2. CASE DISCUSSION
• 64-yr-old man presents with right flank pain, no hematuria
• Past medical history includes:
• Mild hypertension (140/85 mmHg, not on medication),
hypercholesterolemia, no other cardiac history
• 20 pack-yr smoker
• Family history: negative for cancer
• Physical exam: right flank fullness, otherwise normal
• ECOG PS 0
• Labs: hemoglobin: 11.0 g/dL, ANC and platelets normal,
creatinine: 1.2 mg/dL, LDH: 287 U/L, calcium normal
5. WHAT IS THE NEXT STEP FOR THIS
PATIENT ?
1. Radical Nephrectomy
2. Start Systemic therapy
6. CASE DISCUSSION
• Patient undergoes right
radical nephrectomy
• Pathology: grade 3 clear-
cell RCC; margins negative;
T3aN0
• Returns 6 wks after
nephrectomy; fully
recovered
• ECOG PS 0, creatinine 1.5
mg/dL; all other labs
normal
7. WHAT IS ROLE OF ADJUVANT THERAPY
IN THIS PATIENT..?
ADJUVANT THERAPY INDICATED
NO EVIDENCE
EQUIVOCAL
8. S-TRAC PHASE III TRIAL: DFS WITH SUNITINIB VS PLACEBO
IN PATIENTS WITH LOCOREGIONAL, HIGH-RISK CCRCC
51.3%
59.5%
5-yr
DFS rate: Median DFS, Yrs (95% CI)
Sunitinib 6.8 (5.8-NR)
Placebo 5.6 (3.8-6.6)
Yrs
HR: 0.761 (95% CI: 0.594-0.975)
2-sided log-rank P = .030 stratified by UISS high-risk group
3-yr
DFS rate:
64.9%
59.3%
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8 9
Patients at Risk, n
Sunitinib
Placebo
309
306
225
220
173
181
153
150
144
135
119
102
53
37
10
10
3
2
0
0
Proportion
Disease
Free
9. PUBLISHED TYROSINE KINASE INHIBITOR
ADJUVANT TRIALS
Trial Therapy N Histology Stage
Starting
Dose
Minimum
Dose
DFS OS
ASSURE[1] Sunitinib
Sorafenib
Placebo
1943 79% ccRCC
> pT1b, G3-4,
or N+
50 or 37.5
mg (Su)/
400 mg
(So)
25 mg
(Su)/40 mg
(So)
No No
S-TRAC[2] Sunitinib
Placebo
615 ccRCC > pT3b or N+ 50 mg 37.5 mg Yes No
PROTECT[3] Pazopanib
Placebo
1538
ccRCC or
mostly
ccRCC
pT2 (G3-4), ≥
pT3, or N+
600 mg 400 mg No No
10. ONGOING PHASE III ADJUVANT TRIALS:
IMMUNOTHERAPY VS PLACEBO
Parameter
IMmotion010[1]
(NCT03024996)
PROSPER[2] (NCT03055013)
KEYNOTE-564[3]
(NCT03142334)
CheckMate 914[4]
(NCT03138512)
Drug Atezolizumab Nivolumab Pembrolizumab Nivolumab + ipilimumab
Histology
Clear-cell ± sarcomatoid
histology
RCC of any histology
Clear-cell ± sarcomatoid
features
Clear-cell ± sarcomatoid
features
Dose duration 1 yr
2 doses prior to surgery and
adjuvant nivolumab for 9
mos
1 yr 6 mos
Risk
classification
T2 grade 4, T3a grade 3/4,
T3b/c any grade, T4 any grade,
or TxN+ any grade
Clinical stage ≥ T2 or
any N+
pT2, grade 4; pT3/4, any
grade; N+ M0; M1 NED
pT2aN0, grade 3-4; pT2b-T4;
N+
Primary
endpoint
DFS RFS at 5 yrs DFS DFS
BICR Yes Yes Yes Yes
Status Active, recruiting Active, recruiting Active, recruiting Active, recruiting
1.
11. CASE DISCUSSION
CT scans first reveal small,
indeterminate lung nodules
approximately 18 mos after
surgery
12. CASE DISCUSSION
Patient undergoes a lung biopsy,
further progression of lung lesions and
development of mediastinal lymph
node involvement
Pathology consistent with clear-cell RCC
ECOG PS 0
Lab results are all within normal limits
The patient has mild HTN controlled
with amlodipine
Favorable risk per IMDC criteria
13. Do you do risk stratification of your patients
in clinical practice..?
If Yes, which one do you prefer
‒ IMDC
‒ MSKCC
14. WHAT ARE THE PROGNOSTIC
INDICATORS IN mRCC DO YOU
CONSIDER WHILE CHOOSING THE
TREATMENT OPTIONS ?
20. During AS, the best overall responses were stable disease for 48 patients (83 %) and progressive disease (PD) for 10 patients (17 %), and 47 patients
With a median follow-up of 31.4 months, the
median TTP was 12.4 months (95 % confidence interval
8.4–16.5) and median overall survival was not reached
Karnofsky performance status <100 %, liver metastasis, and a time from diagnosis to AS of less
than 1 year were found to be predictive factors for a shorter TTP
29. CheckMate 214: OS and Response by IMDC Risk
Category
Tannir. ASCO GU 2020. Abstr 609. Slide credit: clinicaloptions.com
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)
30. KEYNOTE-426: OS, PFS, and ORR in
IMDC Favorable-Risk Group
OS
HR: 1.06 (95% CI: 0.60-1.86)
PFS
HR: 0.76 (95% CI: 0.57-1.09)
Mos
Patients
at Risk, n
P + A
S
Plimack. ASCO 2020. Abstr 5001.
ORR
(%)
ORR
69.6% vs 50.4%
Pembro + Axi Sunitinib
11% CR
6% CR
CR
PR
100
90
80
70
60
50
40
30
20
10
0
OS
(%)
100
90
80
70
60
50
40
30
20
10
0
85%
88%
Events, n Median
26 NR
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
*Nominal P value.
Mos
PFS
(%)
100
90
80
70
60
50
30
20
10
0
45%
42
0 6 12 18 24 30 36
138
131
111
99
88
66
67
46
41
26
13
8
0
0
0
0
Events, n
77
75
Median, Mos
(95% CI)
20.8 (15.4-28.8)
18.0 (12.5-20.8)
40
35%
31.
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
45. Considerations for Next-Line Treatment Selection
If disease control > 1 yr on first-line single-agent VEGF inhibitor, continue VEGF
inhibition with sequential single agents: such as Cabozantinib or Axitinib
If brief response to single-agent VEGF inhibition, consider a VEGF IO combination:
Axitinib + Pembrolizumab (based on Lenvatinib + Pembro data)
If no response to first-line VEGF inhibition, drop VEGF and switch to
immunotherapy: Ipilimumab + Nivolumab or Nivolumab
If no response to combination VEGF + IO switch to second line VEGF such as
Cabozantinib or Axitinib or Lenvatinib + Everolimus
‒ Phase III data support sequential VEGF therapy
‒ Limited data to support sequential IO therapy
46. WHEN WOULD YOU PREFER THE LENVATINIB +
EVEROLIMUS COMBINATION IN THE
MANAGEMENT OF mRCC?
47. 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
48. 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
49. 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
50. 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
