1. Therapeutic Algorithm for Renal Cancer
Walter M. Stadler MD, FACP

2. Disclosures Consultant: Speakers Bureau:
Bayer, Caremark/CVS, Genentech, Johnson & Johnson, MedPacto, Merck Millenium, NCI/SAIC-Frederick, Sotio
Speakers Bureau:
CME providers (sponsorship unknown): Imedex, CME Innovations, CME Network, Dava Oncology, Research-to-Practice, Medical Communications Media,
Grant/Research Support (to institution):
Active Biotech, Bayer, Bristol-Myers-Squibb, Boerhinger-Ingelheim, Dendreon Exilixis, Novartis, Genentech (Roche), Glaxo-Smith-Kline, Merck, Medivation, Millenium (Astellas), Pfizer, NIH, Alliance
Stockholder:
None
Expert Witness
Miscellaneous/Editorial:
Cancer (ACS), BCAN, Demos Medical Publishing, KCA, Up-To-Date, Wolters-Kluwer

3. Pathology Clear cell (conventional) Papillary Chromophobe
Fuhrman grading 1-4
Papillary
Type 1 & 2
Mucinous-tubular and spindle?
Clear-cell papillary
Chromophobe
Genetically related to benign oncocytoma
Collecting duct
Genetically related to urothelial
Medullary (only in sickle cell trait or disease)
TFE-3 translocation tumor
Same translocation as alveolar-soft part sarcoma
More than one translocation
Renal Cancer|

4. Therapy: What we know Disease natural history is highly variable
Metastatic site ablative therapy has a role
Primary tumor resection has a role in low volume metastatic disease
Immunotherapy has activity
HD IL2 leads to dramatic and durable tumor responses in a very small minority of clear cell renal cancer patients
Immune checkpoint inhibitors are rapidly emerging as effective
VEGF pathway inhibitors slow disease progression in majority of clear cell renal cancer patients
Likely improve survival
mTOR inhibitors have modest anti-tumor activity
Survival improved in untreated poor prognosis patients

5. International prognostic modelβ SE
Square root of days from diagnosis to study entry
−0.0192
0.002
ECOG performance status 0
−1.524
0.11
ECOG performance status 1
−0.838
Number of metastatic sites
0.324
0.032
Protocol immunotherapy
−0.574
0.094
Natural log of hemoglobin
−2.47
0.20
Natural log of LDH
0.611
0.062
Square root of white blood count
0.623
0.071
1/Square root of alkaline phosphatase
−6.665
1.39
Serum calcium
0.105
0.033
Overall survival by risk category for the original data set (solid line) and validation data set (dashed line).
Manola J et al. Clin Cancer Res 2011;17:

6. Take Home Point 1
For asymptomatic metastatic patients with minimal burden of disease consider
Ablative therapy to render NED
Active surveillance

7. Treatment: HD IL2 Cytokine Working Group trial HD IL2 vs sc IL2/IFNA
HD IL2: 600,000 IU/kg q8o x 14 doses
sc IL2/IFNA: 5 x 106 IU/m2 4d/wk IL2; 5 x106 IU/m2 2d/wk
Selection criteria
Non-clear cell have minimal to no benefit
Suggestion that post-VEGFR TKI treatment has higher toxicity and lower efficacy
sc IL2/IFNA
HD IL2
Pt number 91 95
Deaths 1 CR 3
8 (p= 0.21) PR 6 14
Resp. Duration
15 mo
24 mo (p=0.18)
Med. Surv.
13 mo
17 mo (p = 0.21)
Durable 3 yr CR
7 (p=0.01)

8. Duration of Response (mo)
Nivolumab (anti-PD1) in renal caner
Population
Dose
(mg/kg)
Patients
(n)
ORR
n (%)
Duration of Response (mo)
SD 24 wk
PFSR at 24 wk
(%)
ALL RCC
1, 10 33
9 (27)
5.6+ to 22.3+ 56
RCC 1 17
4 (24)
5.6+ to17.5+ 47 10 16
5 (31)*
8.4 to 22.3+
5 (31) 67
*One CR.
Phase 3 vs everolimus completed accrual

9. RECIST 1.1 Response Rate (ORR)
MPDL3280A Phase 1a (anti-PDL1)
RECIST 1.1 Response Rate (ORR)
SD of 24 Weeks or Longer
24-Week PFS
Overall population (N = 140)
21%
16%
45%
RCC*
(n = 47)
13%
32%
53%
Clear cell (n = 40)
35%
57%
Non-clear cell (n = 6)
17%
20%
* 1 patient with unknown histology. Includes sarcomatoid and papillary RCC.
All patients first dosed prior to August 1, 2012; data cutoff February 1, 2013.
ORR includes unconfirmed PR/CR and confirmed PR/CR.
Cho, et al, ASCO 2013

10. Nivolumab + Ipilimumab
Hammers, et al, ASCO 2014
Renal Cancer|

11. Take home point 2
Consider HD IL2 first in patients with clear cell, good PS, and good cardiopulmonary reserve
Should be performed at center with experience
Utility in comparison to PD1 checkpoint inhibitors?
Investigational immunotherapy approaches are reasonable
Large number of phase 2 and phase 3 trials in process
Anti- PD1 pathway agents likely to enter armamentarium

12. Kinase interaction map
Sorafenib
Sunitinib
Karaman, et al Nature Biotech. 26:127, 2008

13. First line: Sunitinib vs IFNA
Total Death
Sunitinib 190
IFN-a 13

14. Motzer RJ et al. N Engl J Med 2013;369:722-731.
Kaplan–Meier Estimates of Progression-free Survival According to Independent Review.
First line:Sunitinib vs Pazopanib
Motzer RJ et al. N Engl J Med 2013;369:

15. Context of Definitive Trial(s)
VEGF Pathway inhibitors in renal cancer
Agent(s)
Context of Definitive Trial(s)
Comparator
No Prior Therapy
Prior IL2 or IFNA
Prior VEGF Pathway
Outcome
Bevacizumab/IFNA
IFNA X
PFS (bev)
Sunitinib
OS (sun)
Sorafenib
Placebo
PFS (sor)
Pazopanib
PFS (Paz)
Axitinib
PFS (Ax)
None
Tivozanib
OS (sor)
Dovitinib
X (and 1 prior mTOR)

16. VEGF pathway inhibitor toxicities
Cardiac (~73%)
Hypertension
Reversible Posterior Leukoencephalopathy MI
CVA
CHF
Integument
Hand/Foot
Mucositis
Diarrhea
Systemic
Fatigue
Dysgeusia
Metabolic
Liver toxicity
Hypothyroidism
The degree that patients experience these toxicities varies a little bit from one agent to the other but they're present in almost all of them.
Discuss when therapy might need to be discontinued.
Hall, et al. J Am Coll Cardiol HF, 2013

17. Take home point 3
There is no definitive data as to which VEGF pathway inhibitor to use first
Best evidence suggests pazopanib
Dose intensity probably matters
VEGF pathway inhibitors can be used sequentially
Is there an advantage to intermittent therapy?
Every drug company has at least one VEGFR inhibitor (The Lemming Principal)
There are pharmacologic, but minimal clinical differences between the agents

18. mTOR Inhibitors (The Lemming Principal Revisited)
Sirolimus (Rapamycin)
Temsirolimus
Everolimus (RAD001)

19. First line: Temsirolimus vs IFNA
Renal Cancer|

20. Second line: Everolimus vs Placebo
Renal Cancer|

21. Cross-over upon progression
Comparative and sequential data
Primary
PFS-1st line
Secondary
Combined PFS
ORR-1st line OS
Safety
Study endpoints
1 : 1 R A N D O M I Z
E**
Everolimus 10 mg/day
SCREEN
Sunitinib 50 mg/day***
1st Line
Everolimus 10 mg/day
Sunitinib 50 mg/day***
2nd Line
Cross-over upon progression
N = 471
*NCT **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.
Motzer, et al; ASCO 2013 21

22. Sunitinib versus everolimus sequential
Renal Cancer|

23. mTOR toxicities Metabolic Integument Systemic Infectious risks
Hyperglycemia
Hyperlipidemia
Increased creatinine
Integument
Diarrhea
Mucositis
Pruritic rash
Systemic
Fatigue
Edema
Pneumonitis
Infectious risks
Hematologic
Thrombocytopenia
Discuss how to handle side effects.
In particular, TP w and w/o symptoms
Issues in discontinuation

24. Context of Definitive Trial
mTOR inhibitors
Agent
Context of Definitive Trial
Comparator
No Prior Therapy
Prior VEGF Pathway
Outcome
Temsirolimus*
IFNA X
OS (tem)
Everolimus
Placebo
PFS (ev)
Temsirolimus
Sorafenib
OS (sor)
Sunitinib
OS (sun)
*Poor prognosis only, included non-clear cell

25. Take home point 4
It’s not clear where and when mTOR inhibitors should be used with best data as first line therapy in poor prognosis pts

26. Adjuvant therapy Large randomized placebo controlled phase 3 trials
Sorafenib, Sunitinib (ECOG ASSURE)
pT1b G3-4 N0 (or pNX where clinically N0) M0
pT2 G (any) N0 (or pNX where clinically N0) M0
pT3 G (any) N0 (or pNX where clinically N0) M0
pT4 G (any) N0 (or pNX where clinically N0) M0 or
T(any) G (any) N+(fully resected) M0
Pazopanib
Everolimus (in progress)
Renal Cancer|

27. ASSURE: Disease-Free Survival
Median 5.8 yrs
Median 6.0 yrs
Events
Patients
5-yr DFS
97.5% CI HR
Sunitinib
265
647
53.8%
49.0 – 59.1%
1.01
0.83 – 1.23
Sorafenib
272
649
52.8%
48.0 – 58.0%
0.98
0.81 – 1.19
Placebo
270
55.8%
51.2 – 60.9%
The DFS for sunitinib, sorafenib and placebo demonstrated very tightly overlapping kaplan meier curves with little separation. Median DFS for sunitinib is 70 months (5.83 years), for sorafenib is 69.7 months (5.81 years), for placebo is 72.4 months (6.03 years).
Presented by: Naomi B. Haas, MD

28. RCC Conclusions
VEGF pathway directed agents are active in clear cell RCC
Sunitinib, Pazopanib, Sorafenib, Axitinib and Bevacizumab/IFNA improve PFS
Pazopanib is first line reference standard
Sequential VEGF pathway directed therapy probably improves survival
mTOR inhibitors are active in RCC
Temsirolimus improves survival of poor prognosis RCC over IFNA
Everolimus improves PFS of RCC patients previously treated with a VEGFR inhibitor
Role of mTOR inhibitors is decreasing
Immunotherapy is active
HD-IL2 leads to long term complete responses, but only in ~5% of highly selected patients
PD1 pathway inhibitors likely to play a role