokinase-type plasminogen activator receptor; TSP, thrombospondin; VEGF, vascular endothelial growth factor.   Multiple factors affect resistance. These include factors that decrease angiogenesis and factors that increase angiogenesis, both in a single patient or a single model. Several of these factors need to be accounted for when developing a comprehensive treatment approach and in understanding why a patient may be resistant to any one approach.
  19. cell carcinoma based on a select number of genes even in a localized situation.
  20. dovitinib lactate  The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types. FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). receptor tyrosine kinase inhibitor TKI258 RTK inhibitor TKI258
  21. Activating mutations or overexpression of fibroblast growth factor receptors (FGFRs) or their ligands have been associated with neoplastic progression and tumor vascularization in multiple cancer types, including breast cancer, bladder cancer, multiple myeloma, hepatocellular, and renal cell carcinoma.17–21 Aberrant activation of FGFR signaling has been shown to result in poor patient prognosis. In a recent analysis of 880 unselected breast carcinomas, amplification of FGFR1 was the strongest independent predictor of poor outcome.17 Inhibition of FGFR may have clinical utility in cancers that over express FGFRs, such as breast cancer,17 or display a prevalence of FGFR mutations, such as bladder cancer.22 FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). Dovitinib, orally bioavailable, has demonstrated inhibition of VEGFR and FGFRs in clinical trials.23 BGJ398 is an orally bioavailable, selective inhibitor of the FGFRs at nanomolar concentrations in enzymatic assays and proliferative assays and in in vivo models.24 Dovitinib is in phase II development in renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. A Phase I study with BGJ398 is ongoing. 23. Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma. J Clin Oncol . 2009;27(suppl.) Abstract 9020.
  22. I target dei diversi farmaci TKI NON SONO esattamente gli srtessi
  23. NB: Anche l’affinità per i singoli TARGET e’ DIVERSA Pur appartenendo alla stessa categoria di farmaci, la potenza dell’attività anti VEGF-R è molto diversa a seconda delle molecole, così come quella antiPDGFR
  24. Thoroughly: interamente
  25. Display Settings: Format Send to: Choose Destination Cancer. 2010 Jun 14. [Epub ahead of print] Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; for the RECORD‐1 Study Group. Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York. Abstract BACKGROUND:: A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported. METHODS:: Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus. RESULTS:: The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P &lt; .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P &lt; .001) by investigators. Serious adverse events with everolimus, independent of causality, in &gt;/=5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P &lt; .01). CONCLUSIONS:: These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010. (c) 2010 American Cancer Society.
  26. dovitinib lactate  The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types. FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). receptor tyrosine kinase inhibitor TKI258 RTK inhibitor TKI258
  27. Activating mutations or overexpression of fibroblast growth factor receptors (FGFRs) or their ligands have been associated with neoplastic progression and tumor vascularization in multiple cancer types, including breast cancer, bladder cancer, multiple myeloma, hepatocellular, and renal cell carcinoma.17–21 Aberrant activation of FGFR signaling has been shown to result in poor patient prognosis. In a recent analysis of 880 unselected breast carcinomas, amplification of FGFR1 was the strongest independent predictor of poor outcome.17 Inhibition of FGFR may have clinical utility in cancers that over express FGFRs, such as breast cancer,17 or display a prevalence of FGFR mutations, such as bladder cancer.22 FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as vascular endothelial growth factor receptor (VEGFR). Dovitinib, orally bioavailable, has demonstrated inhibition of VEGFR and FGFRs in clinical trials.23 BGJ398 is an orally bioavailable, selective inhibitor of the FGFRs at nanomolar concentrations in enzymatic assays and proliferative assays and in in vivo models.24 Dovitinib is in phase II development in renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. A Phase I study with BGJ398 is ongoing. 23. Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma. J Clin Oncol . 2009;27(suppl.) Abstract 9020.
  28. PHASE I J Clin Oncol 27:15s, 2009 (suppl; abstr 3563) Author(s): E. Angevin, J. A. Lopez, A. Pande, C. Moldovan, M. Shi, J. C. Soria, X. Wang, A. Harzstark, J. Saro, B. Escudier; Institut Gustave Roussy, Villejuif, France; Hospital 12 de Octubre, Madrid, Spain; Novartis Oncology, East Hannover, NJ; University of California, San Francisco, CA Abstract: Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29-66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180-487 ng/mL, n = 8), and AUC range (2200-8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node &amp; suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort.
  29. OR/TS, objective response/tumor shrinkage; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.   5. ClinicalTrials.gov. NCT00474786. 6. ClinicalTrials.gov. NCT00678392. This table shows a summary of selected trials of second‑line agents in metastatic kidney cancer. The first 4 rows have been discussed, with the 3 phase II studies and 1 phase III trial showing variable response in degrees of tumor burden shrinkage and a progression‑free survival time averaging approximately 4-7 months. The bottom 2 rows show prospective ongoing trials that are studying metastatic kidney cancer patients who failed previous therapy. The first is examining temsirolimus vs sorafenib in patients previously treated with sunitinib; in essence, comparing switching to an mTOR‑directed approach vs continuing with a VEGF‑targeted approach. The AXIS trial is comparing more- vs less-potent VEGF inhibition by comparing axitinib vs sorafenib in patients who have failed frontline therapy for metastatic RCC. These important and large trials will help shape the landscape of sequenced therapy in kidney cancer. NB: non ci sono studi di confronto tra mTOR in. e nuove molecole anti VEGF (es. Axitinib)  
  30. NB: in trials quindi in seconda linea arrivano circa il 50% dei pts; ma fuori trials sono circa il 30%!!!
  31. NB: non ci sono studio di confronto tra mTOR in. e nuove molecole (es. Axitinib) Prospective ongoing trials that are studying metastatic kidney cancer patients who failed previous therapy. The first is examining temsirolimus vs sorafenib in patients previously treated with sunitinib; in essence, comparing switching to an mTOR‑directed approach vs continuing with a VEGF‑targeted approach. The AXIS trial is comparing more- vs less-potent VEGF inhibition by comparing axitinib vs sorafenib in patients who have failed frontline therapy for metastatic RCC. These important and large trials will help shape the landscape of sequenced therapy in kidney cancer. RECORD III Sub-category:Kidney Cancer Category:Genitourinary Cancer Meeting:2010 ASCO Annual Meeting Session Type and Session Title:Trials in Progress Poster Session, Trials in Progress Poster Session Abstract No:TPS232 Citation:J Clin Oncol 28:15s, 2010 (suppl; abstr TPS232) Author(s):J. J. Knox, A. C. Kay, E. Schiff, N. Hollaender, N. Rouyrre, A. Ravaud, R. J. Motzer; Princess Margaret Hospital, Toronto, ON, Canada; Novartis Oncology, Florham Park, NJ; Novartis Pharmaceuticals Corporation, Florham Park, NJ; Novartis Pharma AG, Basel, Switzerland; Oncology, Hospital Saint Andre CHU, Bordeaux, France; Memorial Sloan-Kettering Cancer Center, New York, NY Abstract: Background: Targeted therapies for advanced renal cell carcinoma (RCC) have changed treatment paradigms. Currently, sequential monotherapy with targeted agents is the standard of care. Sunitinib is a multikinase inhibitor approved for first-line use in advanced RCC; everolimus, an oral inhibitor of mTOR, is approved for use following sunitinib. Currently, these 2 agents have level 1 recommendations for use in the first and second line settings, respectively. However, the most appropriate sequence for everolimus and sunitinib has not been established in a prospective clinical trial. The RECORD-3 (Renal Cell Cancer Treatment with Oral RAD001 Given Daily) trial will assess progression-free survival (PFS) for everolimus- sunitinib versus sunitinib-everolimus in treatment naïve patients with mRCC. RECORD-3 is the first trial to evaluate everolimus as second-line therapy after treatment solely with sunitinib. Methods: RECORD-3 is a randomized, open-label, multicenter phase II trial currently recruiting participants. Up to 390 patients with mRCC (clear-cell or non-clear-cell), with or without nephrectomy, ≥1 measurable baseline lesion (per RECIST criteria), Karnofsky performance status ≥70%, adequate liver, renal, and bone marrow function, and left ventricular ejection fraction ≥ lower limit of normal will be enrolled. The primary objective is to determine whether everolimus is noninferior to sunitinib, as assessed by PFS, for first-line treatment of mRCC. Patients are randomized 1:1 to receive everolimus 10 mg/d PO once daily or sunitinib 50 mg/d PO for 4 wk followed by 2 wk off therapy until disease progression; upon progression, patients will cross over to second-line treatment with the opposite drug until the second occurrence of progression. The primary endpoint will assess PFS after first-line treatment. Overall efficacy of the 2 sequences will be compared based on the time from start of the sequence to progression after second-line therapy, or death. Overall survival, objective response rate, patient-reported outcomes, and safety also will be assessed. The first patient visit was October 22, 2009; 11 patients have entered the study to date.
  32. EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  33. GI, gastrointestinal.   This table shows the different major toxicities of available agents, including where they overlap. In early studies, bevacizumab and temsirolimus appear to be the most combinable agents, perhaps because of the nonoverlapping nature of their toxicity profiles.
  34. EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  35. EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  36. Memorial Sloan-Kettering Cancer Center, New York, NY. Fox Chase Cancer Center, Philadelphia, PA; Pfizer Oncology, La Jolla, CA; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC. In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination. Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg ( grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in &gt;2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions. In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
  37. EGFR, epidermal growth factor receptor; IFN, interferon; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.   In other oncology settings, combining multiple active agents, if tolerated, can increase the cure rate. This schematic shows where different inhibitors may act upon the tumor pathway, that is, through angiogenesis or directly on the tumor cells. The VEGF and mTOR inhibitors are most prominent in the setting of kidney cancer. Epidermal growth factor receptor inhibitors have not shown significant clinical activity in RCC. Angiogenesis inhibitors, including inhibitors of Tie‑2    , which is a receptor on endothelial cells, and integrin inhibitors are in clinical development.  
  38. DUBBIA
  39. Dati preliminari ad ASCO 2008 SONO le PFS più lunghe mai ottenute
  40. CALG:
  41. NB: primo endpoint NON RAGGIUNTO. PFS per Sunitinib molto breve. Perche?
  42. Most common events included gastrointestinal fistula/rectal hemorrhage, general physical health deterioration, Fatigue/asthenia/malaise and renal failure
  43. Most common events included gastrointestinal fistula/rectal hemorrhage, general physical health deterioration, Fatigue/asthenia/malaise and renal failure
  44. Nashville, Florida Center, USA
  45. Beva 10 mg/kg evary 2 ww ev; Eve 10 mg/die os.
  46. Beva 10 mg/kg evary 2 ww ev; Eve 10 mg/die os.
  47. Journal of Clinical Oncology , Vol 25, No 22 (August 1), 2007: pp. 3288-3295 Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins, Lin Gu, Bercedis L. Peterson, John J. Wright From the Division of Medical Oncology, Department of Medicine, and Departments of Biostatistics and Bioinformatics, Duke University Medical Center, Durham; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD Address reprint requests to Jared A. Gollob, MD, Duke University Medical Center, DUMC 3441, Durham, NC 27710; e-mail: jared.gollob@duke.edu Purpose We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN- -2b) as first- or second-line therapy in metastatic renal cell cancer (RCC). Patients and Methods Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN- -2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN- -2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity. Results The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) –treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients. Conclusion The combination of sorafenib and IFN- -2b has substantial activity in treatment-naïve and IL-2–treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.
  48. NB: PFS di solo Sora in II linea: 7 mesi. Auspicato dall’Autore uno studio di fase III (Sora vs Sora + IFN) mai fatto.