1. Emerging Role of Nivolumab in Advanced Renal Cell Carcinoma
Yu-Chieh Tsai, MD, PhD (蔡育傑)
Medical oncologist
Department of Oncology
National Taiwan University Hospital

2. Disclosure Honorarium (Speaker):
AstraZeneca, Astellas, BMS/Ono, Janssen, MSD,
Novartis, Pfizer, Roche, Sanofi　

3. Kidney Cancer : Global Overview
Globally
~338,000 new cases of kidney cancers were diagnosed in 2012 with ~143,000 deaths.
Unmet need:
Traditionally, renal cell carcinoma (the most common type of kidney cancer) is chemo-resistant and not responsive to systemic therapy.
World Cancer Reports (WHO)

4. Renal Cancer in Taiwan New case Renal Cell Ca. Histology Mortality
2003
628
545
459
2004
646
589
427
2005
733
657
488
2006
743
665
478
2007
798
720
522
2008
887
814
526
2009
937
847
468
2010
1,028
938
490
2011
1,044
954
2012
1,222
1,125
496
2013
1,228
1,144
2014
1,382
1,290
Cancer Registry Annual Report (Taiwan)

5. US FDA Approved Drugs for mRCC
Targeted therapy
Pazopanib
Sunitinib
Bevacizumab
Axitinib
Lenvatinib
1992~
Temsirolimus
Sorafenib
Cabozantinib
Everolimus
High dose interleukin-2
IFN-
Nivolumab
Immunotherapy

6. Cytokine Era ( )
Inspired by rare report of spontaneous regression of metastatic tumors
14% response rate (CR 5% + PR 9%) with durable responses in a small percentage of patients
Systemic toxicities
High dose interleukin-2
Motzer criteria
Fyfe et al J Clin Oncol. 1995
Motzer et al. J Clin Oncol. 1999

7. Targeted Therapy Era (2005-2012 )
Included 5 VEGF/VEGFR & 2 mTOR inhibitors
Most of them showed PFS benefit (except temsirolimus)
Overall response rates
- 1st line : 26~47%
- 2nd line (after TKI) : 2~19%
Median overall survival may reach 32.0 months in RECORD-3 randomized trial
Most patients ultimately develop resistance and few have durable disease control
Modified from Brugarolas J. N Engl J Med 2007

8. Most Targeted Therapy Trials Showed Benefit in PFS but not in OS
Drug
Control
Study Design
PFS, Mos
OS, Mos
VEGF Inhibitors
Sorafenib[1]
Placebo
Pts previously treated with IL-2 or IFN-α
5.5 vs 2.8
(HR: 0.44;
P < )
17.8 vs 15.2
(HR: 0.88; P = .146)
Axitinib[2]
Sorafenib
Pts previously treated with sunitinib, bevacizumab with IFN-α, temsirolimus, or cytokines
8.3 vs 5.7
(HR: 0.66; P < .0001)
20.1 vs 19.2
(HR: 0.97; P = .374)
mTOR inhibitors
Everolimus[3]
Pts previously treated with VEGFR TKI
4.9 vs 1.9
(HR: 0.33; P < .001)
14.8 vs 14.4
(HR: 0.87; P = .162)
Temsirolimus[4]
Pts previously treated with sunitinib
4.3 vs 3.9
(HR: 0.87; P = .19)
12.3 vs 16.6
(HR: 1.31; P = .01)
1. Escudier B, et al. J Clin Oncol. 2009;27: Motzer RJ, et al. Lancet Oncol. 2013;14: Motzer R, et al. Cancer. 2010;116: Hutson TE, et al. J Clin Oncol. 2014;32:

9. New Era (2015- ) Included 2 VEGFR TKI & 1 PD-1 inhibitor
2nd line trials. control: everolimus
Nivolumab & cabozantinib showed OS benefit
- mOS: 21.4~25 months
Lenvatinib + everolimus (phII) showed amazing PFS
- mPFS: 14.6 months
Overall response rates
- Cabozantinib : 21 %
- Lev+Eve : 43 %
Choueiri et al. N Engl J Med. 2017

10. Cancer Immunoediting
Schreiber et al. Science. 2011

11. Activation of T Cells Requires Two Signals
Sharma et al. Science. 2015

12. Mechanism of Immune checkpoint Inhibitors
Ribas A. N Engl J Med. 2012

13. mRCC : anti-CTLA-4 Therapy (ipilimumab)
(3mg/kg)
(Gr.3~5)
(3mg/kg -> 1mg/kg)
Yang et al. J Immunother. 2007

14. mRCC : anti-PD-L1 Therapy (atezolizumab)
(20.6 months)
(29.1 months)
Status of prior VEGF TKI
Phase Ia Study
For ccRCC p’t (n = 63)
- mOS: 28.9 months
- mPFS: 5.6 months
- ORR: 15%
For patients with Fuhrman grade4 and/or sarcomatoid histology ORR was 22% (n=18)
McDermott et al. J Clin Oncol. 2016

15. Restoring Active T-cell Response by PD-1 Inhibition
1. Normal Immune Response
2. Tumor Immune Evasion
3. Immune Response Restored
T-cell activation and tumor attack.
T-cell inactivation through the PD-1 immune checkpoint.
T-cell reactivation and decreased tumor growth* through PD-1 immune checkpoint inhibition. While having an effect on the tumor, this could also affect normal cells.
Opdivo＠ is a fully human IgG4 anti-PD-1 monoclonal antibody

16. mRCC: anti-PD-1 Therapy (nivolumab): CheckMate-025
Eligibility Criteria
aRCC with clear-cell component
KPS  70%
1-2 prior anti-angiogenic therapies
Progression within 6 months prior to enrollment
Nivolumab*
3 mg/kg IV every 2 weeks
Primary Endpoint: OS
Secondary Endpoints:
PFS
ORR
Duration of response
Safety
Survival by PD-L1 expression
N =
821
R ANDOM I S E 1:1
Everolimus*
10 mg/d orally
Stratification factors
Region
MSKCC risk group
No. of prior anti-angiogenic Tx
Patients were treated until progression or intolerable toxicity occurred
Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted

17. Demographic and Clinical Characteristics
Nivolumab Group (N=410)
Everolimus Group (N=411)
Median age (range) - yr
62 (23-88)
62 (18-86)
Sex - no. (%)
Male
315 (77)
304 (74)
Female
95 (23)
107 (26)
MSKCC risk group
- No. (%)
Favorable
145 (35)
148 (36)
Intermediate
201 (49)
203 (49)
Poor
64 (16)
60 (15)
Site of metastasis - No. (%)
Lung
278 (68)
273 (66)
Liver
100 (24)
87 (21)
Bone
76 (19)
70(17)
Motzer et al. N Engl J Med. 2015

18. Previous Treatment Characteristic Nivolumab Group (N=410)
Everolimus Group (N=411)
Previous nephrectomy
- no. (%)
Yes
364 (89)
359 (87) No
46 (11)
52 (13)
Median time from initial diagnosis to randomization (range) – mo
31 (1-392)
31 (2-372)
Previous antiangiogenic regimens - No. (%) 1
294 (72)
297 (72) 2
116 (28)
114 (28)
Previous systemic cancer therapy - No. (%)
Sunitinib
246 (60)
242 (59)
Pazopanib
119 (29)
131 (32)
Axitinib
51 (12)
50 (12)
Motzer et al. N Engl J Med. 2015

19. Nivolumab Achieved an Unprecedented Median OS of More Than 2 years
Escudier et al. Eur Urol. 2017
Median OS, months (95% CI)
Nivolumab
26.0 (22.2–29.6)
Everolimus
19.7 (17.6–22.3)
HR (95% CI)
0.73 (0.61–0.88) P =
Overall Survival (Probability)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 6 12 18
Months 24 30 36 42
76%
67%
52%
Nivolumab
42%
Everolimus 3 9 15 21 27 33 39
No. at risk
Nivolumab
Everolimus
410
359
305
251
204
129 38
411
325
268
214
162
103 32
390
337
276
225
171 80 5
367
289
247
183
130 61
Motzer et al. N Engl J Med. 2015; Plimack et al. 15th International Kidney Cancer Symposium 2016

20. Overall Survival by MSKCC Risk Group
Escudier et al. Eur Urol. 2017

21. Nivolumab Demonstrated Long-term OS Benefit
Atkins et al. Ann Oncol. 2017
McDermott et al. ASCO 2016 Abstract #4507

22. Progression-Free Survival: No significant Difference
Motzer et al. N Engl J Med. 2015

23. Objective Response Rate
Escudier et al. Eur Urol. 2017
Nivolumab Group (N=410)
Everolimus Group (N=411)
Objective response rate, %
103 (25%)
22 (5%)
Odds ratio; p value
5.98; p<0.001
Best overall response
Complete response
4 (1%)
2 (1%)
Partial response
99 (24%)
20 (5%)
Stable disease
141 (34%)
227 (55%)
Progressive disease
143 (35%)
114 (28%)
Not evaluated
23 (6%)
48 (12%)
Median time to response, months (range)
3.5( )
3.7( )
Median duration of response, months (range)
12.0 (0-27.6)
12.0 (0-22.2)
Motzer et al. N Engl J Med. 2015

24. Safety Data and irAEs CheckMate 025
McDermott et al. ASCO 2016 Abstract #4507

25. Safety and Adverse Events
Nivolumab Group (n = 406)
Everolimus Group (n =397)
Any Grade
Grade 3 or 4
All events
319 (79)
76 (19)
349 (88)
145 (37)
Fatigue
134 (33)
10 (2)
134 (34)
11 (3)
Nausea
57 (14)
1 (<1)
66 (17)
3 (1)
Diarrhea
50 (12)
5 (1)
84 (21)
Decreased appetite
48 (12)
2 (<1)
82 (21)
4 (1)
Rash
41 (10)
79 (20)
Cough
36 (9)
77 (19)
Anemia
32 (8)
7 (2)
94 (24)
31 (8)
Dyspnea
30 (7)
51 (13)
2 (1)
Peripheral edema
17 (4)
56 (14)
Pneuomnitis
16 (4)
6 (1)
58 (15)
Mucosal Inflammation
75 (19)
12 (3)
Dysgeusia
Hyperglycemia
9 (2)
46 (12)
15 (4)
Stomatitis
8 (2)
117 (29)
Hypertriglyceridemia
64 (16)
20 (5)
Epistaxis
Motzer et al.
N Engl J Med. 2015

26. Time to Onset and Resolution of Treatment-related Select AEs with Nivolumab
aTime to resolution is based on the time of onset of the AE (not at the start of treatment). + indicates a censored value
GI = gastrointestinal; NR = not reached
Plimack et al. 15th International Kidney Cancer Symposium 2016

27. Health Related Quality of Life (FKSI-DRS)4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
100
104
Time (week) -6 -4 -2 2 6
Numner at risk
Nivolumab group
EveArolimus group
361
343
334
316
302
270
267
219
236
191
208
157
186
143
164
122
159
102
144 97
132 87
119 74
112 73 63 90 58 89 49 81 35 30 59 53 21 43 15 31 26 9
Average amount of change from baseline (31.0 for both arm)
Everolimus group
The questionnaire consists of 9 symptom-specific questions that address lack of energy, pain, weight loss, bone pain, fatigue, dyspnea, cough, fevers, and hematuria.
Scoring range is form 0 to 36 (36 means no symptom)
FKSI-DRS：Functional Assessment of Cancer Therapy Kidney Symptom index – Disease-Related
Cella et al. Lancet Oncol. 2016

28. Other Considerations of CheckMate-025 1. Asian population 2
Other Considerations of CheckMate Asian population Treatment beyond progression Predictive biomarkers

29. CheckMate 025 in Japanese Patients: Antitumor activity
Tomita et al. Jpn J Clin Oncol. 2017

30. Treatment-related AEs Occurring in >15% of Japanese Patients
Tomita et al. Jpn J Clin Oncol. 2017

31. Treatment Beyond Progression in CheckMate 025
Escudier et al. ASCO 2016 Abstract #4509; Eur Urol. 2017

32. Treated Beyond Progression with Nivolumab: Benefit in Overall Survival
Escudier et al. ASCO 2016 Abstract #4509

33. Tumor Burden Change Post Progression
A total of 142 of 153 p’t treated with nivolumab beyond progression had tumor measurements
Of these 142 p’t, 14% (n=20) had  30% tumor burden reduction post-progression
A total of 52 of 56 p’t treated with everolimus beyond progression had tumor measurements
None of these 52 p’t had  30% tumor burden reduction post-progression
Escudier et al. ASCO 2016 Abstract #4509; Eur Urol. 2017

34. Robert S. Kerbel TJCC 2017

35. Overall Survival by Tumor PD-L1 Expression
Patients with qualifiable PD-L1 expression No. (%)
Nivolumab Group (370/410, 90%)
Everolimus Group (386/411, 94%)
 1%
94 (25)
87 (23)
<1%
276 (75)
299 (77)
5%
44 (12)
41 (11)
<5%
326 (88)
345 (89)
N Engl J Med. 2015; 373:

36. Estimate of the Neoantigen Repertoire
Nat Rev Cancer. 2017; 17:
Science. 2015; 348:69-74

37. Presented By Toni Choueiri at 2015 ASCO Annual Meeting
Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker correlations with clinical outcomes
Presented By Toni Choueiri at 2015 ASCO Annual Meeting

38. Summary and conclusions
Presented By Toni Choueiri at 2015 ASCO Annual Meeting

40. Therapeutic Evolution of mRCC Therapy
Hsieh et al. Nat Rev Dis Primers. 2017

41. First-Line Challengers: Ongoing Trials (1)
(IO+IO versus sunitinib)
IO: immuno-oncology
Laurence Albiges EAU 2017

42. Hypothetical Effect on OS of Blocking Two T-cell Checkpoint Pathways
The preliminary data of combining CTLA-4 and PD-1 blockade in mRCC were presented in ASCO 2014 (abstract #4504) & ASCO 2015 (abstract #4516)
Antonia et al. Clin Cancer Res. 2014

43. First-Line Challengers: Ongoing Trials (2)
(IO+TT versus sunitinib)
IO: immuno-oncology
TT: targeted therapy
Laurence Albiges EAU 2017

44. Robert S. Kerbel TJCC 2017

45. IMmotion 150 Phase II Study
RANDOMIZATION
Atezolizumab 1200 mg +
Bevacizumab 15mg/kg q3w
Locally advanced or metastatic RCC with clear cell and/or sarcomatoid component
Previously untreated with any systemic therapy
Crossover Tx permitted
Atezolizumab+Bevacizumab
Atezolizumab 1200mg q3w PD
Sunitinib 50mg
(4wk on, 2wk off)
Atezolizumab+Bevacizumab
N=305
1:1:1
Primary Endpoint : PFS
Secondary Endpoint : ORR, duration of response, OS, ..

46. Baseline Demographics
Thomas Powles ASCO GU 2017

47. Primary Endpoint: Progression-free Survival (ITT)
Thomas Powles ASCO GU 2017

48. IMmotion 150 Biomarkers: Angiogenesis
David McDermott AACR 2017

49. IMmotion 150 Biomarkers: Immune
David McDermott AACR 2017

50. IMmotion 150 Biomarkers: Myeloid Inflammation
David McDermott AACR 2017

51. First-Line Challengers: Ongoing Trials (3)
(IO+TT versus TT+TT versus sunitinib)
IO: immuno-oncology
TT: targeted therapy
Laurence Albiges EAU 2017

52. Lenvatinib and/or Everolimus in mRCC 2nd Line
(VEGFR / FGFR inhibitor)
Key eligibility criteria
Advanced or metastatic RCC
Measurable disease
Progression on/after 1 prior VEGF-targeted therapy
Progression within 9 mos of stopping prior treatment
ECOG PS ≤1 R A N D O M I Z T
LENVATINIB
18 mg PO qd +
EVEROLIMUS
5 mg PO qd
Primary objective
PFS (LEN ± EVE vs EVE)
Secondary objectives
PFS (LEN + EVE vs LEV)
ORR (RECIST v1.1) OS
Safety and tolerability (CTCAE v4.0)
LENVATINIB
24 mg PO qd
EVEROLIMUS
10 mg PO qd
Median PFS
Lenvatinib + everolimus:
14.6 months
Lenvatinib : 7.4 months
Everolimus: 5.5 months
Combo vs. Everolimus
-> HR 0·40; p=0·0005
Lancet Oncol. 2015; 16:

53. Take Home Message
In CheckMate 025 phase III study, Opdivo＠ (nivolumab) showed (compared with everolimus in mRCC 2nd line)
- Longer overall survival
- Better objective response rate
- Better health-related QoL
- Less treatment-related AE
Opdivo＠ (nivolumab) is well tolerated in Asian patients with mRCC.
Opdivo＠ (nivolumab) is approved in Taiwan to treat patients with mRCC whose disease progressed on an antiangiogenic therapy.

54. Case Presentation

55. Brief History A 77 y/o male patient, no major systemic disease
Left renal cancer, cT3bN0M1 with left renal vein and IVC thrombi, lung metastasis (+) s/p CT-guided biopsy on pathology reported clear cell RCC

56. Pazopanib / Sunitinb
Pazopanib 800mg daily was used on ~
Intermittent hematuria, not sure if drug-related
Sunitinib 50mg daily (2 weeks on /1 week off) since
-> shifted gradually to 37.5mg daily (9 days on /5 day off)
for better QoL
Hypertension, Gr.3, controlled with multiple drugs

57. Sunitinib

58. Nivolumab Ataxia in 2016.10 Nivolumab 3mg/kg every 2 weeks x 3 months
- Well tolerated, no treatment-related AE
1 month after Cyberknife

59. T-cell receptor sequencing
Presented By Toni Choueiri at 2015 ASCO Annual Meeting