e-session 548000

Treatment choice and sequence for kidney cancer: updates

Expert: Dr Matias Chacon, Instituto Alexander Fleming, Buenos Aires, Argentina

Discussant: Dr Berardino De Bari, Réseau Hospitalier Neuchâtelois, La Chaux-de-Fonds, Switzerland

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Sequences in the treatment
of advanced kidney cancer

Matías Chacón
Instituto Fleming- Buenos Aires
Hospital de Agudos Ramón Madariaga- Misiones
Presidente Honorario Vicare
Director INCOAS (investigadores en oncología)
 Agenda

• General considerations in kidney cancer

• Standard treatment in first line of advanced disease

• Standard treatment in second line of advanced disease

• Are any standard sequence in advanced disease?

• Conclusions
Cancer mortality in Argentina

10.662 68.778
7.462
Renal cancer
2.314
6.380

3.970
IARC 2018
 Pathology
Adenoma Papilar
Oncocitoma
Carcinoma de Células claras
Neoplasia Quística Multilocular de células claras de bajo potencial de malignidad
Carcinoma Papilar
Carcinoma Cromófobo
Tumor híbrido oncocítico-cromófobo
Carcinoma de los conductos colectores de Bellini
Carcinoma Medular
Carcinoma de Células Renales con Traslocación de Genes de la Familia MiT
Carcinoma asociado a Neuroblastoma
Carcinoma mucinoso tubular y de células fusiformes
Carcinoma tubuloquístico
Carcinoma de células renales asociado a enfermedad quística adquirida
Carcinoma de células renales (túbulo) papilar de células claras
Carcinoma de células renales no clasificado
Carcinoma asociado al síndrome de leiomiomatosis hereditaria y carcinoma de células renales
Carcinoma asociado a translocación Xp11.
Carcinoma asociado a translocación t(6;11)
 Change in the paradigm of physiopathogenesis of kidney cancer

von Hippel- Lindau

Eugen von Hippel Arvid Lindau

Pathogenesis
 Prognostic factors in advanced renal cancer

IMDC
27:5794-5799 2009

First line

Second line

Lancet 2015
“Other” options to sequence in advanced disease: Active Surveillance

Fase 2
> 18 años
Todas las histologías
Asintomáticos
Metasectomías permitidas
No sponsor
Tac cada 3 meses
Ansiedad y depresión evaluadas
Perfil inmunológico
 “Other” options to sequence in advanced disease: Active Surveillance (AS)

Results

8-2008 to 6-2013
48 pts
FUP 38 months
Median Time of AS 14.9 months
TTP 9.4 months
OS 44.5 months
ITK (RR32%)
> LT IFN
< Tregs y cells mieloides

Rini, B.et al (2016). Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. The Lancet Oncology, 17(9)
 “Other” options to sequence in advanced disease: Surgery

Results

• 16 retrospective trials

• More common sites: lung, bone, liver and brain

• Clear cells carcinoma

• 37-54% pts alive at 5 years

• Consensus

• The adition of systemic therapy did not not showed OS benefits

(Sorafenib- Pazopanib)

Dabestani, S. et al. Local treatments for metastases of renal cell carcinoma: a systematic review. The Lancet Oncology 2014
 “Other” options to sequence in advanced disease: SBRT

Meta analysis

• 2000-2019
• 265 trials--- 28
• 1602 patients (679 intracraneal y 923 EC)
• 90% of patients 12 months local control
• Low toxicity
VEGF-R
Comparison between TKIs
VEGF and immune response are the keys of therapy

Einstein DJ, McDermott DF. Clin Adv in Hematol & Oncol. 2017;15:478-488
 Agenda

• General considerations in kidney cancer

• Standard treatment in first line of advanced disease

• Standard treatment in first second of advanced disease

• Are any standard sequence in advanced disease?

• Conclusions
 Objectives in 1L

OS PFS RR PR QOL TLT

 1L
26 years
14 years
4 years

IL 2 TKI IO+TKI

12 months 24 months > 30 months

 1L
Sunitinib 2006
Temsirolimus 2007
Interferon + Bevacizumab 2009
Pazopanib 2009
Ipilimumab+Nivolumab 2019
Axitinib +Avelumab 2020
Axitinib+Pembrolizumab 2020
Internacional guidelines-NCCN 1L
 2L

Sorafenib 2005
Everolimus 2009
Axitinib 2012
Nivolumab 2016
Cabozantinib 2020
Lenvatinib+everolimus 2020
2106 pts • 1 line

820 pts
• 2 line
(39%)
 2L
15 years
11 years
4 years

ITK mTOR IO
ITK

10 months 14 months > 20 months

 The 4 giants

KEYNOTE-426 CheckMate 214

Javelin-101
CheckMate 9ER
 The 4 giants

KEYNOTE-426 CheckMate 214

Javelin-101
CheckMate 9ER
Javelin 101- Baseline characteristics
Javelin 101- Primary and secondary objectives

Clinical benefits for the combinations in PD-L1 positive or negative

Javelin 101- Secondary Objective
Javelin 101- OS
Javelin 101- OS
Javelin 101- Safety
• First IO+TKI combination approved

• Short follow up

• Less CR

• Less Toxic?
 The 4 giants

KEYNOTE-426 CheckMate 214

Javelin-101
CheckMate 9ER
 KEYNOTE-426
Phase III Pembrolizumab plus Axitinib versus Sunitinib in advanced CCR

Key Inclusion Criteria: Pembrolizumab

200 mg IV Q3W
• Newly diagnosed or recurrent stage IV clear-cell RCC N = 432 for up to 35 cycles
+
• No previous systemic treatment for advanced disease
Axitinib 5 mg
• Karnofsky performance status ≥70 R orally twice dailya
1:1
• Measurable disease per RECIST v1.1
Sunitinib
• Provision of a tumor sample for biomarker assessment 50 mg orally once daily
for the first 4 weeks
• Adequate organ function N = 429 of each 6-week cycleb

Secondary End Points:

Stratification Factors:
• IMDC risk group (favorable vs intermediate vs poor)
• Geographic region (North America vs Western
Europe vs rest of the world)
Dual Primary End Points:
• ORR (RECIST v1.1, BICR) in ITT,
• OS and PFS (RECIST v1.1, BICR) in ITT • DOR (RECIST v1.1 BICR), patient-
reported outcomes, safety and tolerability

Plimack ASCO 2020

KEYNOTE-426: Baseline characteristics

Plimack ASCO 2020

KEYNOTE-426: update OS y PFS ASCO 2020

OS in the ITT Population

Plimack ASCO 2020

Subgroups
 KEYNOTE-426: OS by subgroups

Subgroup No. of Events/No. of Patients Hazard Ratio (95% Cl)

Overall 156/861 0.53 (0.38-0.74)
Age
<65 years 91/538 0.47 (0.30-0.73)
≥65 years 65/323 0.59 (0.36-0.97)
Sex
Male 108/628 0.54 (0.37-0.80)
Female 48/233 0.45 (0.25-0.83)
Region of enrollment
North America 31/207 0.69 (0.34-1.41)
Western Europe 31/210 0.46 (0.22-0.97)
Rest of world 94/444 0.51 (0.33-0.77)
IMDC risk category
Favorable 17/269 0.64 (0.24-1.68)
Intermediate 93/484 0.53 (0.35-0.82)
Poor 46/108 0.43 (0.23-0.81)
Karnofsky performance score
90 or 100 88/688 0.53 (0.35-0.82)
70 or 80 67/172 0.49 (0.30-0.81)
PD-LI CPS
<1 54/325 0.59 (0.34-1.03)
≥1 90/497 0.54 (0.35-0.84)
No. of metastatic organs
1 21/210 0.20 (0.07-0.57)
≥2 134/646 0.60 (0.42-0.85)
0.1 0.5 1 2
Database cutoff date: August 24, 2018. Pembrolizumab-Axitinib Sunitinib
Better Better
Plimack ASCO 2020
 KEYNOTE-426: PFS by subgroups
Subgroup No. of Events/No. of Patients Hazard Ratio (95% Cl)
Overall 395/861 0.69 (0.57-0.84)
Age
<65 years 248/538 0.70 (0.54-0.90)
≥65 years 147/323 0.63 (0.45-0.88)
Sex
Male 287/628 0.77 (0.61-0.97)
Female 108/233 0.54 (0.37-0.81)
Region of enrollment
North America 75/207 0.79 (0.50-1.25)
Western Europe 97/210 0.59 (0.39-0.89)
Rest of world 223/444 0.71 (0.54-0.92)
IMDC risk category
Favorable 90/269 0.81 (0.53-1.24)
Intermediate 232/484 0.70 (0.54-0.91)
Poor 73/108 0.58 (0.35-0.94)
Karnofsky performance score
90 or 100 292/688 0.69 (0.54-0.87)
70 or 80 102/172 0.67 (0.45-1.00)
PD-LI CPS
<1 137/325 0.87 (0.62-1.23)
≥1 240/497 0.62 (0.47-0.80)
No. of metastatic organs
1 75/210 0.54 (0.33-087)
≥2 317/646 0.73 (0.58-0.91)
0.1 0.5 1 2
Database cutoff date: August 24, 2018.
Pembrolizumab-Axitinib Sunitinib
Better Better
Plimack ASCO 2020
KEYNOTE-426: update ORR ASCO 2020

Plimack ASCO 2020

 KEYNOTE-426: update Favorable Risk group ASCO 2020

Plimack ASCO 2020

 KEYNOTE-426: update Intermediate and poor risk ASCO 2020

Plimack ASCO 2020

 KEYNOTE-426: safety

Median follow-up: 16.6 months

All Cause Treatment-Related

Pembrolizumab Sunitinib Pembrolizuma Sunitinib

+ Axitinib N = 425 b + Axitinib N = 425
Event, n (%) N = 429 N = 429
Any AE 422 (98.4) 425 (100.0) 412 (96.0) 415 (97.6)
Grade 3-5 AE 340 (79.3) 315 (74.1) 282 (65.7) 253 (59.5)
Death because of AE 14 (3.3) 16 (3.8) 4 (0.9)a 6 (1.4)b
Led to discontinuation of any treatment 142 (33.1) 63 (14.8) 119 (27.7) 46 (10.8)

Led to discontinuation of both pembrolizumab and

35 (8.2) – 28 (6.5) –
axitinib

Led to axitinib or sunitinib dose reduction 91 (21.2) 128 (30.1) 90 (21.0) 121 (28.5)
Led to interruption of any treatment 321 (74.8) 223 (52.5) 283 (66.0) 176 (41.4)

1. Soulieres et al. Presented at IKCS 2019.

KEYNOTE-426: Aes

Median follow-up: 16.6 months

Events are shown in decreasing incidence in the total population.

Data cutoff date: January 2, 2019.
KEYNOTE-426
Key note 426
Pembrolizumab + Axitinib > SUNITINIB

Clinical benefit in all subgroups

RR benefit in favorable risk group

Approved in Argentina March 2020

 The 4 giants

KEYNOTE-426 CheckMate 214

Javelin-101
CheckMate 9ER
 ESMO Presidential Symposium II
Sunday 10th September, 2017 Design CheckMate 214

Randomize 1:1 Arm A

NIVO 3 mg/kg + IPI 1 mg/kg
• Treatment-naïve Stratified by every 3 weeks for 4 doses
aRCC • IMDC prognostic score then NIVO 3 mg/kg every 2 weeks Treatment until
‒ 0 (favorable risk) progression or
• Clear-cell Patients receiving NIVO monotherapy could switch to
unacceptable
component ‒ 1 or 2 (intermediate risk) NIVO 240 mg flat dosinga
‒ 3 to 6 (poor risk) toxicity
• Measurable • Region
disease ‒ US Arm B
Patients in arm A could
‒ Canada/Europe SUN 50 mg once daily discontinue after 2 years of
• KPS ≥70%
‒ Rest of world for 4 weeks on, 2 weeks off study treatmenta
(6-week cycles)

• Co-primary endpoints: In IMDC intermediate- and poor-risk patients Crossover from SUN to NIVO+IPI was permitted for
– ORR (per IRRC), PFS (per IRRC), OS
intermediate/poor-risk patientsa
• Secondary endpoints: In intention-to-treat (ITT) patients
– ORR, PFS, OS, AE incidence rate (in all treated patients)
• Exploratory endpoints Fup minimun 17 months
– ORR, PFS, and OS in favorable-risk patients Fup median 25 months
– Outcomes by tumor PD-L1 expression level
– HR QoL based on NCCN Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) Escudier B, et al. Presented at ESMO 2017
 CheckMate 214 Baseline characteristics
IMDC intermediate/poor risk Intention to treat
NIVO + IPI SUN NIVO + IPI SUN
Characteristic
N = 425 N = 422 N = 550 N = 546
Median age, years 62 61 62 62

Male, % 74 71 75 72
IMDC prognostic score (IVRS), %
Favorable (0) 0 0 23 23
Intermediate (1–2) 79 79 61 61
Poor (3–6) 21 21 17 16

Region (IVRS), %
USA 26 26 28 28
Canada/Europe 35 35 37 36
Rest of the world 39 39 35 36

Quantifiable tumor PD-L1 expression, % n = 384 n = 392 n = 499 n = 503

<1% 74 71 77 75
≥1% 26 29 23 25

• Baseline characteristics in favorable-risk patients were similar, except tumor PD-L1

expression was lower than the intermediate/poor-risk patients and ITT population

Escudier B, et al. Presented at ESMO 2017

 42 months update
OS: IMDC Intermediate-poor risk group CheckMate 214

1.0

0.9
Minimum NIVO+IPI SUN
OS
Overall survival (probability)

0.8 follow-up N = 425 N = 422

74%
Median,
0.7 mo
NR 26.0
(28.2–NE) (22.1–NE)
60% 17.5 mo1
(95% CI)
0.6 52% HR 0.63 (0.44–0.89)
0.5 60% (99.8% CI) P < 0.001

Median,
0.4 47% mo (95%
NR 26.6
(35.6–NE) (22.1–33.4)
CI)
0.3 39% 30 mo2
HR 0.66 (0.54–0.80)
0.2 13% Absolute benefit (95% CI) P < 0.0001

Median,
0.1 47.0a 26.6
mo (95%
(35.6–NE) (22.1–33.5)
CI)
42 mo
0.0
HR 0.66 (0.55–0.80)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 (95% CI) P < 0.0001
No. at risk Months
NIVO+IPI 425 399 372 348 332 317 306 287 270 254 241 230 220 216 202 162 78 27 1 0
SUN 422 388 353 318 291 258 237 220 206 193 184 178 169 161 145 118 64 25 3 0

.
1. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290. 2. Motzer RJ, et al. Lancet Oncol 2019;20:1370–1385.
 42 months update CheckMate 214
OS: IMDC favorable risk group
1.0 93%
0.9 85%
Minimum NIVO+IPI SUN
OS
Overall survival (probability)

0.8 88% 73% follow-up N = 125 N = 124

0.7 80% Median,

NR NR
mo
(NE) (NE)
(95% CI)
0.6 -3% Absolute benefit 70%
17.5 mo1,a
HR 1.45 (0.51–4.12)
0.5 (99.8% CI) P = 0.27

Median,
0.4 mo (95%
NR NR
(NE) (NE)
CI)
30 mo2
0.3
HR 1.22 (0.73–2.04)
0.2 (95% CI) P = 0.44

Median,
0.1 mo (95%
NR NR
(NE) (NE)
CI)
42 mo
0.0
HR 1.19 (0.77–1.85)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 (95% CI) P = 0.44
No. at risk Months
NIVO+IPI 125 124 121 117 112 109 105 103 102 99 96 93 89 86 84 79 57 22 2 0
SUN 124 119 119 117 114 111 110 106 104 101 97 90 88 86 83 79 61 24 1 0
aOnly 37 deaths had occurred at the time of the database lock (21 in the NIVO+IPI arm and 16 in the SUN arm).
1. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290. 2. Motzer RJ, et al. Lancet Oncol 2019;20:1370–1385.
42 month update CheckMate 214

PFS in Intermediate-poor risk by IRC

1.0
Progression-free survival (probability)

0.9 16% Absolute benefit

0.8
Minimu
0.7 m follow- PFS
NIVO+IPI SUN
N = 425 N = 422
up
0.6
Median, mo 11.6 8.4
0.5 43% (95% CI) (8.7–15.5) (7.0–10.8)
37% 17.5 mo1
0.4 35% HR 0.82 (0.64–1.05)
(99.1% CI) P = 0.03
0.3
35% Median, mo 12.0 8.3
0.2 (95% CI) (8.7–15.5) (7.0–11.1)
22%
0.1 19% 42 mo
HR 0.76 (0.63–0.91)
(95% CI) P < 0.01
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
No. at risk Months
NIVO+IPI 425 302 229 182 159 144 126 113 98 95 90 82 75 70 56 34 13 2 0
SUN 422 280 188 136 104 88 73 59 45 36 30 25 21 16 11 8 3 0 0

1. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290.

 42 months update
PFS in Favorable risk by IRC CheckMate 214

1.0
Progression-free survival (probability)

0.9
0.8
70%
Minimu
0.7 m follow- PFS
NIVO+IPI SUN
N = 125 N = 124
up
0.6
Median, mo 15.3 25.1
0.5 46% (95% CI) (9.7–20.3) (20.9–NE)
17.5 mo1
0.4
46% 34% HR 2.18 (1.29–3.68)
(99.1% CI) P < 0.0001
0.3 33%
-6% Absolute benefit 28% Median, mo 17.8 27.7
0.2 (95% CI) (10.3–20.7) (23.2–34.5)
42 mo
0.1
HR 1.62 (1.14–2.32)
(95% CI) P < 0.01
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
No. at risk Months
NIVO+IPI 125 103 80 62 52 48 41 35 30 28 25 24 21 18 17 12 5 0
SUN 124 105 98 79 73 66 58 45 41 36 30 25 18 16 15 12 1 0

1. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290.

42 month update
ORR by IRC CheckMate 214

P < 0.0001 P = 0.02 P < 0.0001

Objective response rate, % 60 42 26 39 33 29 54

50 6

NIVO+IPI SUN
40
10 2
CR 11
30 1
PR 48
13
20
32 30
28
25
10
16

0
Primary: Intermediate/poor risk Secondary: ITT population Exploratory: Favorable risk
NIVO+IPI SUN NIVO+IPI SUN NIVO+IPI SUN
N = 425 N = 422 N = 550 N = 546 N = 125 N = 124
Median DOR, months (95% CI) NR (NE) 19.7 (16.4–26.4) NR (NE) 24.8 (19.4–27.3) NR (40.1–NE) 27.4 (23.5–40.3)
Ongoing response, n/N (%) 121/179 (68) 58/111 (52) 146/215 (68) 94/178 (53) 25/36 (69) 36/67 (54)
Stable disease, % 31 44 36 42 54 32

RC 10% Intemediate-poor risk

RC 13% Favorable risk
42 month update AEs CheckMate 214
100 97
92
90
NIVO+IPI SUN
New events/ patients at risk, %a,b

80 Grade 1–2
70 Grade 3–4
61
60

50
44 43
40
32
30 28
55 24
21 21
20 17
38 16
12 11
8
10 21 7
15
11 9
8 8 7 6
4 3
0
1 ≤6 mo 2 >63 to ≤12 4
mo >12
5 to ≤18 6
mo >18
7 to ≤24 8
mo >24
9 to ≤30 10
mo >30
11 to ≤36 12
mo >36
13 to ≤42 14
mo 15>42 mo 16
No. at risk Time interval
NIVO+IPI
SUN 547 535 491 468 442 402 410 346 372 309 336 278 309 256 286 227

AEs 94% vs 97%

AEs grado 3-4 47% vs 64%
AEs 3- 4 with NIVO+IPI after 2 years was ≤2.4%
 CheckMate 214

At 4 years clear benefit with IO+IO vs TKI

Longest fup clinical trial after 2006

CR in more than 10% of patients

High Toxicity but manageable

Why so many CR in favorable risk group but without

advantage in PFS
 The 4 giants

KEYNOTE-426 CheckMate 214

Javelin-101
CheckMate 9ER
 Still not
approved
 Still not
Población de checkmate 9er approved

esmo2020
 Still not
approved

CHECKMATE 9ER

esmo2020
Slide 5
 Agenda

• General considerations in kidney cancer

• Standard treatment in first line of advanced disease

• Standard treatment in second line of advanced disease

• Are any standard sequence in advanced disease?

• Conclusions
Options in second line

PD

2 line
 Phase 2-3 that support evidence in second line therapy

Everolimus Axitinib Nivolumab Cabozantinib Everolimus + lenvatinib

2L
 AXIS: diseño del estudio
AXIS: design
RA
Advanced Clear cell carcinoma N
D
After 1 line: O Axitinib
M 5 mg BID*
• Sunitinib I
N=361
Z
• Bevacizumab +IFN N=723 A
• Temsirolimus C Sorafenib
Í 400 mg BID*
• Citoquines O
N N=362
1:1
9-2008 a 7-2010
Primary objective: PFS
Secondary objective: OS, ORR, safety, QoL (FKSI, EQ-5D)

Rini BI, et al. Lancet 2011;378:1931–1939

 AXIS: PFS (IRC)
Dose intensity: Axitinib 99% vs Sorafenib 92%

1.0 mPFS, mo 95% CI

0.9 Axitinib 6.7 6.3, 8.6
0.8 Sorafenib 4.7 4.6, 5.6
PFS (probability) 0.7 P<0.0001 (log-rank)
0.6 Stratified HR 0.665
0.5 (95% CI: 0.544, 0.812)
0.4
0.3
0.2
0.1
0.0
0 2 4 6 8 10 12 14 16 18 20
Time (months)
Subjects at risk, n
Axitinib 361 256 202 145 96 64 38 20 10 1 0
Sorafenib 362 224 157 100 51 28 12 6 3 1 0

Rini BI, et al. Lancet 2011;378:1931–1939

Phase III Study Design
“Otras” opciones en cáncer renal avanzado: Terapias dirigidas
 METEOR Study Design

8-2013 a 11-2014
173 centros PFS
26 países OS-RR-Seguridad
Meteor- safety

Dose reduction 64% Dose reduction 25%

Median dose 42.8 mg Median dose 9.1 mg
Discontinuation 13 % Discontinuation 11 %
Indirect comparison in 2-3L
 International guidelines 2L
NCCN

ESMO
 Agenda

• General considerations in kidney cancer

• Standard treatment in first line of advanced disease

• Standard treatment in second line of advanced disease

• Are any standard sequence in advanced disease?

• Conclusions
Sequences or subsequent therapies?

A --------> B
vs
B--------->A

A --------> B
La población con cáncer renal como ¨foco¨ de atención

4 GIANTS

Keynote 426 10-2016 to 2-2018

Check-mate 214 10-2014 to 2-2016

Javelin 101 3-2016 to 12-2017

Check-mate9er too young

 Subsequent therapies

42%

20.8%

54%

Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib

vs sunitinib in first-line treatment for advanced renal cell
carcinoma: First results from the randomized phase III CheckMate 43%
9ER trial. ESMO Virtual Congress 2020.
 True sequences trials in RCC

Sunitinib post everolimus Everolimus post Sunitinib

Sunitinib post Sorafenib Sorafenib post Suniinib

56 year old female, non smoker, incidental finding (9/2020)

Your recommendation is …
SUNITINIB
OS NS

Surgery ---> SUNITINIB

INNOVATION?
 TIVO-3
Randomized Trial in Relapsed Advanced Renal Cell Carcinoma

N = 350

• Recurrent/metastatic RCC Tivozanib

Endpoints

RANDOMIZE 1:1
• ECOG PS 0 or 1
• Primary: PFS
• Failed at least two prior regimens
including • Secondary: OS, ORR, DoR,
VEGFR-TKI Sorafenib Safety and Tolerability for ITT
• Stratified by IMDC and prior regimen
(TKI-TKI; TKI-CPI; TKI-Other)

TKI – VEGFR TKI; CPI – checkpoint inhibitor

N 159 ORR 32% RC 6% PFS 8.3 meses (19.5 y 5.5) Salvataje RR 13%

N 46 ORR 15.2% DCR 52.2%. PFS 16 semanas

 NIVO + IPI as rescue therapy

HCRN GU16-260 OMNIVORE FRACTION TITAN RCC Salvage Ipi/Nivo

ASCO 2020 ASCO 2020 ASCO 2020 ESMO 2019 (JCO 2020)

N 123 83 46 207 45
Prior TKI No Yes Yes Yes Yes
Timing Nivo→Ipi Nivo→Ipi Nivo+Ipi Nivo→Ipi I/N after prior IO

Ipi doses 4 2 4 4 4
ORR 13% 4% 15% 12% 20%
CR 0% 0% 0% 3% 0%
YES

No
Is there any biomaker for TTD or IO?

Best biomakers are toxicities

IO: NO Hypertension
FATIGUE
ASTHENIA
MYELOSUPRESION
HYPOTIROIDISM

TT: YES
 Kidney ccRCC immune classification (KIC) enhances the predictive value of T effector (Teff) and
angiogenesis (Angio) signatures in response to nivolumab (N)

Si

Results from the phase II biomarker driven trial with nivolumab (N) and ipilimumab or VEGFR tyrosine
kinase inhibitor (TKI) in naïve metastatic kidney cancer (m-ccRCC) patients (pts): The BIONIKK trial

Ni
 Axitinib+Pem
Sunitinib IO+IO+ITK?
Axitinib+Avelumab
Pazopanib
Ipi+Nivolumab
Cabozantinib+Nivolumab
 Agenda

• General considerations in kidney cancer

• Standard treatment in first line of advanced disease

• Standard treatment in second line of advanced disease

• Are any standard sequence in advanced disease?

• Conclusions
 Sequences in advanced kidney cancer
Conclusions

• Genetic knowledge in RCC is one of the signals of the advance in therapies

• Systemic and local therapies are showing new scenarios for the MDT in RCC cancer patients

• First line therapy in RCC is evolving so fast

• Second line therapies are doing well

• Sequences are missinterpreted as the subsecuent therapies of RCT

• Lack of prospective evidence in sequences with new IO+IO or IO+TKI combinations

• New design in clinical trials…

Case- G 74 years old

2018
2003 Lung and bone PD +
2014 Intraventricular
Small lung nodules recurrence and one
symptomatic bone relapse
Lung PD but PS 0 SBRT and Nivolumab

1996 2012 2016 2020

CCC 3 cm SQ Nodule resection Lung PD Lung PD
Radical nephrectomy Intraventricular lesion Cabozantinib
Sunitinib SD
Case- G 74 años

2018
PD leve pulmonar y ósea
2014 + Intraventricular
PD leve pulmonar- PS0 SBRT y Nivolumab

1996 2016 2020

2012
CCC 3 cm Resección de nódulo PD leve pulmonar- lesión PD leve pulmonar
Nefrectomía radical SC sintomático intraventricular Cabozantinib
Sunitinib EE
Case
G 74 años