1. Second-line Therapy and Beyond for Advanced Renal Cell Carcinoma
M. Dror Michaelson, MD, PhD Clinical Director, Genitourinary Cancer Center Associate Professor of Medicine Massachusetts General Hospital Cancer Center Boston, Massachusetts
This program is supported by educational grants from

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3. Faculty Disclosures
M. Dror Michaelson, MD, PhD, has no significant financial relationships to disclose.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

4. Case Study 1
66-yr-old woman presented with R hip pain; films demonstrated a lytic lesion
CT scans showed a 9-cm R renal mass, a 4-cm R iliac crest mass, and numerous subcentimeter lung nodules
Medical history of obesity, hemorrhoids, and trigeminal neuralgia; no medications, nonsmoker
Married with 4 children; no family history of RCC

5. Case Study 1 Cytoreductive nephrectomy showed clear-cell RCC
Following biopsy of R iliac crest, completed XRT course
Restaging showed increase in hip, lung, and mediastinal disease
Began sunitinib 50 mg on 4/2 schedule and reduced to 37.5 mg after second cycle due to intolerable skin toxicity
Restaging showed improvement at all sites
Continued skin toxicity; after 3 additional mos with SD, reduced further to 25 mg
Mild disease progression; escalated to 37.5 mg; after 3 interrupted mos, had further progression
RCC, Renal cell carcinoma; XRT, external beam radiation therapy

6. Case Study 1: Question
This patient has radiographic progression on first-line reduced-dose sunitinib. What systemic therapy would you select at this time?
IFN, interferon

7. Timeline of Development of Targeted Agents for RCC
Sunitinib (advanced RCC)
Axitinib (advanced RCC after failure of 1 systemic therapy)
Pazopanib (advanced RCC)
Bevacizumab + IFN-α (metastatic RCC)
VEGF pathway
inhibitors
Sorafenib [advanced RCC]
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
2012
2013
2014
2015
Immunotherapy with IFN-α or IL-2
IFN-a, interferon alpha; IL-2, interleukin 2; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor
mTOR inhibitors
Temsirolimus (advanced RCC)
Everolimus (advanced RCC after failure of sorafenib or sunitinib)
US Food and Drug Administration.

8. NCCN Recommendations for Treatment of Clear-Cell RCC
Treatment Option
NCCN Recommendation
First Line
Second Line
VEGF Inhibitors
Sorafenib
Selected patients
Following cytokine (category 1)
Following TKI (category 2A)
Sunitinib
Advanced RCC
(category 1)
Pazopanib
Following TKI (category 3)
Axitinib
After cytokines or TKI (category 1)
Bevacizumab
Following cytokine (category 2A)
Following TKI (category 2B)
mTORs
Temsirolimus
Poor prognosis (category 1)
Favorable, intermediate prognosis (category 2B)
Everolimus
Following TKI (category 1)
Cytokines
IL-2
Selected patients (category 2A)
Category 2B
IL-2, interleukin 2; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network; RCC, renal cell carcinoma; TKI, Tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor
NCCN. Clinical practice guidelines in oncology: kidney cancer. v

9. Pivotal Phase III Data in Second Line
Drug
Control
Study Design
ORR, %
PFS, Mos
OS, Mos
VEGF Inhibitors
Sorafenib[1,2]
Placebo
Randomized 1:1; patients previously treated with
IL-2 or IFN-α
10 vs 2
(P < .001)
5.5 vs 2.8
(HR: 0.44; P < .01)
17.8 vs 15.2
(HR: 0.88; P = .146)
(17.8 vs 14.3‡;
HR: 0.78; P = .029)
Axitinib[3]
Sorafenib
Randomized 1:1; patients previously treated with sunitinib, bevacizumab with IFN-α, temsirolimus, or cytokines
19 vs 9
(P = .0001)
6.7 vs 4.7
(HR: 0.665; P < .0001)
20.1 vs 19.2
(HR: 0.969; P = .374)
mTORi
Everolimus[4]
Randomized 2:1; patients previously treated with VEGFR TKI
2.0 vs 0
4.9 vs 1.9* (HR: 0.33; P < .001)*
5.5 vs 1.9† (HR: 0.32; P < .001)†
14.8 vs 14.4
(HR: 0.87; P = .162)
HR, hazard ratio; IF- or IFN- , interferon alpha; IL-2, interleukin 2; mTORi, mammalian target of rapamycin inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor
*Independent review. †Investigator. ‡Post-crossover placebo-censored OS data.
1. Escudier B, et al. N Engl J Med. 2007;356: Escudier B, et al. J Clin Oncol. 2009;27: Rini BI, et al. Lancet. 2011;378: Motzer R, et al. Cancer. 2010;116:

10. AXIS Trial: Axitinib Superior to Sorafenib in Second-line mRCC Therapy
1.0
Median PFS, Mos (95% CI) 6.7 ( ) 4.7 ( )
0.9
Axitinib Sorafenib
0.8
0.7
Stratified HR: (95% CI: ; P < .0001)
0.6
Probability of PFS
0.5
0.4
0.3
0.2
0.1
CI, confidence interval; HR, hazard ratio 2 4 6 8 10 12 14 16 18 20
Months
Pts at Risk, n Axitinib Sorafenib
96 51
64 28
38 12
20 6
10 3
1 1
0 0
Rini BI, et al. Lancet. 2011;378:

11. RECORD-1: Everolimus (RAD001) in mRCC
Placebo (n = 138)
Patients with mRCC following failure of VEGFR therapy, clear-cell histology, previous therapy with sunitinib or sorafenib within 6 mos, Karnofsky PS ≥ 70
R A N D O M I Z A T I O N
Everolimus (RAD001) 10 mg QD (n = 272)
QD, per day; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor
Reference
Escudier B, Szczylik C, Eisen T, et al. Randomized Phase III Trial of The Multi-kinase Inhibitor Sorafenib (BAY ) in Patients With Advanced RCC. Paper presented at: The European Cancer Conference; October 30-November 3, 2005; Paris, France.
Primary endpoint: PFS(central review)
Secondary endpoints: safety, response rates, OS, QoL
Motzer RJ, et al. Lancet. 2008;372:

12. Progression-Free Survival
100
Median PFS, Mos Everolimus: 4.0 Placebo: 1.9
P < .0001 80 60
Probability of PFS (%) 40 20
PFS, Progression free survival
Everolimus Placebo 2 4 6 8 10 12
Mos
Pts at Risk, n Everolimus Placebo
132 32
47 4
8 1
2 0
0 0
0 0
Motzer RJ, et al. Lancet. 2008;372:

13. INTORSECT Study Design
Patients with mRCC and PD on first-line sunitinib (N = 512)
Stratification factors:
Duration of sunitinib therapy (≤ or > 6 mos)
MSKCC risk group
Histology (clear cell or non–clear cell)
Nephrectomy status
RANDOMIZE
Temsirolimus 25 mg IV weekly* (n = 259)
Primary endpoint: PFS (per IRC)
Sorafenib 400 mg oral BID* (n = 253)
BID, twice daily; IRC, independent review committee; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan Kettering Cancer Center; PD, progressive disease; PFS, progression-free survival.
Treat until PD, unacceptable toxicity, or discontinuation for any other reason
1:1
*Dose reductions were allowed: temsirolimus (to 20 mg, then 15 mg), sorafenib (to 400 mg/day, then every other day).
ClinicalTrials.gov. NCT

14. PFS (IRC Assessment) 1.0 0.9 Median PFS, Mos (95% CI) 0.8 Temsirolimus
4.28 ( )
0.7
Sorafenib
3.91 ( )
0.6
Probability of PFS
0.5
Stratified HR: 0.87 (95% CI: ; log rank P = .1933)
0.4
0.3
0.2
CI, confidence interval; HR, hazard ratio; IRC, internal review committee; PFS, progression-free survival.
0.1 5 10 15 20 25
Mos
Pts at Risk, n
Sorafenib
252 72 22 11 6
Temsirolimus
259 96 28 9 5
Hutson T, et al. ESMO Abstract LBA22.

15. Overall Survival 1.0 0.9 Median OS, Mos (95% CI) 0.8 Temsirolimus
12.27 ( )
0.7
Sorafenib
16.64 ( )
0.6
Probability of OS
0.5
Stratified HR: 1.31 (95% CI: ; log rank P = .014)
0.4
0.3
0.2
CI, confidence interval; HR, hazard ratio; OS, overall survival.
0.1 10 20 30 40 50
Mos
Pts at Risk, n
Sorafenib
253
158 74 34 13
Temsirolimus
259
132 54 22 8
Hutson T, et al. ESMO Abstract LBA22.

16. OS by Duration of Previous Sunitinib (ITT Population)
Previous Sunitinib Use
Temsirolimus (n = 259)
Sorafenib (n = 253)
HR (95% CI)
P Value*
< 90 days, n (%) Median OS, mos (95% CI)
38 (15) 8.0 ( )
29 (12) ( )
( )
.708
days, n (%) Median OS, mos (95% CI)
99 (38) ( )
97 (38) ( )
( )
.096
> 270 days, n (%) Median OS, mos (95% CI)
121 (47) ( )
126 (50) ( )
( )
.036
*Unstratified log rank test.
HR, hazard ratio; TKI, tyrosine kinase inhibitor; ITT, intention to treat (?); OS, overall survival.
Longer time on first-line TKI predicts for greater benefit from second-line TKI
Hutson T, et al. ESMO Abstract LBA22.

17. Case Study 2 77-yr-old man underwent CT scan due to L flank pain
Scans showed a 7-cm L renal mass and multiple lung nodules up to 1.2 cm
Medical history of HTN and nephrolithiasis; on amlodipine, metoprolol, and aspirin
Retired oral surgeon; nonsmoker
No family history of RCC
aaaaaa
HTN, hypertension; RCC, renal cell carcinoma; L, left

18. Case Study 2
Cytoreductive nephrectomy showed clear-cell RCC, grade 4/4
Scans 9 mos later showed increase in lung nodules, new mediastinal and hilar adenopathy, and new liver metastases
Began sunitinib 37.5 mg; scans after 2 cycles showed SD
Struggled with fatigue, diarrhea, malaise, rash; admitted with dehydration after cycle 3
Resumed treatment after 3-wk break; scans after 2 more cycles showed disease progression in liver
RCC, renal cell carcinoma

19. Case Study 2: Question 3
Radiographic progression on frontline TKI has been demonstrated. What would you recommend at this time?

20. Case Study 2: Question 5
After 8 mos on everolimus, he develops R facial droop and slurred speech that resolve after 5 mins. MRI as shown. Restaging scans show improvement in lung and liver metastases. Following SRS, what would you recommend?
MRI, magnetic resonance imaging; SRS, stereotactic radiosurgery (?)
He remains on everolimus 14 mos later with SD and no toxicity other than grade 1 pneumonitis

21. Second-line Post-TKI Results
Agent
PFS, Mos
OS, Mos
Comments
Everolimus
4.9 (5.4 in second line only)
14.8
Second and third line
Temsirolimus
4.3
12.3
Shorter OS than sorafenib
Axitinib
4.8
15.2
Substantially higher in non-sunitinib subgroups
Sorafenib
3.4 (AXIS) 3.9 (INTORSECT)
16.5 (AXIS) (INTORSECT)
Consistent low PFS but high OS results
Placebo
1.9
14.4
80% crossover to everolimus (5.0 mos PFS)
Motzer RJ, et al. Cancer. 2010;116:
Rini et al, Lancet Oncology. 2011;378:
Hutson T, et al. ESMO Abstract LBA22.
Motzer RJ, et al. Cancer. 2010;116: Rini et al, Lancet Oncology. 2011;378: Hutson T, et al. ESMO Abstract LBA22.

22. PERCY Quattro Trial in mRCC: OS
1.0
Median OS, Mos
0.9
MPA
14.9
0.8
IFN
15.2
0.7
IL-2
15.3
0.6
IFN + IL-2
16.8
Survival (%)
0.5
0.4
0.3
0.2
Reference
Negrier S, for the French Immunotherapy Intergroup. Results of randomized trial PERCY Quattro in patients with metastatic renal cell carcinoma of intermediate prognosis. Paper presented at: ASCO; May 13-17, 2005; Orlando, FL.
0.1 8 12 18 24 30 36 42 48
Mos From Randomization
492 pts enrolled Primarily intermediate risk Negrier S, et al. Cancer. 2007;110:

23. Current Management of Advanced RCC
First-line Therapy
Second-line Therapy
Favorable risk
Sunitinib
or pazopanib
(or other TKI)
Everolimus
or axitinib
(or TKI, temsirolimus, bevacizumab)
Intermediate risk
Poor risk
Temsirolimus
Unknown
((sunitinib, clinical trial, supportive care)
NCCN. Clinical practice guidelines in oncology: kidney cancer. v

24. Second-line Trials to Watch
Phase III BMS (anti-PD1) vs everolimus
Phase III cabozantinib (XL184) vs everolimus
Phase III dovitinib vs sorafenib (completed, third line)
Phase III everolimus with or without bevacizumab (CALGB, closed)

25. Conclusions
Both VEGF and mTOR-directed drugs have important activity in second-line treatment of RCC
OS for RCC is clearly longer than historical controls
Predictive factors of response have not been defined
Mechanisms of resistance to VEGFR and mTOR therapy remain poorly understood
Clinical trial enrollment remains an important priority for RCC patients
mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.

26. Go Online for More RCC Education!
ClinicalThought™: Expert faculty members describe how they tackle challenging clinical decisions in renal cell carcinoma Expert Insight Into Optimal Treatment for Individuals With Advanced Renal Cell Cancer Research Focus: MET Pathway and MET-Inhibiting Anticancer Agents
clinicaloptions.com/oncology