treatment paradigm shift of m RCC IN 2021

1. Treatment paradigm shift in
management of advanced/
metastatic RCC
Presented by :
Ass. Lecturer : HebatAllah Mahmoud Bakri
AUH
JAN- 2021

2. Agenda : 1st part rapid look
- Epidemiology
- Pathology and its relation to survival
- Causes ( genetics ) & risk factors
- clinical picture
- Staging , risk stratification and its relation to survival
- Treatment of RCC in the adjuvant setting

3. Agenda 2nd part : to answer the following
questions
• Is there a role of nephrectomy in m.Rcc ??
• Are we dare enough to put m.RCC patient on active surveillance ??
• Is there any difference between TKIs in 1st line in m.RCC ?
• What are 2nd options in refractory or relapsed m.RCC ??

4. Agenda 3rd part : 2020 hope
• Imm.oncology in m.RCC is it a new standard of care ???
• ESMO & ASCO GU updates in 2020 -----
• Wrap up and conclusion

6. Epidemiology
• (RCC) accounts for 3% of adult solid tumors with growing incidence in
recent decades.
• More than 25% of patients metastatic disease at the time of
diagnosis and about 20–30% will develop metastases during follow
up after surgery for localized disease

8. Causes of kidney cancer
• We don’t know the full story , but we understand a few pieces of the
puzzle, especially for more common forms of the disease.
• In most cases, kidney cancer begins when there are mutations in
certain genes that normally keep cell division in check.
For example, people with clear cell renal cell carcinoma often have a
mutation that causes extra blood vessels to grow inside the kidney.

9. • Most kidney cancer patients acquire these mutations over their
lifetime, meaning they’re born with perfectly healthy genes
• Notably, these changes usually occur in conjunction with other factors
before cancer shows up.

10. • Other people inherit certain conditions .
Here are a few of those inherited disorders:
• Von Hippel-Lindau disease
• Hereditary papillary renal carcinoma
• Birt Hogg-Dubé (BHD)
• Hereditary leiomyoma (HLRCC)
• Succinate dehydrogenase deficiency
• Tuberous sclerosis
• PTEN hamartoma tumor syndrome (including Cowden syndrome)

11. When to consider genetic counselling ?
• If patient is diagnosed before 47 y.o
• If tumors on both kidneys
• If patient have a family history of kidney cancer
• If the patient have any of the previous inherited diseases

12. Risk factors of kidney cancer
• male sex : 60 % cases are male
• Age > 55
• Habit : smoking increase risk 20 %
• Wight : obesity increase risk 20 – 30 %
• Disaeses : High Blood Pressure – Chronic Kidney Diseases .

13. Symptoms and signs

14. Pathological subtypes of RCC :

16. TNM staging 8th edition

17. Stage and survival
• Stage I – Survival more than 90 percent
• Stage II – between 75 to 95 percent
• Stage III – between 60 to 90 percent depending on
nephrectomy status and size of tumor
• Stage IV – Median survival between 28 to 30 months, which
varies according to risk group

18. Risk stratification

19. Heng. JCO. 2009;27:5794.
IMDC Prognostic Criteria
 Favorable:
0 risk factors
 Intermediate:
1-2 risk factors
 Poor:
3+ risk factors
Mos Since Therapy Initiation
OS
(%)
0
20
40
60
80
100
0 12 24 36 48 60
No. of Events/No. at Risk
Favorable
Intermediate
Poor
11/133
61/301
94/152
16/110
50/182
19/36
4/62
17/82
1/3
2/22
2/18
0/1
0/3
0/3
0/0
Favorable
Intermediate
Poor

20. Treatment options in RCC

21. Summary of phase 3 adjuvant trials in RCC

23. Agenda 2nd part : to answer the following
questions
• Is there a role of nephrectomy in m.Rcc ??
• Are we dare enough to put m.RCC patient on active surveillance ??
• Is there any difference between TKIs in 1st line in m.RCC ?
• What are 2nd options in refractory or relapsed m.RCC ??

24. 2nd part
Prof. Roberts.J.Mortez
MSKCC
Prof . Toni Choueiri
Harvard school of
medicine
Brian I Rini,
Cleveland Clinic Lerner
College of Medicine.

25. 1- Is there a role of nephrectomy and
metastatectomy in m.RCC ???

27. CARMENA: Prospective, Multicenter, Open-Label,
Randomized Phase III Noninferiority Study
 Primary endpoint: OS
 Secondary endpoints: PFS, ORR (RECIST v1.1), clinical benefit, safety
Follow-up for
minimum of 2 yrs
Nephrectomy
(n = 226)
Sunitinib 50 mg QD† 4 wks on/2 wks off
(n = 224)
Confirmed metastatic clear-cell RCC/biopsy;
ECOG PS 0/1;
amenable to nephrectomy
eligible for sunitinib;
brain metastases absent/controlled by treatment;
no prior systemic therapy for RCC
(N = 450) *
Stratified by center, MSKCC risk group (intermediate vs high risk)
*114 patients versus 115 received other lines of therapy in each group, respectively
†Dose reductions/interruptions allowed for managing AEs.
Sunitinib 50 mg QD*
4 wks on/2 wks off
(n = 226)
3-6 wks
Méjean. NEJM. 2018;379:417

29. No statistically significant differences in OS or PFS Median OS
was 18.4 mos in sunitinib group vs 13.9 mos in nephrectomy

30. Conclusion
 Sunitinib alone is non inferior to cytoreductive nephrectomy followed
by sunitinib for overall survival, both in intermediate and poor risk
patients with metastatic RCC
 Clinical benefit was also significantly better in the sunitinib alone arm
 Cytoreductive nephrectomy should no longer be considered standard
of care in intermediate and poor risk MSKCC groups of metastatic RCC,
at least when medical treatment is required

31. Drawbacks of CARMENA
1- Possible patient selection bias
• 43% of the patients had poor-risk disease and the remaining patients
had intermediate-risk disease.
• nephrectomy group had a higher percentage of locally advanced tumors
of stage T3 or T4 than the sunitinib group (70.1% vs. 51.0%)
2- Inconsistent outcomes versus other trials
median overall survival was 18.4 months (95% CI, 14.7 to 23.0) in the
sunitinib-alone group but Other trials report median 21-26 months
sunitinib alone.

32. 3- Significant patient attrition
• Nephrectomy–sunitinib group :
a) 40 patients [17.7%] did not receive sunitinib
b) 16 [7.1%] did not undergo nephrectomy
• Sunitinib-alone group :
a) 11 patients [4.9%] did not receive sunitinib
b) 38 [17.0%] underwent delayed nephrectomy
c) Median of 11mos from randomization?!?

33. Considerations for Nephrectomy

34. 2- Is there a role of active surveillance in
m. RCC ?????

35. Prospective, Phase II Observational Study in Patients
With Asymptomatic Metastatic RCC
Initiation of
systemic
treatment
per doctor/
patient
discretion
CT every 3 mos in Yr 1, every 4 mos in Yr 2,
then every 6 mos
 FKSI-DRS (QoL) and HADS (anxiety/depression) assessments
administered at baseline and at every CT scan timepoint
 Peripheral blood for immune cell quantification drawn at
baseline and at every CT scan time point
Rini. Lancet Oncol. 2016;17:1317.
 Patients with clinically evident metastatic
RCC of any histologic subtype (N = 48)
 First documentation (radiographic or
histologic) of metastatic RCC up to 12
months prior to registration on study
 No prior systemic therapy for RCC in the
metastatic or neo/adjuvant setting
 Prior XRT (including for CNS metastases)
and prior nephrectomy/metastasectomy
permitted but not required
 No disease-related symptoms
 Measurable/evaluable disease per
RECIST v1.0

39. The Argument for Active Surveillance
 done In selected patients (favorable risk) active surveillance to :
‒ Avoids the certain toxicity of systemic therapy
‒ No clearly the benefit of therapy when initiated
 NCCN Guidelines list active surveillance as “useful in certain
circumstances” (2A)
 The selection and outcomes of patients undergoing active surveillance
for mRCC have not been well described

40. 3- How to choose 1st line anti VEGF
in m.RCC ?? Case study

43. What to do next regarding 1st line setting ?
 1- start sunitinib
 2- start pazobanib
 3- start INF + bevacizumab
 4- start sorafinib
 5- uncertain

45. 1st
2nd

54. 800 m.g daily
50 m.g 4wks on + 2 wks off

57. 4- what are options after TKI ??

72. Back to our patient :
m.PFS : 5m
No OS
m. PFS : 7 m
No OS
No m.PFS
m.OS : 25
m.PFS : 7m
m OS : 21 m
m.PFS : 14 m
m.OS : 25m

73. Before era of IO in 1st line

74. Dose : 5m.g BID
3m.g / kg every 2 wks

75. If combined with evrolimus :
18 m.g + evrolimus m.g once
If alone :
24 m.g daily
• Is there a role of nephrectomy in m.Rcc
?? Yes in good PS and limited extra
renal disease
• Are we dare enough to put m.RCC
patient on active surveillance ?? Yes in
favorable risk with no benefit of
starting ttt
• Is there any difference between TKIs in
1st line in m.RCC ? Nooo
• What are 2nd options in refractory or
relapsed m.RCC ?? Many acc .
Avialbility

77. Agenda 3rd part : 2020 hope
• Imm.oncology in m.RCC is it a new standard of care ???
• ESMO & ASCO GU updates in 2020 -----
• Wrap up and conclusion

78. PD-1 is expressed on activated T cells and when it binds to its ligand PD-L1 on tumor cells leads to T
cell exhaustion.
CTLA-4 competes with CD28 (costimulatory T cell molecule) for B7 ligands (CD80 and CD86 that are
not shown in the figure) and upon activation decreases T cell proliferation as well as activity.
Blockade of CTLA-4 (by anti-CTLA-4) and PD-1 (anti-PD-1) or PD-L1 stimulates effector T cells to
produce antitumor responses

79. case study
• Female 70 y PS 0 8/2017 underwent nephrectomy with no adj ttt
observation For 1 y ( ccRCC T2N0MO GR 2)
• 8/2018 : App. Of lung nodules but were not much burden by RECIST
criteria
• so kept on active surveillance 1.5 yr
• 2/2020 on routine follow up :
DP lung nodules and hilar with retroperitoneal LND
Biopsy lung nodules : same renal pathology

80. What are Options for Subsequent Management?
‒ VEGFR TKI monotherapy
‒ Combination immunotherapy (CTLA-4/PD-1)
‒ Combination VEGFR/PD-1 therapy

81. Frontline RCC Therapy: 1st line Recent Phase III Trials in
2020 vs SOC (SUNITINIB)
 CheckMate 214: Ipilimumab/nivolumab vs sunitinib (OS benefit)
 KEYNOTE-426: Pembrolizumab/axitinib vs sunitinib (OS benefit)
 Others:
‒ Avelumab/axitinib vs sunitinib (PFS benefit, FDA approved)
‒ Atezolizumab/bevacizumab vs sunitinib (PFS benefit, NO OS )
‒ Pembrolizumab/lenvatinib vs sunitinib (completed waiting result )
‒ Nivolumab/cabozantinib vs sunitinib (completed, reported in ESMO
2020)

82. 1- CheckMate 214: Nivolumab + Ipilimumab vs Sunitinib
for Untreated Advanced RCC
 Endpoints: ORR, PFS, OS and incidence of AEs
 Grade 3/4 AEs: Nivo + Ipi, 46% (22% discontinued) and sunitinib, 63% (12% discontinued)
Patients with previously
untreated advanced clear-
cell RCC, Karnofsky PS
≥ 70, without brain mets or
autoimmune disease, with
measurable disease by
RECIST 1.1 criteria
(N = 1096)
Nivolumab
3 mg/kg IV +
Ipilimumab
1 mg/kg IV every
3 wks
x 4 doses
(n = 550)
Sunitinib 50 mg PO x 4 wks with cycles
repeated every 6 wks
(n = 546)
Stratified by IMDC risk score
(0 vs 1-2 vs 3-6), region (US
vs Canada/W Europe/N
Europe vs rest of world) Nivolumab
maintenance 3
mg/kg every 3
wks
Motzer. NEJM. 2018;378:1277.

83. OS, PFS and Response By Subgroup
Slide credit: clinicaloptions.com
Co-Primary Endpoints Secondary Endpoints Exploratory Analysis
Outcome
Intermediate/Poor Risk (n = 847) ITT (N = 1096) Favorable Risk (n = 249)
Nivo + Ipi
(n = 425)
Sunitinib
(n = 422)
Nivo + Ipi
(n = 550)
Sunitinib
(n = 546)
Nivo + Ipi
(n = 125)
Sunitinib
(n = 124)
ORR, %
(95% CI)
42 27 39 32 29 52
P < .001 P = .02 P < .001
Median
PFS, mos
(95% CI)
11.6
(8.7-15.5)
8.4
(7.0-10.8)
12.4
(9.9 to 16.5)
12.3
(9.8 to 15.2)
15.3
(9.7 to 20.3)
25.1
(20.9-NE)
HR: 0.82 (99.1%: 0.64-1.05)
P = .03
HR: 0.98 (99.1%: 0.79-1.23)
P = .85
HR: 2.18 (99.1% CI: 1.29-3.68)
P < .001
Median OS,
mos
(95% CI)
NR
(28.2-NE)
26.0
(22.1-NE)
NR 32.9 NR
32.9
(95% CI: NE)
HR: 0.63 (99.8%: 0.44-0.89)
P < .001
HR: 0.68 (99.8%: 0.49-0.95)
P < .001
HR: 1.45 (99.8% CI: 0.51-4.12)
P = .27
Motzer. NEJM. 2018;378:1277.

84. OS in Intermediate-/Poor-Risk Patients
Slide credit: clinicaloptions.com
Motzer. NEJM. 2018;378:1277.
OS among IMDC Intermediate-Risk and Poor-Risk Patients
3 6 12
9 15
Mos
18 21 24 27 30 33
Patients at Risk, n
Nivolumab 425 399 372 348 332 318 300 241 119 44 2 0
422 387 352 315 288 253 225 179 89 34 3 0
Sunitinib
20
40
60
80
100
OS
(%)
0
0
Nivolumab + ipilimumab
Sunitinib
425
422
NR (28.2-NE)
26.0 (22.1-NE)
Patients,
n
Median, Mos
(95% CI)
HR for death: 0.63 (99.8% CI: 0.44-0.89;
P < .001)
Nivolumab + ipilimumab
Sunitinib
Nivolumab +
ipilimumab
Sunitinib
12-Mo OS
(95% CI)
18-Mo OS
(95% CI)
80 (76-84)
72 (67-76)
75 (70-78)
60 (55-65)
FDA Approval on
18/4/2018 :
Nivolumab +
ipilimumab as
combination
treatment of
intermediate or poor
risk, previously
untreated RCC

85. Main Conclusions
 “This trial showed an efficacy and overall survival benefit of nivolumab
plus ipilimumab over sunitinib in the first-line treatment of
intermediate-risk or poor-risk advanced clear-cell renal cell carcinoma”
 The incidence of grade 3/4 adverse events of ipilimumab/nivolumab
was less than sunitinib (47% vs 64%)
 This study changed practice patterns in RCC

86.  Open-label, phase 3 trial
 Co-primary endpoint: OS and PFS in the ITT population
 Secondary endpoints: ORR
Patients with newly diagnosed/recurrent
stage IV ccRCC, no prior systemic treatment for
advanced disease, Karnofsky PS ≥ 70, measurable
disease (RECIST v1.1), with tumor sample for
biomarker evaluation, adequate organ function
(N = 861)
Axitinib 5 mg orally twice daily +
Pembrolizumab 200 mg IV once every 3 weeks
for up to 35 cycles
(n = 432)
Sunitinib 50 mg orally once daily x the first 4
weeks of a 6-week cycle
(n = 429)
Stratified by IMDC risk group (0 vs
1-2 vs 3-6), region (N America vs
W Europe vs rest of world)
2- KEYNOTE-426: Pembrolizumab + Axitinib in
Treatment-Naive Advanced RCC
Rini. NEJM 2019;380:1116.

87. PFS in ITT Population
OS in ITT Population
UPDATED AT ASCO GU 2019
Median PFS, Mos (95% CI)
Pembrolizumab + axitinib: 15.1 (12.6-17.7)
Sunitinib: 11.1 (8.7-12.5)
PFS
(%)
Mos
20
40
60
80
0
16
42
29
0
432
429
2 4
357
302
6 8
251
193
10 12
140
89
14 18 20
3
1
22 24
0
0
100
Patients at Risk, n
59.6%
46.2%
41.1%
32.9%
89.9%
78.3%
82.3%
72.1%
HR: 0.69 (95% CI: 0.57-0.84; P < .001)
Median OS, Mos
Pembrolizumab + axitinib: NR
Sunitinib: NR
HR: 0.53 (95% CI: 0.38-0.74; P < .0001)
OS
(%)
Mos
20
40
60
80
100
0
16
136
110
0
432
429
4
417
401
8
378
341
12
256
211
20
18
20
24
0
0
Patients at Risk, n

88. Response (ITT)
*Nominal P value. †Postbaseline assessment not evaluable. ‡No postbaseline assessment available for evaluation.
Response
Pembrolizumab +
Axitinib (n = 432)
Sunitinib
(n = 429)
Best overall response, n (%)
 CR 25 (5.8) 8 (1.9)
 PR 231 (53.5) 145 (33.9)
 SD 106 (24.5) 169 (39.4)
 PD 47 (10.9) 73 (17.0)
 NE† 8 (1.9) 6 (1.4)
 NA‡ 15 (3.5) 28 (6.5)
Median DoR,
mos (range)
Not reached
(1.4+ to 18.2+)
15.2
(1.1+ to 15.4+)
ORR
(%)
P < .0001
Pembro + Axi Sunitinib
59.3%
35.7%
CR
PR
100
90
80
70
60
50
40
30
20
10
0
Rini. NEJM. 2019; 380:1116.

89. Main Conclusions
 Treatment with pembrolizumab plus axitinib resulted in significantly
longer overall survival and progression-free survival and a significantly
higher objective response rate than sunitinib alone”
 Benefit was observed across all IMDC groups
 The incidence of grade 3/4 adverse events was similar (67% with
pembrolizumab + axitinib vs 62% with sunitinib)
 This study changed practice patterns in RCC

90. What is “big-picture” benefit achieved in patients
with IMDC intermediate-/poor-risk RCC receiving
these new standard regimens?

91. regarding OS for Intermediate-/Poor-Risk Disease
1. Tannir. ASCO GU 2020. Abstr 609. 2. Plimack. ASCO 2020. Abstr 5001
CheckMate 214: Nivo + Ipi vs Sunitinib
Intermediate-/Poor-Risk Disease (n = 847)[1]
KEYNOTE-426: Axitinib + Pembro vs Sunitinib
Intermediate-/Poor-Risk Disease (n = 592)[2]
 Similar outcome on same comparator arm
 Early separation of curves for both
 Longer follow-up for CheckMate 214
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 4548 51 54 57
60%
47%
39%
74%
60%
52%
Nivo + Ipi (n = 425)
Sunitinib (n = 422)
Median OS, Mos
(95% CI)
47.0*(35.6-NE)
26.6 (22.1-33.5)
HR: 0.66 (95% CI: 0.55-0.80;
P < .0001)
100
OS
(%)
*Nivo + Ipi 47 mos median OS
may be unstable due to censoring.
Pembro + axi
Sunitinib
Median OS, Mos
(95% CI)
NR
28.8 (23.7-34.3)
Mos
90
80
70
60
50
40
30
20
10
0
69%
56%
42
0 6 12 18 24 30 36
HR: 0.63 (95% CI:
0.50-0.81)

92. regrding Response Rate for IMDC Intermediate-/Poor-
Risk Disease
1. Tannir. ASCO GU 2020. Abstr 609. 2. . Soulières. IKCS 2019. 3. Plimack. ASCO 2020. Abstr 5001.
Response, %
Patients
(n = 425)
Confirmed ORR 42
 CR 10
 PR 32
SD 31
PD 27
CheckMate 214: Nivo + Ipi[1]
Response, %
Median F/U:
16.6 Mos
(n = 294)
Minimum F/U
23 Mos
(n = 294)
ORR 55.4 55.8
 CR 6.5 8
 PR 49.0 47.8
SD 23.5 Not reported
PD 14.6 Not reported
KEYNOTE-426: Axitinib + Pembro[2,3]

93. Median DoR, Mos
Nivo + Ipi NR
Sunitinib 18.0
HR: 0.51 (95% CI: 0.38-0.68)
24 mos: curve starts to
plateau for Nivo + Ipi
Nivo + Ipi
Sunitinib
225
(0)
186
(0)
Mos From Randomization
Overall
Response
(%)
20
40
60
80
100
0
3 6 9 12 15 18 21 24 27 30 33 36 39
0
205
(5)
164
(9)
175
(10)
136
(17)
160
(13)
116
(19)
146
(16)
98
(21)
136
(19)
86
(24)
120
(27)
72
(30)
111
(29)
60
(34)
102
(34)
49
(37)
90
(43)
40
(40)
55
(77)
27
(48)
20
(112)
7
(64)
4
(127)
0
(69)
0
(131)
0
(69)
1. Motzer. Lancet Oncol. 2019;20:1370. 2. Soulières. IKCS 2019.
CheckMate 214: Nivo + Ipi in ITT Responders
(n = 225)[1]
KEYNOTE-426: Axitinib + Pembro in ITT Responders
(n = 259)[2]
Pembro + axi
Sunitinib
259
165
221
123
126
63
64
26
8
1
0
0
72.0
63.3
Remaining
in
Response
(%)
20
40
60
80
100
0
5 10 15 20 25
Mos
0
Too early
to tell
Patients at Risk, n (number censored)
Patients at Risk, n
Pembro + axi
Sunitinib
Median DoR,
Mos (Range)
20.9 (1.4+ to 20.9)
15.2 (1.4+ to 21.0+)

94. Regarding PFS for IMDC Intermediate-/Poor-Risk
Disease ---- 9m
1. Tannir. ASCO GU 2020. Abstr 609. 2. Plimack. ASCO 2020. Abstr 5001
CheckMate 214: Nivo + Ipi vs Sunitinib (n = 847)[1] KEYNOTE-426: Axitinib + Pembro vs Sunitinib (n = 592)[2]
Patients at Risk, n
P + axi
Sunitinib
100
80
60
40
20
0
PFS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Mos
425
422
302
280
229
188
182
136
159
104
144
88
126
73
113
59
98
45
95
36
90
30
82
25
75
21
70
16
56
11
34
8
13
3
2
0
0
0
35%
22%
19%
43%
37% 35%
Patients at Risk, n
Nivo + Ipi
Sunitinib
Median PFS, Mos
Nivo + Ipi 12.0 (8.7-15.5)
Sunitinib 8.3 (7.0-11.1)
HR: 0.76 (95% CI: 0.63-0.91; P < .01)
Mos
100
90
80
70
60
50
30
20
10
0
34%
23%
42
0 6 12 18 24 30 36
294
298
189
149
146
93
113
66
68
35
23
11
2
0
0
0
40
Median PFS, Mos
Pembro + axi 12.7 (11.3-18.0)
Sunitinib 8.3 (6.7-10.1)
HR: 0.69 (95% CI: 0.56-0.84) ?

95. Palmar-plantar erythrodysesthesia
13.9
60
70 100
3.8
Recurrent Treatment-Related AEs for Combination
Therapy vs TKI Alone
CheckMate 214: Nivo + Ipi vs Sunitinib in ITT Population[1] KEYNOTE-426: Axitinib + Pembro vs Sunitinib in ITT
Population[2]
Nivo + Ipi grade 3/4 AEs
Nivo + Ipi any-grade AEs
Sunitinib grade 3/4 AEs
Sunitinib any-grade AEs
Nivo + Ipi Group
(n = 547)
Sunitinib Group
(n = 535)
Diarrhea
Fatigue
Palmar-plantar erythrodysesthesia
Hypertension
Nausea
Dysgeusia
Mucosal inflammation
Stomatitis
Hypothyroidism
Decreased appetite
Vomiting
Dyspepsia
Thrombocytopenia
Asthenia
Anemia
Rash
Increased lipase concentration
Pruritus
Patients (%)
60
60 50 40 30 20 10 0 10 20 30 40 50
28.2 5.8 52.7
37.8 4.4 9.5 49.7
1.1
2.2
9.2 43.6
40.9
38.3
1.3
1.5
20.1
5.7
2.6
33.6
4.4
28.8
28.0
16.8
2.8
2.6
1.1
1.3
16.3 26.0
25.2
21.5
1.9
11.0
2.9 18.1
0.5 17.8
4.3
17.2
2.4
1.8
13.5
4.3 15.5
22.7 1.6
16.8 11.4
6.6
12.9
29.3 9.2
6.7
10.4
Grade 1/2
Grade 3-5
Grade 1/2
Grade 3-5
90
100 90 60 30 20 10 0 10 20 30 40 70
Patients (%)
50 80
80 50 40
Pembro + Axitinib Sunitinib
Diarrhea
Hypertension
Fatigue
Hypothyroidism
Nausea
Decreased appetite
Dysgeusia
ALT increased
AST increased
Stomatitis
Mucosal inflammation
Dysphonia
Thrombocytopenia
42.6
51.5
43.5
42.9
39.8
28.4
34.4
31.2
29.9
33.8
27.3
22.4
26.1
22.8
30.8
10.5
13.2
24.5
14.1
23.1
20.2
14.5
21.4
13.1
3.1
23.1
22.6
2.3

96. CheckMate 214: Health-Related Quality of Life in IMDC
Intermediate-/Poor-Risk Patients
Rini. NEJM. 2019;380:1116. Slide credit: clinicaloptions.com
Wk
Mean
Change
From
Baseline
FKSI-19
Score
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
Sunitinib
Nivolumab + ipilimumab
104
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100
0
Patients at Risk, n
Nivolumab + ipilimumab
Sunitinib
425
422
347
371
281
284
239
221
212
184
180
147
166
127
152
113
143
104
139
93
125
80
108
64
76
43
44
26

97. PD-1–Based Combinations in IMDC Intermediate-/
Poor-Risk Patients how to choose
 Short-term efficacy:
‒ TTR and PFS were superior to
sunitinib for both regimens
‒ The rate of PD as best response
was near double for Nivo + Ipi vs
Axitinib + Pembro
 Long-term efficacy:
‒ Unequivocal long-term benefit for
Nivo + Ipi
‒ Do not yet have data for long-term
benefit with Axitinib + Pembro
 Toxicity:
‒ Worse chronicity for axitinib +
Pembro; even in patients without
irAES, there is ongoing QoL impact
from axitinib
‒ Greater need for toxicity-related
treatment discontinuation, and for
immunosuppression, with Nivo +
Ipi

98. 3

99. PFS in ITT Population OS in ITT Population
Median PFS, Mos (95% CI)
Avelumab + axitinib: 13.8 (11.1-NE)
Sunitinib: 8.4 (6.9-11.1)
HR: 0.69 (95% CI: 0.56-0.84; P < .001)
PFS
(%)
Mos
20
40
60
80
100
0
16
0 2 4 6 8 10 12 14 18 20 22 24
OS
(%)
Median OS, Mos
Avelumab + axitinib: NR
Sunitinib: NR
HR: 0.78 (95% CI: 0.55-1.08; P = .14)
Mos
20
40
60
80
100
0
16
0 2 4 6 8 10 12 14 18 20 22 24 26

100. 4

105. 5- Phase II KEYNOTE-146 Lenvatinib + Pembrolizumab
After Progression on Previous IO Therapy
 A multicenter, open-label phase Ib/II study, RCC Cohort (N = 104)
Patients metastatic clear-cell
RCC with PD after anti–PD-1/
PD-L1 therapy; ≥ 1 previous
lines of therapy
(N = 104)
Lenvatinib 20 mg QD PO
Pembrolizumab 200 mg Q3W IV
Lee. ASCO 2020. Abstr 5008.
Primary Endpoint:
 ORR at 24 wks
Key Secondary Endpoints:
 ORR, PFS, DoR
 Safety and tolerability
Baseline Characteristic Patients (N = 104)
1/ ≥ 2 Prior anticancer regimens, % 39 / 62
Prior ICI regimen, %a
Anti–PD-L1/anti–PD-1 in combination or as monotherapy
Anti–PD-L1/anti–PD-1 and anti-VEGF in combination or sequentially
Ipilimumab/nivolumab
100
65
37
Median duration of prior ICI therapy, mos (IQR) 7 (3-13)

106. Response to Lenvatinib + Pembrolizumab:
Change in Tumor Size
Note: Each bar represents 1 patient.
Lee. ASCO 2020. Abstr 5008.

107. Response to Lenvatinib + Pembrolizumab:
Change in Tumor Size by Prior Anti-VEGF
Therapy
Note: Each bar represents 1 patient.
Lee. ASCO 2020. Abstr 5008.
Note: Each bar represents 1 patient.

108. Response to Lenvatinib + Pembrolizumab:
Change in Tumor Size by Prior IO Therapy
Lee. ASCO 2020. Abstr 5008.
Note: Each bar represents 1 patient.

109. Back to our patient

110. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V2.2020. © National Comprehensive Cancer Network, Inc
2020. All rights reserved. Accessed June 10, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.

111. ESMO 2020
ASCO GU 2020

112. MK-6482 in Advanced Clear-Cell RCC:
 Among patients with clear-cell RCC, at least one half possess mutations
in the tumor suppressor gene VHL encoding pVHL[1,2]
 pVHL deficiency leads to constitutive activation of transcription factor
HIF-2α, a renal oncoprotein[1,2]
 MK-6482: investigational, selective, small-molecule inhibitor of HIF-2α[3]
 Current analysis evaluated safety and efficacy of MK-6482 in patients
with heavily pretreated, advanced clear-cell RCC enrolled on dose-
expansion cohort of ongoing phase I/II trial[4]
1. Shen. Semin Cancer Biol. 2013;23:18. 2. Courtney. Clin Cancer Res. 2020;26:793.
3. Xu. J Med Chem. 2019;62:6876. 4. Choueiri. ASCO GU 2020. Abstr 611. Slide credit: clinicaloptions.com

113. MK-6482 in Advanced Clear-Cell RCC: Study Design
 Analysis of dose-expansion cohort for multicenter, single-arm,
open-label phase I/II trial
 Primary endpoint: safety
 Key secondary endpoints: ORR, DoR, PFS
Choueiri. ASCO GU 2020. Abstr 611. NCT02974738.
Patients with advanced
clear-cell RCC previously
treated with ≥ 1 therapy
(N = 55)
Until PD or toxicity
MK-6482 120 mg PO QD

114. MK-6482 in Advanced Clear-Cell RCC: PFS
Choueiri. ASCO GU 2020. Abstr 611.
PFS
All Patients
(N = 55)
IDMC Risk Category
Favorable
(n = 5)
Intermediate
(n = 40)
Poor
(n = 10)
Median PFS, mos 11.0 16.5 11.0 6.9
12-mo PFS rate, % 49 80 47 Not reached

115. Conclusions
 In this analysis of the dose-expansion cohort of an ongoing phase I/II trial in patients with
heavily pretreated advanced clear-cell RCC, MK-6482 was associated with on-target
toxicities of anemia and hypoxia
‒ Any grade/grade 3: anemia, 75%/26%; hypoxia, 26%/15%
 Clinical activity was observed across IDMC risk categories in this study population
‒ ORR of 24% (all PRs), with responses lasting ≥ 6 mos in 81% of patients
‒ Median PFS: 11 mos; 12-mo PFS rate: 49%
 Recruitment ongoing for phase III trial comparing MK-6482 vs everolimus in patients with
advanced RCC after progression on anti–PD-1/PD-L1 and anti-VEGF agents (NCT04195750)
Choueiri. ASCO GU 2020. Abstr 611.

116. Update of First-line Nivolumab + Ipilimumab vs Sunitinib in
Patients With Adv RCC (CheckMate 214)
‒ Median OS: NR (95% CI: 35.6-NE) for Nivo + Ipi vs 26.0 mos for sunitinib (HR: 0.63; P < .001)
‒ ORR: 42% with Nivo + Ipi vs 27% with sunitinib (P < .001)
‒ Median PFS per IRRC: 11.6 mos with Nivo + Ipi vs 8.4 mos with sunitinib (P = .03)
 This follow-up of CheckMate 214 reports on efficacy and safety at 42 mos[2]
1. Motzer. NEJM. 2018;378:1277. 2. Tannir. ASCO GU 2020. Abstr 609. Slide credit: clinicaloptions.com

117. Updated OS in Intermediate-/ Poor-Risk Population
Tannir. ASCO GU 2020. Abstr 609. Reproduced with permission. Slide credit: clinicaloptions.com
*With a minimum 42 mos of follow-up, Nivo + Ipi 47 mos median OS may be unstable due to censoring.
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Mos
Patients at Risk, n
Nivo + Ipi
Sunitinib
425
422
399
388
372
353
348
318
332
291
317
258
306
237
287
220
270
206
254
193
241
184
230
178
220
169
216
161
202
145
162
118
78
64
27
25
1
3
0
0
60%
47%
39%
74%
60%
52%
Minimum
Follow-
up, Mos
OS
Nivo + Ipi
(n = 425)
Sunitinib
(n = 422)
17.5
Median,
mos
(95% CI)
NR
(28.2-NE)
NR
(22.1-NE)
HR
(99.8% CI)
0.63 (0.44-0.89)
P < .001
30
Median,
mos
(95% CI)
NR
(35.6-NE)
26.6
(22.1-33.4)
HR
(95% CI)
0.66 (0.54-0.80)
P < .0001
42
Median,
mos
(95% CI)
47.0*
(35.6-NE)
26.6
(22.1-33.5)
HR
(95% CI)
0.66 (0.55-0.80)
P < .0001

118. Minimum
Follow-
up, Mos
OS
Nivo + Ipi
(n = 125)
Sunitinib
(n = 124)
17.5*
Median,
mos
(95% CI)
NR
(NE)
NR
(NE)
HR
(99.8% CI)
1.45 (0.51-4.12)
P = .27
30
Median,
mos
(95% CI)
NR
(NE)
NR
(NE)
HR
(95% CI)
1.22 (0.73-2.04)
P = .44
42
Median,
mos
(95% CI)
NR
(NE)
NR
(NE)
HR
(95% CI)
1.19 (0.77-1.85)
P = .44
70%
Updated OS in Favorable-Risk Population
Tannir. ASCO GU 2020. Abstr 609. Reproduced with permission. Slide credit: clinicaloptions.com
*37 deaths occurred at time of database lock (Nivo + Ipi, n = 21; sunitinib, n = 16).
100
80
60
40
20
0
OS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Mos
125
124
124
119
121
119
117
117
112
114
109
111
105
110
103
106
102
104
99
101
96
97
93
90
89
88
86
86
84
83
79
79
57
61
22
24
2
1
0
0
88%
80%
93%
85%
73%
Patients at Risk, n
Nivo + Ipi
Sunitinib

119. Minimum
Follow-
up, Mos
PFS
Nivo + Ipi
(n = 425)
Sunitinib
(n = 422)
17.5
Median,
mos
(95% CI)
11.6
(8.7-15.5)
8.4
(7.0-10.8)
HR
(99.1% CI)
0.82 (0.64-1.05)
P = .03
42
Median,
mos
(95% CI)
12.0
(8.7-15.5)
8.3
(7.0-11.1)
HR
(95% CI)
0.76 (0.63-0.91)
P < .01
Updated PFS in Intermediate-/ Poor-Risk Population
Tannir. ASCO GU 2020. Abstr 609. Reproduced with permission. Slide credit: clinicaloptions.com
100
80
60
40
20
0
PFS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Mos
425
422
302
280
229
188
182
136
159
104
144
88
126
73
113
59
98
45
95
36
90
30
82
25
75
21
70
16
56
11
34
8
13
3
2
0
0
0
35%
22%
19%
43%
37% 35%
Patients at Risk, n
Nivo + Ipi
Sunitinib

120. Minimum
Follow-
up, Mos
PFS
Nivo + Ipi
(n = 125)
Sunitinib
(n = 124)
17.5
Median,
mos
(95% CI)
15.3
(9.7-20.3)
25.1
(20.9-NE)
HR
(99.1% CI)
2.18 (1.29-3.68)
P < .0001
42
Median,
mos
(95% CI)
17.8
(10.3-20.7)
27.7
(23.2-34.5)
HR
(95% CI)
1.62 (1.14-2.32)
P < .01
Updated PFS in Favorable-Risk Population
Tannir. ASCO GU 2020. Abstr 609. Reproduced with permission. Slide credit: clinicaloptions.com
100
80
60
40
20
0
PFS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Mos
125
124
103
105
80
98
62
79
52
73
48
66
41
58
35
43
30
41
28
36
25
30
24
25
21
18
18
16
17
15
12
12
5
1
0
0
46%
33%
28%
70%
46%
34%
Patients at Risk, n
Nivo + Ipi
Sunitinib

126. We also determined chromosome copy-number aberrations,
methylation status, and gene mutations in von Hippel-Lindau
and PBRM1. Molecular data were analyzed in relation with
response rate (RR), progression-free survival (PFS), and overall
survival (OS).
ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter
PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003,
respectively).

127. crcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and
CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not
exhibit cellular response to hypoxia.
Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong
inflammatory, Th1-oriented but suppressive immune microenvironment, with high
expression of PDCD1 (PD-1) and its ligands

134. First-Line Treatment Considerations for RCC: Summary
 Multiple good systemic therapy options for metastatic RCC, with no obvious
clear choice in some cases
 Good-risk patients, and those with “favorable intermediate” risk, can have
survival of many yrs—with and without therapy
 Consider debulking nephrectomy and/or active surveillance in selected patients
Patients with:
• IMDC intermediate/poor-risk
disease
• No significant autoimmune
disease
• VEGF contraindications
• A need to avoid chronic
VEGF AEs
Consider
Nivo + Ipi
Patients with
• IMDC favorable- or
intermediate-risk disease
• Intermediate- or poor- risk
disease who need rapid
response
• A need to avoid irAEs associated
with dual IO therapy
Consider
Pembro +
Axitinib

135. Post TKI Therapy in 2nd line :
Parameter
RECORD-1[1,2] AXIS[3,4] METEOR[5,6] CheckMate 025[7] LEN EVE[8]
Everolimus
vs
Placebo
Axitinib
vs
Sorafenib
Cabozantinib
vs
Everolimus
Nivolumab
vs
Everolimus
Lenvatinib + Everolimus
vs
Everolimus
Patients, n 410 723 658 821 153
MSKCC risk, %
 Good 29 28 46 36 23
 Intermediate 56 37 42 49 36
 Poor 15 33 13 15 40
Prior TKI Anti-VEGF Sunitinib Anti-VEGF Anti-VEGF Anti-VEGF
Line of therapy 2nd or beyond 2nd 2nd or beyond 2nd or 3rd 2nd
ORR, % 2 vs 0 19 vs 9 21 vs 5 25 vs 5 43 vs 3
Median OS, mos 14.8 vs 14.0 20.1 vs 19.2 21.4 vs 17.1 25.0 vs 19.6 25.5 vs 15.4
1. Motzer. Lancet. 2008;372:449. 2. Motzer. Cancer 2010;116:4256. 3. Rini. Lancet. 2011;378:1931. 4. Motzer. Lancet Oncol. 2013;14:552.
5. Choueiri. NEJM. 2015;373:1814. 6. Motzer. Br J Cancer. 2018;118:1176. 7. Motzer. NEJM. 2015;373:1803. 8. Motzer. Lancet. 2015;16:1473.
Phase III Phase II

136. Phase III Trials on the Radar Screen
Study Treatment Setting Phase Status N
Metastatic RCC
CLEAR
NCT02811861
Len + Pembro vs
Sunitinib vs Len + Eve
First line III
Completed
accrual
1100
CheckMate-9ER
NCT03141177
Cabo + Nivo vs
Suntinib
First line III
Completed
accrual
500+
COSMIC 313
NCT03937219
Cabo + Nivo + Ipi vs
Nivo + Ipi
First line III Accruing 700+
Locally Advanced/Adjuvant
KEYNOTE 564
NCT03142334
Pembro vs
Placebo
T2, T3, N1
M1 NED
III
Completed
accrual
950
CHECKMATE-914
NCT03138512
Nivo + Ipi vs
Placebo
T2, T3, T4, N1, NED III Accruing 800

138. General Principles for Managing irAEs
 Consult promptly with relevant specialists for affected organ systems (eg, GI, dermatology)
 Management generally based on severity of symptoms
‒ Mild (grade 1): supportive care, consider holding ICI
‒ Moderate (grade 2): hold ICI, re-dose if AE improves, consider low-dose steroids (prednisone
0.5-1 mg/kg/day)
‒ Severe (grade 3): discontinue ICI, monitor closely (likely inpatient), start high-dose steroids
(prednisone 1-2 mg/kg/day) with a slow taper (≥ 1 mo)  If not improving in 1-3 days, increase
immunosuppression
 For steroid-refractory AEs, consider adding infliximab, mycophenolate mofetil, etc
‒ Diarrhea  consider adding infliximab or vedolizumab
‒ Hepatitis  consider adding mycophenolate mofetil
Slide credit: clinicaloptions.com
Brahmer. JCO. 2018;36:1714.
‒ Pneumonitis  consider adding
infliximab, mycophenolate
mofetil, or IVIG