This document discusses a clinical case presentation of a patient with metastatic renal cell carcinoma (mRCC). Key details include that the patient previously underwent nephrectomy and radiation therapy and is now being discussed for systemic therapy options. The document reviews several clinical trials evaluating different combination regimens for first-line and subsequent lines of treatment in mRCC. Factors like prognostic risk categories and biomarkers are discussed for guiding treatment selection. The merits and limitations of different studies are evaluated.

1. RADAR ON RCC
DR.R.RAJKUMAR D.M
CONSULTANT MEDICAL
ONCOLOGIST
VELAMMAL SPECIALITY
HOSPITALS

2. CASE PRESENTATION
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3. CASE PRESENTATION

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5. METASTATIC RCC
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6. CASE DISCUSSION

7. CASE DISCUSSION

8. CASE PRESENTATION
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9. THE NEXT STEP FOR THIS PATIENT ?
1.
2.

10. CASE PRESENTATION
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11. CARMENA TRIAL
• RCT of 450 Patients with IMDC Intermediate to Poor Risk Disease

12. CARMENA: Prospective, Multicenter, Open-Label,
Randomized Phase III Noninferiority Study
 Multicenter, randomized, open-label noninferiority phase III trial
 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
Intermediate / poor -risk disease
(N = 450)
Stratified by center, MSKCC risk group (intermediate vs high risk)
*Dose reductions/interruptions allowed for managing AEs.
Sunitinib 50 mg QD*
4 wks on/2 wks off
(n = 226)
3-6 wks
Méjean. ASCO 2018. Abstr LBA3. Méjean. NEJM. 2018;379:417.

13. CARMENA: Overall Survival (ITT)
HR: 0.89 (95% CI: 0.71-1.10; noninferiority ≤ 1.20)
Median follow-up: 50.9 mos (range: 0-86.6)
Méjean. ASCO 2018. Abstr LBA3.
Median OS, Mos
Nephrectomy → sunitinib 13.9
Sunitinib alone 18.4
0
10
20
30
40
50
60
70
80
90
100
Patients
Who
Were
Alive
(%)
Mos
0 12 24 36 48 60 72 84 96
Patients at Risk, n
Nephrectomy→ sunitinib
Sunitinib alone
226
224
110
128
61
76
40
44
19
26
11
8
4
3
1
1
0
0
64.4
42.6
29.1
55.2
35.0
25.9

14. Considerations for Nephrectomy

15. RESULTS AND CONCLUSIONS
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16. MERITS & DE-MERITS OF THE STUDY
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18. What are the prognostic indicators in mRCC do you
consider while choosing the treatment options ?

19. Do you do risk stratification of your patients
in clinical practice..?
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20. COMPARISON OF MSKCC AND IMDC PROGNOSTIC
MODELS FOR RCC

21. IMDC (HENG) CRITERIA FOR METASTATIC RCC
International Kidney Cancer Coalition. Heng. JCO. 2009;27:5794.

22. IMDC (HENG) CRITERIA FOR METASTATIC RCC

23. CASE DISCUSSION
CHOICE OF SYSTEMIC THERAPY
 TKI
 IO
 IO+TKI

24. HOW TO CHOOSE AMONG
EXPANDING SYSTEMIC OPTIONS IN mRCC

25. EVOLUTION OF TREATMENTS FOR MRCC

26. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V4.2021. © National Comprehensive Cancer Network, Inc
2021. All rights reserved. Accessed June 13, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

28. CheckMate 214: OS and Response by IMDC Risk
Category
Tannir. ASCO GU 2020. Abstr 609.
OS in Intermediate-Risk and Poor-Risk Patients OS in Favorable-Risk Patients
Nivolumab + ipilimumab (n = 425)
Sunitinib (n = 422)
Outcome in
Favorable-Risk Patients
Nivolumab + Ipilimumab
(n = 125)
Sunitinib
(n = 124)
HR (95% CI) P Value
ORR, % (95% CI) 29 54 -- < .0001
Median PFS, mos (95% CI) 17.8 (10.3-20.7) 27.7 (23.2-34.5) 1.62 (1.14-2.32) < .01
100
80
60
40
20
0
OS
(%)
0 3 6 9 12151821242730333639424548515457
60%
47%
39%
74%
60%
52%
HR: 0.66 (95% CI: 0.55-0.80; P < .0001)
Mos
70%
100
80
60
40
20
0
OS
(%)
0 3 6 9 12151821242730333639424548515457
Mos
88%
80%
93%
85%
73%
Nivolumab + ipilimumab (n = 125)
Sunitinib (n = 124)
HR: 1.19 (95% CI: 0.77-1.85; P = .44)

29. KEYNOTE-426: First-line Pembrolizumab + Axitinib vs
Sunitinib in Advanced or Metastatic RCC
HR: 0.63 (95% CI: 0.50-0.81;
P = .0001)
Median OS, Mo
Pembro + Axi NR
Sunitinib 28.8 (23.7-34.3)
Powles. Lancet Oncol. 2020;21:1563. Slide credit: clinicaloptions.com
Mo
80
60
40
20
0
69.2%
42
0 6 12 18 24 30 36
100
OS
(%)
Patients at Risk, n
Pembro + Axi
Sunitinib
294
289
274
250
254
213
220
188
195
160
100
74
11
7
0
0
55.8
86.7%
72.0%
INTERMEDIATE / POOR RISK

30. KEYNOTE-426: First-line Pembrolizumab + Axitinib vs
Sunitinib in Advanced or Metastatic RCC
HR: 1.06 (95% CI: 0.60-1.86;
P = .58*)
Mo
Patients at Risk, n
Pembro + Axi
Sunitinib
OS
(%)
100
80
60
40
20
0
87.7%
Events, n Median
Pembro + Axi 26 NR
Sunitinib 24 NR
42
0 6 12 18 24 30 36
138
131
134
129
131
123
126
118
110
108
63
60
12
9
0
0
Powles. Lancet Oncol. 2020;21:1563.
*Nominal P value.
Slide credit: clinicaloptions.com
85.3%
94.6%
95.6%
FAVORABLE RISK

31. First-line IO Combination Trials in mRCC
CheckMate 214 (Ipi/Nivo) 1
(n = 550 vs n = 546)
KEYNOTE-426 (Axi/Pembro)2
(n = 432 vs n = 429)
CheckMate 9ER (Cabo/Nivo)3
(n = 323 vs n = 328)
CLEAR (Len/Pembro)4
(n = 355 vs n = 357)
mOS, mo
HR (CI)
NR vs 38.4
0.69 (0.59-0.81)
45.7 vs 40.1
0.73 (0.60-0.88)
NR vs 29.5
0.66 (0.50-0.87)
NR vs NR
0.66 (0.49-0.88)
Landmark OS 12 mo
Landmark OS 24 mo
83% vs 78%
71% vs 61%
90% vs 79%
74% vs 66%
86% vs 76%
72% vs 60% (est)
90% vs 79%
79% vs 70% (est.)
mPFS, mo
HR (CI)
12.2 vs 12.3
0.89 (0.76-1.05)
15.7 vs 11.1
0.68 (0.58-0.80)
17.0 vs 8.3
0.52 (0.43-0.64)
23.9 vs 9.2
0.39 (0.32-0.49)
ORR, % 39 vs 32 60 vs 40 55 vs 27 71 vs 36
CR, % 11 vs 3 10 vs 4 9 vs 4 16 vs 4
Med f/u, mo 55 42.8 23.5 27
Prognostic risk, %
 Favorable
 Intermediate
 Poor
23
61
17
32
55
13
23
58
19
31
59
9
Prior nephrectomy 82% 83% 69% 74%
Subsequent systemic
therapies for sunitinib
arm, %
Overall (69%)
IO (42%)
Overall (69%)
IO (48%)
Overall (40%)
IO (29%)
Overall (71%)
IO (53%)
1. Albiges. ESMO Open. 2020;5:epub001079. 2. Rini. ASCO 2021. Abstr 4500.
3. Choueiri. NEJM. 2021;384:829. 4. Motzer. NEJM. 2021;384:1289.
@brian_rini and @Uromigos (podcasts: https://anchor.fm/the-Uromigos)
Adapted from

32. 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

33. mRCC 1ST LINE SYSTEMIC THERAPY: DECISION TREE

34. CASE PRESENTATION

35. CASE DISCUSSION

36. CASE DISCUSSION
 STARTED ON PALLIATIVE RT
 10/30GY

37. CASE DISCUSSION
CHOICE OF SYSTEMIC THERAPY
 TKI
 IO
 IO+TKI
 mTOR
 TKI+mTOR
 Anti VEGF monolonal antibodies

38. HOW DO YOU CHOOSE THE TREATMENT
IN mRCC AFTER PROGRESSION?

39. SEQUENCING OF AGENTS 5 YEARS BACK…
mTOR
inhibitor
VEGF
TKI mTORi
TKI TKI
Sunitinib
Pazopanib
Axitinib
Sorafenib
Everolimus
mTORi
TKI TKI
SIMPLER TIMES

40. SEQUENCING OF AGENTS IN 2020
VEGF
+
mTORi
VEGF
TKI
CPI
+
Bev
CPI
+
CPI
CPI
CPI
+ TKI

41. Pivotal Randomized Trials in Clear-Cell RCC
Post TKI Therapy
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
Slide credit: clinicaloptions.com
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

42. 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.
dHudes. NEJM 2007;356:2271-2281.

43. WHEN WOULD YOU PREFER THE LENVATINIB +
EVEROLIMUS COMBINATION IN THE
MANAGEMENT OF mRCC?

44. STUDY 205: A RANDOMISED, PHASE 2,
OPEN-LABEL, MULTICENTRE TRIAL
aRCC: advanced renal cell carcinoma, Ca: calcium, ECOG: Eastern Cooperative Oncology Group, Hb: haemoglobin, IRR: independent radiological review, mmHg: millimeter of mercury, mRCC: metastatic renal cell carcinoma, ORR: objective response
rate, OS: overall survival, PFS: progression-free survival, RCC: renal cell carcinoma, RECIST: Response Evaluation Criteria in Solid Tumours, VEGF: vascular endothelial growth factor.
1. Motzer RJ et al. Lancet Oncol 2015;16(15):1473‒1482.
Key Eligibility Criteria:
• Histologically verified clear-cell RCC
• Radiographic evidence of progressive aRCC or mRCC
within 9 months of stopping previous treatment
• 1 previous disease progression with VEGF treatment
• ECOG PS 0 or 1
• Measurable disease per RECIST v1.1
• ≤ 150/90 mmHg blood pressure
• Adequate renal, bone marrow, blood coagulation, liver
and cardiac function
Stratification Factors:
• Hb
(Men: ≤130 g/L and >130 g/L, Women: ≤115 g/L
and >115 g/L)
• Corrected serum Ca
(≥2.5 mmol/L and <2.5 mmol/L)
End Points:
• Primary: PFS
• Key secondary: ORR, OS and safety
18 mg lenvatinib plus 5 mg everolimus
Once per day
10 mg everolimus monotherapy
Once per day
R
(1:1:1)
24 mg lenvatinib monotherapy
Once per day
n = 51
n = 50
n = 52

45. PRIMARY ENDPOINT – PROGRESSION-FREE
SURVIVAL
CI: confidence interval, HR: hazard ratio.
1. Motzer RJ et al. Lancet Oncol 2015;16(15):1473‒1482.
PFS was significantly
prolonged with
lenvatinib plus
everolimus, compared
with everolimus alone
(p=0.0005)1
• Approximately 9
additional months of
PFS benefit1
• 60% reduction in the
risk of
progression or death1

46. SECONDARY ENDPOINT – ORR
Assessed by Investigator review per RECIST v1.1
CI.
Lenvatinib plus
everolimus
(n=51)
Lenvatinib
monotherapy
(n=52)
Everolimus
monotherapy
(n=50)
OBJECTIVE RESPONSE
Events 22 (43%) 14 (27%) 3 (6%)
95% CI 29–58 16–41 1–17
Best overall response
Complete
response
1 (2%) 0 0
Partial response 21 (41%) 14 (27%) 3 (6%)
Stable disease 21 (41%) 27 (52%) 31 (62%)
Progressive
disease
2 (4%) 3 (6%) 12 (24%)
Not assessed 6 (12%) 8 (15%) 4 (8%)
43% ORR
for lenvatinib plus
everolimus vs 6% with
everolimus alone
(rate ratio [RR] 7·2, 95% CI:
2·3–22·5; p<0·0001)1
Lenvatinib plus everolimus
• Duration of response was
13.0 months1
• Time to response was 1.9
months2

47. SECONDARY ENDPOINT – ORR
Treatment Group:
Lenvatinib 18 mg plus Everolimus 5 mg
Treatment Group:
Lenvatinib 24 mg
Treatment Group:
Everolimus 10 mg
Figure S1. Maximum percentage change in sum of diameters of target lesions, for A) lenvatinib/everolimus combination arm, B) lenvatinib , and C) everolimus.
More patients in the lenvatinib plus everolimus group experienced measurable tumour shrinkage vs
those treated with everolimus alone

48. CASE DISCUSSION

49. Summary
Cabozantinib or Axitinib
Axitinib + Pembrolizumab (based on
Lenvatinib + Pembro data)
Ipilimumab + Nivolumab
Nivolumab
Cabozantinib or Axitinib or Lenvatinib +
Everolimus
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50. Thank you