1. XIV WORKSHOP ON ONCOLOGICAL UROLOGY
Alternating therapy with VEGF inhibitors and
mTOR Inhibitors in metastatic Renal Cancer: yes or no?
Luis Costa, MD, PhD
Serviço de Oncologia – HSM-CHLN
Instituto de Medicina Molecular
Faculdade de Medicina de Lisboa

2. Regulates the expression of HIF
In clear renal cell carcinoma:
mutation, deletion or silencing by hypermethylation of the
promoter of the VHL gene is the defining somatic genetic event
and is found in 90% of cases*
VHL
HIF
Target Genes
VEGF
PDGF
and others…
bFGF
mTOR
Regulates the expression of HIF
PI3K
↑ VEGF receptor
* Kaelin Jr WG. Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer 2009;115:2262–72

3. The expression of the VEGFA (A) and
the most significantly dysregulated factors in the indicated subtypes of RCC (B)
Expression data and associated publications describing the data can be obtained from National Center of
Biomedical Informatics Gene Expression Omnibus (GEO ID: GSE11024, GSE14762, GSE8271, and GSE7023).
Kyle A Furge, Jeff rey P MacKeigan, Bin T Teh in Lancet Oncol 2010; 11: 571–78

4. Molecular and cellular mediators of angiogenesis in
clear cell renal cell carcinoma
Keith T. Flaherty, Igor Puzanov. Biochemical Pharmacology 80 (2010) 638–646

5. Targeted agents approved in mRCC
Two main types of targeted agents are approved for use in mRCC:
Angiogenesis inhibitors
Multi-targeted tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib)
Monoclonal antibodies (bevacizumab)
mTOR inhibitors
Temsirolimus
Everolimus
Two main types of targeted agents are approved for use in mRCC.
The majority of targeted agents are angiogenesis inhibitors. These fall into two classes: multi-targeted tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib); and monoclonal antibodies (bevacizumab).
The other class of targeted agent approved in mRCC are the mTOR inhibitors, temsirolimus and everolimus. These act on the regulatory protein known as mammalian target of rapamycin (mTOR).

6. Risk stratification
Risk stratification is important when selecting therapy
Memorial Sloan-Kettering Cancer Center criteria: adverse prognostic factors are
Good/favorable risk = none of these
Intermediate risk = 1 or 2 risk factors
Poor risk = 3 or more risk factors
High LDH (> 1.5 x uln)
< 1 yr from diagnosis to need for systemic therapy
High blood calcium (> 10 mg/dL corrected)
Poor performance status (KPS < 80%)
Anemia
Risk stratification is important when selecting the most appropriate therapy for patients with mRCC. Risk is assessed using the Memorial Sloan-Kettering Cancer Center criteria. The MSKCC criteria list five adverse prognostic factors:
raised LDH above 1.5 times the upper limit of normal
Blood calcium of over 10 mg/dL when corrected
Anemia
A period of less than 1 year from diagnosis to the need for systemic therapy
And poor performance status
Patients with none of these factors are classed as good risk, those with 1 or 2 factors are classed as intermediate risk and those with 3 or more factors as poor risk.

7. Treatment Algorithm for mRCC
Setting
Patients
Therapy
(Level 1 recommendation)
Other options
(≥ Level 2)
Untreated
Good or intermediate risk*
Sunitinib
Bevacizumab + IFN α
Pazopanib
HD IL-2, Sorafenib, Temsirolimus, Clinical trial, Observation
Poor risk*
Temsirolimus
Sunitinib, Clinical trial
Refractory
After
cytokine
Sorafenib
Temsirolimus, Bevacizumab, IFN or IL-2
VEGFr-TKI
Everolimus
Temsirolimus, sorafenib, sunitinib, bevacizumab, IFN, IL-2
mTOR
Clinical trial
Sunitinib
This is a treatment algorithm for mRCC based on current evidence, and which reflects the NCCN recommendations. We will first discuss initial therapy of patients who have not yet received any systemic treatment.
There are three level one recommendations for this group: sunitinib, bevacizumab + interferon alfa, and most recently pazopanib.
References
Motzer RJ et al NEJM 2007;356:
Motzer RJ et al J Clin Oncol 2009;27:
Escudier B et al. Lancet 2007;370:
Escudier B et al. J Clin Oncol 2009;27:abstr 5020
Sternberg C et al. J Clin Oncol 2010; 28:
Hawkins R et al. J Clin Oncol 2009;27 (15S):abstr 5110
Yang JC et al. J Clin Oncol 2003;21:
Szczylik C et al. J Clin Oncol 2007;25:abstr 5205
Hudes G et al. NEJM 2007;356:
Escudier B et al. NEJM 2007;356:
Escudier B et al. J Clin Oncol 2009; 27:
Motzer RJ et al. J Clin Oncol 2006; 24:16-24
Motzer RJ et al. JAMA 2006;295:
Sternberg C et al. J Clin Oncol 2009;27 (15S):abstr 5021
Motzer RJ et al. Lancet 2008;372:449-56
Motzer RJ et al. Cancer 2010; doi /cncr.25219
Adapted from Bukowski RM et al. J Clin Oncol 2006; 24: 222s. Abstract 4523.
Rini BI et al Presented at ASCO- GU Abstract 350.
*MSKCC criteria
NCCN Practice Guidelines in Oncology – Kidney Cancer v

8. Non-clear cell histology – 1st line therapy
Category 1 recommendations
Clinical trial (preferred)
Temsirolimus1 (poor prognosis patients)
Category 2A recommendations
Temsirolimus1 (good or intermediate risk patients)
Sorafenib2
Sunitinib3
Category 3 recommendations
Chemotherapy: gemcitabine or capecitabine or floxuridine or 5-FU
Chemotherapy: doxorubicin (sarcomatoid only)
There is little data comparing treatment outcomes in patients with non-clear cell histology.
Temsirolimus is the only agent that has shown activity in this group.
The NCCN recommends that patients with non-clear cell histology should be treated in clinical trials.
Temsirolimus is a category 1 recommendation in poor prognosis patients with non-clear cell mRCC. In patients with good or intermediate risk it is a category 2A recommendation. Other category 2 options for this group are sorafenib and sunitinib.
Hudes G et al. NEJM 2007;356:
Szczylik C et al. J Clin Oncol 2007;25:abstr 5205
Motzer RJ et al NEJM 2007;356:
NCCN Practice Guidelines in Oncology – Kidney Cancer v

9. mRCC – a rapidly evolving field
Knowledge about the optimal use of targeted agents is still evolving
Clinical trials continue to play an important role in clarifying optimal treatment for mRCC
Sequential treatment with targeted agents offers the possibility of extended survival
Questions remain regarding
The role of cytoreductive nephrectomy with targeted agents
The optimal role of individual agents
Optimal sequencing of targeted agents
Targeted agents are firmly established as the standard of care for mRCC, but our knowledge of how best to use them is still evolving. Clinical trials continue to play an important role in clarifying the optimal treatment.
One of the most exciting prospects is that sequential treatment with targeted agents may, for the first time, offer the possibility of extended survival for patients with mRCC.
There are still important questions remaining. The role of cytoreductive nephrectomy in the era of targeted agents is still being debated. More data is needed to assess the optimal role of different targeted agents in different clinical scenarios and patient groups.
Finally, more clinical trials are required to determine the optimal sequencing of targeted agents in order to maximise survival time.

10. Possible reasons to alternate therapy:
Cumulative toxicity
Overcome resistance

11. Possible reasons to alternate therapy:
Cumulative toxicity
Overcome resistance

12. Palmar-plantar erythrodysesthesia
induced by TKIs (Sunitinib, Sorafenib)
Mucositis and stomatitis
induced by TKIs

13. Cardiotoxicity with sunitinib: Hypothyroidism (up to 60%)
TKIs Inhibitors
Sunitinib & Sorafenib
Hypertension
Grade 3 or 4 (3%)
Cardiotoxicity with sunitinib:
11% of cardiovascular events
Congestive heart failure (8%)
Absolute LVEF reductions in ejection fraction
Fatigue
Hypothyroidism (up to 60%)

14. Thrombocytopenia Grade 3/4 (5.7%) Liver transaminase changes
TKIs Inhibitors
Sunitinib & Sorafenib
Thrombocytopenia Grade 3/4 (5.7%)
Liver transaminase changes
(Pazopanib)

15. Treatment-Related Adverse Events*
mTOR inhibitors
Treatment-Related Adverse Events*
Everolimus %, (n = 274)
Placebo %, (n = 137)
All Grades
Grade 3/4
Stomatitis 40
3/0 8
0/0
Rash 25
<1/0 4
Fatigue 20 16
Asthenia
Anemia 18
2/0
5/0 5
Diarrhea 17 3
Anorexia 6
Nausea 15
Mucosal inflammation
1/0 2
Pruritus 12
Dry Skin 11
* ≥ 10% of everolimus patients and additional selected AEs.

16. Pneumonitis with Everolimus Therapy
Baseline
Month 5
Everolimus %, (n = 274)
Placebo %, (n = 137)
All Grades
Grade 3/4
Vomiting 12
0/0 4
Cough
Edema peripheral 10 3
Infections (total)
2/1 2
Pneumonitis 8
3/<1
Dyspnea
2/0

17. Change in treatment choice due to toxicity Severe Thrombocytopenia
Cardiotoxicity
Pneumonitis
Liver toxicity
Severe Thrombocytopenia

18. Possible reasons to alternate therapy:
Cumulative toxicity
Overcome resistance

19. Mechanisms of Resistance
VEGF targeted therapy mTOR inhibition
* production of PDGF and bFGF * TORC2 is not inhibited
by tumors
*TGFb, HGF, angiopoetin, and ephrins ↑ Akt
↑ PI3K pathway
* Loss of PTEN

20. Rationale Combinations of Targeted Therapy ‘‘Horizontal blockade’’
where numerous target molecules
downstream from HIF-a are individually or jointly inhibited
In some phase I studies severe toxicity has been reported

21. Rationale Combinations of Targeted Therapy ‘‘Vertical blockade’’
the same pathway is targeted at
two or more different levels by two or more different agents

22. Phase II Trial of Bevacizumab and Everolimus in Patients
With Advanced Renal Cell Carcinoma
John D. Hainsworth, David R. Spigel, Howard A. Burris III, David Waterhouse, Bobby L. Clark,
and Robert Whorf
J Clin Oncol 28. © 2010 by American Society of Clinical Oncology
PFS: 9,1 vs 7,1 months
Objective response
Group A: 50 untreated 30 %
Group B: 30 previously treated 23% 22

23. Role of Surgery in Metastatic Renal Cell Carcinoma
● Nephrectomy
● Metastasectomy targeting NED
Before Medical Treatment
After best response to Medical Treatment
● “Palliative”

24. Can we can safely discontinue targeted agents in highly selected patients with
metastatic renal cell carcinoma who achieve a complete remission after targeted
therapy alone or with no evidence of disease (NED) following targeted therapy
and complete residual metastasectomy ?
Yes,
33,3% remained recurrence free at a median follow-up of 12 month
- sensitivity to the same agent (86,9%) is retained in this situation.
Johannsen et al, Annals of Oncology 2010

25. Should we Alternate therapy with VEGF inhibitors and
mTOR Inhibitors in metastatic Renal Cancer ? No
Do sequential Therapy: chose first line and second line according guidelines
Follow careful for toxicity (in some cases you have to stop or change therapies)
Explore the best benefit of each line,
consider metastases resection after response
It is possible to offer “drug Holidays” in selected cases

26. XIV WORKSHOP ON ONCOLOGICAL UROLOGY
Obrigado pela vossa atenção
Luis Costa, MD, PhD
Serviço de Oncologia – HSM-CHLN
Instituto de Medicina Molecular
Faculdade de Medicina de Lisboa

27. Backup slides

30. Category 1
After TKI:
Everolimus
After Cytokine Therapy:
Sunitinib
Sorafenib
Pazopanib

31. (following Tyrosine Kinase Inhibitor)
Everolimus
(following Tyrosine Kinase Inhibitor)

32. Baseline Characteristics:
Everolimus
Placebo
No. of patients
277
139
Median age, years (range)
61 (27-85)
60 (29-79)
% KPS, ≥ 90/≤ 80
64/36
68/32
% MSKCC risk1
Favorable/intermediate/poor
29/56/14
28/57/15
Sites of metastases, %
Lung 78 79
Bone 38 34
Liver 36 35
1. Motzer et al. J Clin Oncol. 2004;22:

33. Prior Therapies: Prior Treatment Everolimus (n = 277) %
Placebo (n = 139) %
Nephrectomy 96 95
Radiotherapy 31 28
VEGFr-TKI therapy
Sunitinib 46 44
Sorafenib 30
Both 26
Other systemic therapy
Interferon 50
Interleukin 2 22 24
Chemotherapy 13 16
Bevacizumab 9 10

34. Progression-Free Survival by Treatment Central Radiology Review
> 25 %

35. Progression-Free Survival by Treatment Prior Sunitinib
Central Radiology Review

36. Progression-Free Survival by Treatment Prior Sorafenib
Central Radiology Review

37. Subgroup Analysis of Progression-Free Survival Central Radiology Review

38. Maximum % Change in Target Lesions and Objective Response Rate*
100%
Everolimus
Placebo
75%
50%
25% 0%
−25%
Best Response n (%)
PR (2) Stable (67) PD (21) NE (11)
Best Response n (%)
PR Stable (32) PD (53) NE (14)
−50%
−75%
−100%
NE = not evaluable
* Central Radiology Review

39. Partial Response to Everolimus Therapy
Baseline
Month 4

40. Stable Disease to Everolimus Therapy
Baseline
Month 17

41. Pneumonitis with Everolimus Therapy
Baseline
Month 5
Month 11
Month 12

42. Overall Survival by Treatment

43. Prognostic factors for patients under treatment
Favorable: 0 risk factors
Intermediate: 1 or 2 risk factors
Poor: 3 to 6 risk factors
Favorable: 2 year OS is 75%
Intermediate: 2 year OS is 53%
(OS: 27 months)
Poor: 2 year OS is 7%
(OS: 8 months)

44. Evidence Based Medicine
NCCN Guidelines