next generation drugs in kidney...
TRANSCRIPT
KIDNEY CANCER SUBTYPES
Papillary
Type 1 and 2
Medullary Collecting
duct
Clear cell
TranslocationChromophobe
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.
VEGF & MTOR PATHWAYS IN RCC
Reprinted from The Lancet, 373(9669), Rini BI, et al., Renal cell carcinoma, 1119–32. Copyright 2009, with permission from Elsevier.
EVOLUTION OF SYSTEMIC
THERAPIES IN KIDNEY CANCER
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.
OVERALL SURVIVAL IN KIDNEY
CANCER
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.
NEXT GENERATION DRUGS IN
KIDNEY CANCER
Part 1: Recently approved agents
Cabozantinib
Nivolumab
Lenvatinib + everolimus
Part 2: Future directions
Combination targeted therapy and immune checkpoint inhibitor
Combination of immune checkpoint inhibitor
A PHASE I STUDY OF
CABOZANTINIB (XL184)
In patients with renal cell cancer: ORR
Choueiri TK, et al., Ann Oncol 2014;25(8):1603–8. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO).
A PHASE I STUDY OF
CABOZANTINIB (XL184)
In patients with renal cell cancer: PFS and OS
Choueiri TK, et al., Ann Oncol 2014;25(8):1603–8. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO).
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced renal cell carcinoma: METEOR
Choueiri TK, et al., The Lancet Oncology 2016;17(7):917–27.
Cabozantinib versus everolimus in advanced renal
cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced renal cell carcinoma: METEOR
Inclusion Criteria:
Clear cell histology
Progressive disease post at least
1 line VEGF targeted therapy
Primary Endpoint: PFS
Secondary Endpoints: OS, ORR,
safety and tolerability
CABOMETYX™
60 mg once daily§
(N=330)
Everolimus
10 mg once daily§
(N=328)
Randomised
658 patients†‡
Randomisation 1:1
No crossover allowed
Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial, 917-927, Copyright 2016, with permission from Elsevier.
† Dose reductions were allowed in both arms.‡ The primary progression-free survival (PFS) analysis was conducted in the first 375 subjects randomized to treatment. The intent-to-treat (ITT) population included all 658 patients.§Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients in both arms who had disease progression could continue treatment at the
discretion of the investigator.
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced renal cell carcinoma: METEOR: Demographics
Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial, 917-927, Copyright 2016, with permission from Elsevier.
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced RCC: METEOR: PFS
Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial, 917-927, Copyright 2016, with permission from Elsevier.
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced RCC: METEOR: ORR
Choueiri TK, et al., Lancet Oncol 2016;17(7):917–27.
Cabozantinib
N=330
Everolimus
N=328
IRC Investigator IRC Investigator
Objective response rate
(95% CI) 17 (13–22) 24 (19–29) 3 (2–6) 4 (2–7)
Best overall response, n (%)
Confirmed complete response 0 0 0 0
Confirmed partial response 57 (17) 78 (24) 11 (3) 14 (4)
Stable disease 216 (65) 209 (63) 203 (62) 205 (63)
Progressive disease 41 (12) 29 (9) 88 (27) 87 (27)
Not evaluable or missing 16 (5) 14 (4) 26 (8) 22 (7)
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced RCC: METEOR: OS
Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial, 917-927, Copyright 2016, with permission from Elsevier.
OS AND PFS IN SUBGROUPS
Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a
randomised, open-label, phase 3 trial, 917-927, Copyright 2016, with permission from Elsevier.
Tumour MET status
MSKCC risk group
Bone metastases
Visceral and bone metastases
Duration of first VEGFR TKIs
Number of previous VEGFR TKIs
OS PFS
BONE METASTASES
NE, not estimable; SRE, skeletal related event
Escudier B, et al., J Clin Oncol 2018;36(8):765–72.
BONE METASTASES BONE and VISCERAL METASTASES NO BONE METASTASES
CABOZANTINIB
N=77
EVEOLIMUS
N=65
CABOZANTINIB
N=60
EVEOLIMUS
N=52
CABOZANTINIB
N=253
EVEOLIMUS
N=263
ORR
% (95% CI)17 (9–27) 0 20 (11–32) 0 17 (13–23) 4 (2–7)
PFS
MONTHS (95% CI) 7.4 (5.5–10.4) 2.7 (1.9–3.8) 5.6 (4.5–9.4) 1.9 (1.8–2.9) 7.4 (6.5–9.2) 4.2 (3.8–5.5)
OS
MONTHS (95% CI)
20.1
(14.9–NE)
12.1
(9.6-16.4)
20.1
(12.4-NE)
10.7
(7.5-12.5)
NE
(18.4–NE)
17.5
(15.7–19.6)
SRE
No. (%)18 (23) 19 (29) - - 31 (12) 7 (10)
TIME TO SRE
MONTHS (range)3.7 (0.4–14.5) 2.5 (0.3–7.3) - - 5.6 (0.5–18.4) 4.3 (0.7–13.4)
Choueiri TK, et al., Lancet Oncol 2016;17(7):917–27.
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced RCC: METEOR: Toxicity
n (%)
Cabozantinib (N=331) Everolimus (N=322)
Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4
Any adverse event 70 (21) 210 (63) 25 (8) 103 (32) 167 (52) 26 (8)
Diarrhoea 206 (62) 43 (13) 0 85 (26) 7 (2) 0
Fatigue 159 (48) 36 (11) 0 130 (40) 24 (7%) 0
Nausea 158 (48) 15 (5) 0 92 (29) 1 (<1) 0
Decreased appetite 146 (44) 10 (3) 0 111 (35) 3 (1) 0
Palmar-plantar erythrodysaesthesia syndrome 115 (35) 27 (8) 0 16 (5) 3 (1) 0
Vomiting 106 (32) 7 (2) 0 44 (14) 3 (1) 0
Weight decreased 105 (32) 9 (3) 0 42 (13) 0 0
Constipation 89 (27) 1 (<1) 0 64 (20) 1 (<1) 0
Dysgeusia 80 (24) 0 0 30 (9) 0 0
Hypothyroidism 76 (23) 0 0 1 (<1) 1 (<1) 0
Hypertension 73 (22) 49 (15) 0 14 (4) 12 (4) 0
Dysphonia 68 (21) 2 (1) 0 16 (5) 0 0
Cough 67 (20) 1 (<1) 0 107 (33) 3 (1) 0
Stomatitis 65 (20) 8 (2) 0 71 (22) 7 (2) 0
Mucosal inflammation 60 (18) 5 (2) 0 64 (20) 10 (3) 1 (<1)
Dyspnoea 56 (17) 10 (3) 0 82 (26) 11 (3) 3 (1)
Anaemia Hypertriglyceridaemia
42 (13)17 (5)
19 (6)4 (1)
00
73 (23)31 (10)
53 (17)7 (2)
03 (1)
Hyperglycaemia 15 (5) 2 (1) 1 (<1) 46 (14) 16 (5) 0
Proteinuria 37 (11) 8 (2) 0 28 (9) 2 (1) 0
CABOZANTINIB VERSUS
EVEROLIMUS
In advanced RCC: METEOR – Tolerability
Cabozantinibn=331
Everolimusn=322
Median duration exposure, months (IQR) 8.3 (4.2–14.6) 4.4 (1.9–8.6)
Median daily dose, mg (IQR) 43 (36–56) 9 (7–11)
Dose reductions, n (%) 206 (62) 80 (25)
Drug discontinuation*, n (%) 40 (12) 34 (11)
Data at December 2015 cut off
*Discontinuation for adverse event not related to progression
IQR interquartile range
Choueiri TK, et al., Lancet Oncol 2016;17(7):917–27.
CABOZANTINIB VS. SUNITINIB AS
INITIAL TARGETED THERAPY
For patients with metastatic RCC of poor or intermediate risk:
CABOSUN
Choueiri TK, et al., J Clin Oncol 2017;35(6):591–7.
Cabozantinib versus sunitinib as initial targeted therapy for
patients with metastatic renal cell carcinoma of poor or
intermediate risk: The Alliance A031203 CABOSUN Trial
CABOZANTINIB VS. SUNITINIB AS
INITIAL TARGETED THERAPY
For patients with metastatic RCC of poor or intermediate risk:
CABOSUN
Choueiri TK, et al., J Clin Oncol 2017;35(6):591–7.
Cabozantinib
PO QD for 6 weeks
Sunitinib
PO QD for 4 weeks
N=150
Locally advanced or metastatic RCC
No prior systemic treatment
CABOSUN: PFS
Cabozantinib Median PFS 8.2 months
Sunitinib Median PFS 5.6 months
HR 0.66; 95% CI, 0.46–0.95; p=0.012
Choueiri TK, et al., J Clin Oncol 35(6), 2017: 591–7. Reprinted with permission. © 2017, American Society of Clinical Oncology. All rights reserved.
CABOSUN: RESPONSE
Choueiri TK, et al., J Clin Oncol 35(6), 2017: 591–7. Reprinted with permission. © 2017, American Society of Clinical Oncology. All rights reserved.
CABOSUN: OS
Cabozantinib Median OS 30.3 months
Sunitinib Median OS 21.8 months
HR, 0.80; 95% CI, 0.50 to 1.26
Choueiri TK, et al., J Clin Oncol 35(6), 2017: 591–7. Reprinted with permission. © 2017, American Society of Clinical Oncology. All rights reserved.
CABOSUN: TOXICITY
Adverse events
Choueiri TK, et al., J Clin Oncol 35(6), 2017: 591–7. Reprinted with permission. © 2017, American Society of Clinical Oncology. All rights reserved.
A PHASE 1B CLINICAL TRIAL OF
LENVATINIB + EVEROLIMUS
For treatment of mRCC
Molina AM, et al., Cancer Chemother Pharmacol. 2014;73(1):181–9. Licensed under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC
Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82.
Major: Progression-free survivalb
Other: Objective response rateRandomised
1:1:1
Other: Overall survival
LENVIMA 18 mg +
everolimus 5 mg (n=51)
LENVIMA 24 mg (n=52)
Everolimus 10 mg (n=50)
153 patientsa
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: Baseline demographics
Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82.
Lenvatinibplus
everolimus(n=51)
Single-agent
lenvatinib(n=52)
Single-agent
everolimus(n=50)
Age (years) 61 (44-79) 64 (41-79) 59 (37-77)
Sex, n (%)Menwomen
35 (69)16 (31)
39 (75)13 (25)
38 (76)12 (24)
ECOG performance status, n (%)01
27 (53)24 (47)
29 (56)23 (44)
28 (56)22 (44)
MSKCC risk group, n (%)FavourableIntermediatePoor
12 (24)19 (37)20 (39)
11 (21)18 (35)23 (44)
12 (24)19 (38)19 (38)
Heng risk group,* n (%)FavourableIntermediatePoor
8 (16)32 (64)10 (20)
7 (14)33 (64)12 (23)
9 (18)29 (58)12 (24)
Haemoglobin, n (%)≤130 g/L (men) or ≤115 g/L (women)>130 g/L (men) or >115 g/L (women)
33 (65)
18 (35)
36 (69)
16 (31)
31 (62)
19 (38)
Corrected serum calcium, n (%)≥2.5 mmol/L<2.5 mmol/L
6 (12)44 (88)
8 (15)44 (85)
8 (16)42 (84)
Number of metastases, n (%)12≥3
18 (35)15 (29)18 (35)
9 (17)15 (29)28 (54)
5 (10)15 (30)30 (60)
Lenvatinibplus
everolimus(n=51)
Single-agent
lenvatinib(n=52)
Single-agent
everolimus(n=50)
Site of metastasis, n (%)BoneLiverLungLymph nodes
12 (24)10 (20)27 (53)25 (49)
13 (25)14 (27)35 (67)31 (60)
16 (32)13 (26)35 (70)33 (66)
Previous nephrectomy,† n (%) 44 (86) 43 (83) 48 (96)
Previous VEGF-targeted therapy,‡
n (%)AxitinibBevacizumabPazopanibSorafenibSunitinibTivozanibOther
1 (2)0
9 (18)1 (2)
36 (713 (6)1 (2)
2 (4)1 (2)
13 (25)0
35 (67)1 (2)
0
04 (8)
13 (26)2 (4)
28 (56)2 (4)1 (2)
Duration of previous VEGF-targeted therapy (months)
0.8(2.0-66.2)
14.5 (0.7-81.8)
8.9 (1.6-57.8)
Best response for previous VEGF-targeted therapy, n (%)Complete responsePartial responseStable diseaseProgressive diseaseNot evaluated or unknown
1 (2)14 (28)20 (39)7 (14)9 (18)
010 (19)28 (54)10 (19)
4 (8)
010 (20)21 (42)15 (30)
4 (8)
Previous checkpoint inhibitor therapy
1 (2) 2 (4) 2 (4)
Previous interferon therapy 4 (8) 3 (6) 7 (14)
Previous radiotherapy 6 (12) 11 (21) 11 (22)
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: PFS
Lenvatinib
plus
everolimus(n=51)
Single-
agent
lenvatinib(n=52)
Single-
agent
everolimus (n=50)
Progression-free survival
Events26
(51%)
38
(73%)
37
(74%)
Median
(95% CI)
progression-
free survival (months)
14.6
(5.9-20.1)
7.4
(5.6-10.2)
5.5
(3.5-7.1)
Progression-free survival (95% CI)
At 6 months 64% (48-76) 63% (48-75) 39% (24-53)
At 12 months
51% (35-65) 34% (21-48) 21% (10-36)
Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial, 1473–82, Copyright 2015, with permission from Elsevier.
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: Independent assessment of PFS
Lenvatinib + everolimus vs. everolimus
HR 0.45 [95% CI 0.27–0.79]; p=0.0029
Lenvatinib vs. everolimus
HR 0.62 [95% CI 0.37–1.04]; p=0.12
Reprinted from The Lancet Oncology, 17(1), Motzer R, et al., Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma,
e4–e5, Copyright 2016, with permission from Elsevier.
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: ORR
Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial, 1473–82, Copyright 2015, with permission from Elsevier.
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: OS
Lenvatinib + everolimus versus everolimus
HR 0.55, 95% CI 0.30–1.01; p=0.062
Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial, 1473–82, Copyright 2015, with permission from Elsevier.
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: OS
Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial, 1473–82, Copyright 2015, with permission from Elsevier.
LENVATINIB, EVEROLIMUS AND
THE COMBINATION
In patients with mRCC: Lenvatinib + everolimus vs. lenvatinib – PFS
Lenvatinib + everolimus vs. lenvatinib
HR 0.66, 95% CI 0.39–1.10; p=0.12
Reprinted from The Lancet Oncology, 17(1), Motzer R, et al., Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma,
e4–e5, Copyright 2016, with permission from Elsevier.
LENVATINIB, EVEROLIMUS & THE
COMBINATION
In patients with mRCC: Lenvatinib + everolimus vs. lenvatinib – OS
Lenvatinib + everolimus vs. lenvatinib
HR 0.75, 0.43–1.30; p=0.32
Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial, 1473–82, Copyright 2015, with permission from Elsevier.
LENVATINIB, EVEROLIMUS & THE
COMBINATION
In patients with mRCC: Toxicity
Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82.
n (%)
Lenvatinib plus everolimus (n=51) Lenvatinib (n=52) Everolimus (n=50)
Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4
Any TEAE 14 (28) 29 (57) 7 (14) 8 (15) 38 (73) 3 (6) 23 (46) 21 (42) 4 (8)
Diarrhoea 33 (65) 10 (20) 0 31 (60) 6 (12) 0 16 (32) 1 (2) 0
Decreased appetite 23 (45) 3 (6) 0 28 (54) 2 (4) 0 9 (18) 0 0
Fatigue or asthenia 23 (45) 7 (14) 0 22 (42) 4 (8) 0 18 (36) 0 1 (2)
Vomiting 19 (37) 3 (8) 0 18 (35) 2 (4) 0 5 (10) 0 0
Nausea 18 (35) 3 (6) 0 28 (54) 4 (8) 0 8 (16) 0 0
Cough 19 (37) 0 0 8 (15) 1 (2) 0 15 (30) 0 0
Hypercholesterolaemia 16 (31) 1 (2) 0 5 (10) 0 1 (2) 8 (16) 0 0
Decreased weight 15 (29) 1 (2) 0 22 (42) 3 (6) 0 4 (8) 0 0
Stomatitis 15 (29) 0 0 12 (23) 1 (2) 0 20 (40) 1 (2) 0
Hypertriglyceridaemia 14 (27) 4 (8) 0 5 (10) 2 (4) 0 8 (16) 4 (8) 0
Hypertension 14 (27) 7 (14) 0 16 (31) 9 (17) 0 4 (8) 1 (2) 0
Proteinuria 9 (18) 2 (4) 0 6 (12) 10 (19) 0 6 (12) 1 (2) 0
Rash 9 (18) 0 0 9 (17) 0 0 11 (22) 0 0
Hyperglycaemia 8 (16) 0 0 3 (6) 0 0 6 (12) 4 (8) 1 (2)
Back pain 8 (16) 2 (4) 0 11 (21) 0 0 7 (14) 0 0
Mouth-ulceration 5 (10) 0 0 0 0 0 4 (8) 1 (2) 0
Palmar-plantarerythrodysaesthesia syndrome
4 (8) 0 0 8 (15) 0 0 2 (4) 0 0
Anaemia 4 (8) 4 (8) 0 3 (6) 1 (2) 0 7 (14) 6 (12) 0
NIVOLUMAB
Atkins MB, et al., Ann Oncol 2017;28(7):1484–94. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO)
CHECKMATE 010
Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82.
Endpoint0.3 mg/kg
(n=60)
2 mg/kg
(n=54)
10 mg/kg
(n=54)
Overall response 12 (20%) 12 (22%) 11 (20%)
Median progression-free
survival2.7 months 4.0 months 4.2 months
Median overall survival 18.2 months 25.5 months 24.7 months
1-year overall survival 63% 72% 70%
Treatment related serious
adverse events2 (3.4%) 6 (11%) 4 (7.4%)
LONG-TERM OS WITH NIVOLUMAB
In previously treated patients with advancer RCC from
Phase I and II studies
NE, not estimableMcDermott DF, et al., J Clin Oncol 2016;34(15_suppl):abstr. 4507. Reproduced with permission from Dr McDemott.
In Phase I and II studies, minimum follow-up was 50.5 months and 49.2 months,
respectively
CHECKMATE 025
Nivolumab vs. everolimus in advanced RCC
Motzer RJ, et al., N Engl J Med 2015;373(19):1803–13.
Nivolumab versus Everolimus in Advanced
Renal-Cell Carcinoma
CHECKMATE 025
Nivolumab vs. everolimus in advanced RCC
*One or two previous regimens; no more than three total previous regimens, including cytokines and cytotoxic chemotherapy drugs.
†1-hour infusion; dose modifications were not permitted.
Motzer RJ, et al., N Engl J Med 2015;373(19):1803–13.
OPDIVO®
(nivolumab)
monotherapy 3 mg/kg
IV every 2 weeks†
(n=410)
Everolimus
10 mg qd po
(n=411)
Randomised
1:1
Patients with
ADVANCED RCC
previously treated with
a prior anti-angiogenic
systemic therapy*
Primary
endpoint
Overall
survival
Treatment
continued
until disease
progression
or
unacceptable
toxicity
CHECKMATE 025: BASELINE
DEMOGRAPHICS
Nivolumab vs. everolimus in advanced RCC
From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19):1803-13. Copyright © 2015, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
CHECKMATE 025: OS
Nivolumab vs. everolimus in advanced RCC
From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19):1803-13. Copyright © 2015, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
CHECKMATE 025: ORR
Nivolumab vs. everolimus in advanced RCC
*For patients without progression or death, duration of response is defined as the time from the first response (CR/PR) date to the date
of censoring.
Motzer RJ, et al.. N Engl J Med 2015;373(19):1803–13.
Nivolumab (n=410) Everolimus (n=411)
Objective response rate, n (%) 103 (25) 22 (5)
Odds ratio (95% CI) 5.98 (3.68–9.72)
Best overall response, n (%)
Complete response
Partial response
Stable disease
Progressive disease
Not evaluated
4 (1)
99 (24)
141 (34)
143 (35)
23 (6)
2 (1)
20 (5)
227 (55)
114 (28)
48 (12)
Median time to response,
months (range)3.5 (1.4–24.8) 3.7 (1.5–11.2)
Median duration of response,
months (range)*12.0 (0–27.6) 12.0 (0–22.2)
CHECKMATE 025: PFS
Nivolumab vs. everolimus in advanced RCC
From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19):1803-13. Copyright © 2015, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
CHECKMATE 025: TOXICITY
Nivolumab vs. everolimus in advanced RCC
No Grade 5 toxicity associated with nivolumab
Discontinuation for AEs: Nivolumab 8%, everolimus 13%
From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19):1803-13. Copyright © 2015, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
IMMUNE RELATED RESPONSE
CRITERIAChanges in tumour burden in immune-related response criteria (irRC), compared with RECIST
Maronne KA, et al., Oncology (Williston Park) 2016;30(8):713–21.
Criteria irRCª RECIST v1.1
Progressive disease ≥25% ↑vs. nadir (at any time) in two
consecutive images ≥4 wk apart
≥20% ↑ in sum of target lesion diameters, and
must be absolute ↑ of ≥5 mm vs. smallest
diameter sums on study (including baseline sum, if
that is smallest)
Stable disease 50% ↓ vs. baseline cannot be established,
nor can 25% ↑ vs. nadir
Neither sufficient ↑ nor ↓ in target lesion sums to
qualify for PD or PR compared with the smallest
diameter sums on study
Partial response ≥50% ↓ vs. baseline in two observations
≥4 wk apart
≥30% ↓ in sum of target lesion diameters vs.
baseline diameter sums
Complete response Disappearance of all lesions in two
consecutive observations ≥4 wk apart
Disappearance of all target lesions
New, measurable lesions
(≥5 x 5 mm)
Combined into total tumour burden Considered to have PD
New, non-measurable
lesions (<5 x 5 mm)
Do not define progression; preclude irCR Depends on baseline measurements; can be
considered to have CR-PD in certain scenarios
Non-index lesions Contribute to defining irCR; complete
disappearance required
Considered to have PD
ªirRC often require confirmation by a second consecutive assessment ≥4 weeks later.
RECIST, Response Evaluation Criteria in Solid Tumours.
REGULATORY BODY STATUS
FDA approval EMA approval
Cabozantinib April 2016 June 2016
Nivolumab November 2015 February 2016
Lenvatinib + everolimus May 2016 June 2016
CHOICE OF THERAPY
Cabozantinib Nivolumab
PD as best response 14% PD as best response 35%
PFS benefit No PFS benefit
Most benefit in good and intermediate risk Most benefit in poor risk
Equal benefit across all age subgroups Less benefit in patients >75
High rate of toxicity Favourable toxicity profile
Oral administration Intravenous administration
Bone metastases -
NEXT GENERATION DRUGS IN
KIDNEY CANCER
Part 1: Recently approved agents
Cabozantinib
Nivolumab
Lenvatinib + everolimus
Part 2: Future directions
Combination targeted therapy and immune checkpoint inhibitor
Combination of immune checkpoint inhibitor
PRIMARY, ADAPTIVE, AND
ACQUIRED RESISTANCE TO
CANCER IMMUNOTHERAPY
Reprinted from Cell, 168(4), Sharma P, et al., Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy, 707–23, Copyright 2017, with
permission from Elsevier.
THE CANCER IMMUNOGRAM
From Blank CU, et al., The “cancer immunogram”. Science 2016; 352(6286):658–60. Reprinted with permission from AAAS.
COMBINATION THERAPIES
1. Combination targeted therapy and immune checkpoint inhibitor
2. Combination of immune checkpoint inhibitors
CHECKMATE 016: STUDY DESIGN
For expansion cohorts N3I1 and N1I3, 1 prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC was allowed if
recurrence occurred ≥6 months after the last dose of adjuvant or neoadjuvant therapy. Interferon alpha or interleukin-2 were allowed
as prior therapy. DOR, duration of response; ORR, objective response rate; Q2W, every 2 weeks; Q3W, every 3 weeks.
Hammers HJ, et al., J Clin Oncol 2017;35(34):3851–8.
Previously treated or
treatment-naïve
patients with mRCC
Treatment-naïve
patients with mRCC
Arm N3I1:
Nivolumab 3 mg/kg IV +
ipilimumab 1 mg/kg IV Q3W x4
Arm N1I3:
Nivolumab 1 mg/kg IV +
ipilimumab 3 mg/kg IV Q3W x4
Arm N3I3:
Nivolumab 3 mg/kg IV +
ipilimumab 3 mg/kg IV Q3W x4
Ran
do
mis
ed
Co
nti
nu
ou
s n
ivo
lum
ab3
mg
/kg
IV
Q2W
Primary endpoint
Safety
(AEs, serious AEs,
laboratory tests)
Secondary endpoint
Efficacy
(ORR, DOR,
OS, PFS)
CHECKMATE 016: RESPONSES
Hammers HJ, et al. J Clin Oncol 2017;35(34):3851–8. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
CHECKMATE 016: PFS
Hammers HJ, et al., J Clin Oncol 2017;35(34):3851–8. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
CHECKMATE 016: OS
Hammers HJ, et al., J Clin Oncol 2017;35(34):3851–8. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
CHECKMATE 214
IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status;
Q2W, every 2 weeks; QW3, every 3 weeks.
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr. LBA5.
Arm A
Nivolumab 3 mg/kg IV +
ipilimumab 1 mg/kg IV Q3W for
4 doses, then nivolumab 3 mg/kg
IV Q2W
Arm B
Sunitinib 50 mg orally once daily
for 4 weeks (6-week cycles)
Randomised
1:1
Treatment until
progression or
unacceptable
toxicity
Treatment-
naïve advanced
or metastatic
clear-cell RCC
Measurable
disease
KPS ≥70%
Tumour tissue
available for
PD-L1 testing
Stratified by
IMDC prognostic
score (0 vs 1–2 vs
3–6)
Region (US vs
Canada/Europe vs
Rest of World)
Patients Treatment
CHECKMATE 214: ORR
Escudier B, et al,. Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
CHECKMATE 214:
DURATION OF RESPONSE
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
CHECKMATE 214: PROGRESSION
FREE SURVIVAL: CO-PRIMARY ENDPOINT
PFS per IRRC: IMDC intermediate/poor risk
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
CHECKMATE 214: OVERALL
SURVIVAL: CO-PRIMARY ENDPOINT
OS: IMDC intermediate/poor risk
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
CHECKMATE 214: PD-L1
EXPRESSION: EXPLORATORY ENDPOINT
PFS by PD-L1 expression: IMDC intermediate/poor risk
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
EXPLORATORY ENDPOINT
ORR and PFS: IMDC favourable risk
a11% of patients in both arms had tumour PD-L1 expression ≥1%; bIRRC-assessed by RECIST v1.1; cIRRC-assessed.
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
SECONDARY ENDPOINT
Treatment-related adverse events: All treated patients
aTwo patients had grade 5 cardiac arrest. bPneumonitis, immune mediated bronchitis, lower GI haemorrhage, hemophagocytic
syndrome, sudden death, liver toxicity, lung infection. cCardiac arrest (n=2), heart failure, multiple organ failure.
Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
CHECKMATE 214: TOXICITY
Immune-mediated adverse events: All treated patients
Immune-mediated AE analyses included events, regardless of causality, occurring <100 days of the last dose. These analyses were
limited to patients who received immune modulating medication for treatment of the event, except endocrine events that were included
in the analysis regardless of treatment since these events are often managed without immunosuppression.Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.
60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event
Secondary immunosuppression with infliximab (3%) and mycophenolic acid (1%) was reported
COMBINATION TARGETED THERAPY
AND IMMUNE CHECKPOINT INHIBITOR
Decreased vascularity, decreased permeability and Impaired lymphocyte trafficking
The promotion of populations of immunosuppressive immune cells in the tumour
microenvironment
Functional impairment of immune cells
Einstein DJ, McDermott DF, Clin Adv Hematol Oncol 2017;15(6):478–88.
COMBINATION CHECKPOINT
INHIBITOR + TKI
Javelin Renal 100 Phase 1b Axitinib + avelumab First Line
NCT02133742 Phase 1 Pembrolizumab + axitinib First Line
NCT01633970 Phase 1 Atezolizumab + bevacizumab First Line
NCT01472081 Phase 1 Nivolumab + sunitinib or pazopanib≥1 prior systemic
therapy
NCT02014636 Phase 1Pembrolizumab + pazopanib 600 mg or
pazopanib 800 mgFirst Line
IMmotion 150Randomised
Phase 2 Atezolizumab + bevacizumab vs
sunitinibFirst line
AVELUMAB + AXITINIB IN
UNTREATED ADVANCED RCC
JAVELIN Renal 100
Choueiri TK, et al., J Clin Oncol 2017;35(suppl):abstr 4504. Reproduced with permission from Dr Choueiri.
Study design: Phase 1b JAVELIN Renal 100*
*According to RECIST v1.1 per investigator assessment. †1 patient died due to myocarditis prior to the first oncologic assessment, and
1 patient had a first oncologic assessment prior to the protocol-specified time window and then died due to disease progression.Choueiri TK, et al., J Clin Oncol 2017;35(suppl):abstr 4504. Reproduced with permission from Dr Choueiri.
AVELUMAB + AXITINIB IN
UNTREATED ADVANCED RCC
JAVELIN Renal 100: ORR
AVELUMAB + AXITINIB IN
UNTREATED ADVANCED RCC
JAVELIN Renal 100: ORR
Reprinted from Lancet Oncol, Online first 09 March 2018, Choueiri TK, et al., Preliminary results for avelumab plus axitinib as first-line therapy in patients with
advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial, doi.org/10.1016/S1470-
2045(18)30107-4. Copyright 2018, with permission from Elsevier.
JAVELIN RENAL 101
Choueiri TK, et al., J Clin Oncol 35, 2017 (suppl; abstr TPS4594). Reproduced with permission from Dr Choueiri.
PEMBROLIZUMAB + AXITINIB IN
UNTREATED ADVANCED RCC
Reprinted from Lancet Oncol, 19(3), Atkins MB, et al., Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-
randomised, open-label, dose-finding, and dose-expansion phase 1b trial, 405–15. Copyright 2018, with permission from Elsevier.
ORR=73% Median PFS 20.9 months (15.4–NE)
KEYNOTE 426
BICR, blinded independent central review; BID, twice daily; IMDC, International Metastatic RCC Database Consortium; QD, once daily;
Q3W, every 3 weeks; RCC, renal cell carcinoma.aPatients who discontinue treatment for reasons other than BICR-verified progressive disease should continue with imaging
assessments per the protocol-defined schedule until progressive disease is BICR verified or further confirmed by investigator, initiation
of a new anticancer treatment, death, withdrawal of consent, or study conclusion or early termination, whichever comes first.
Rini B, et al., J Clin Oncol 35, 2017 (suppl; abstr TPS4597)
Pembrolizumab
200 mg q3w +
Axitinib 5 mg bid
Sunitinib 50 mg qd
4 weeks on and
2 weeks off
Stratificatino
factors
• IMDC risk
group
• Geographic
region
Patients
• Recurrent or Stage IV
clear cell RCC
• Measurable disease
per RECIST v1.1
• No prior systemic
therapy for advanced
RCC
• Kamofsky performance
status ≥70
Imaging
follow-up
Survival
follow-up
Ran
do
miz
atio
n 1
:1
N=
840
PHASE 1 ATEZOLIZUMAB +
BEVACIZUMAB
Atezolizumab
20 mg/kg every 3 weeks
Starting C2D1
Bevacizumab
15 mg/kg every 3 weeks
Starting C1D1
Wallin JJ, et al., Nat Commun 2016;7:12624. Licensed under CC BY 4.0 http://creativecommons.org/licenses/by/4.0/
PHASE 2 RANDOMISED
Atezolizumab +/- bevacizumab vs. sunitinib in untreated mRCC
(IMmotion 150)
Courtesy of Dr McDermott. McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431)
IMMOTION 150: PFS
Atezo. Atezolizumab; Bev, bevacizumab.
*P values are for descriptive purposes only and not adjusted for multiple comparisons.McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.
IMMOTION 150:
PFS IN PD-L1+ PATIENTS
*P-values are for descriptive purposes only and not adjusted for multiple comparisons.McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.
IMMOTION 150: ORR
Clinical cut-off, Oct 17, 2016. Median duration of follow-up, 2017 mo.McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.
75% of responses are ongoing across treatment arms, and the median DOR is not
estimable due to an insufficient number of PFS events in responders
PHASE 3 RANDOMISED
Atezolizumab + bevacizumab vs sunitinib in untreated mRCC
(IMmotion 151)
Atezolizumab 1200 every 3 weeks
+
Bevacizumab 15 mg/kg every 3 weeks
Sunitinib 50 mg once daily
4 weeks on/2 weeks off
No prior therapy in metastatic
setting
Unresectable locally advanced
or metastatic RCC
Clear cell &/or sarcomatoid
component
R
a
n
d
o
m
i
s
e
d
Primary endpoints:
1. PFS in patients with detectable PD-L1 expression
2. OS in all randomised patients
ClinicalTrials.gov. A Study of Atezolizumab in Combination With Bevacizumab versus Sunitinib in Participants With Untreated Advanced
Renal Cell Carcinoma [IMmotion151]https://clinicaltrials.gov/ct2/show/NCT02420821
IMMOTION 151:
PFS IN PD-L1+ PATIENTS
Motzer RJ, et al., J Clin Oncol 2018;36(6_suppl):abstract 578. Presented at ASCO 2018. Reproduced with permission from Dr Robert J Motzer.
ORR ATEZOLIZUMAB+ BEVACIZUMAB 43%
SUNITINIB 35%
COMBINATION IMMUNOTHERAPY
AND TARGETED THERAPY
Choueiri TK, et al., N Engl J Med 2017;376(4):354-366.
TreatmentPrimary End
Point
Estimated no. of
Patients EnrolledTrial
Clinical
Trials.gov.No.
Pembrolizumab-lenvatinib vs.
everolimus-lenvatinib vs.
sunitinib
PFS 735 CLEAR NCT02811861
Nivolumab-ipilimumab vs.
sunitinib
PFS and OS 1070 CheckMate 214 NCT02231749
Atezolizumab-bevacizumab
vs. sunitinib
PFS and OS in
PD-L1-detectable
tumours
900 IMmotion151 NCT02420821
Avelumab-axitinib vs.
sunitinib
PFS 583 JAVELIN Renal 101 NCT02684006
Pembrolizumab-axitinib vs.
sunitinib
PFS and OS 840 KEYNOTE-426 NCT02853331
NON CLEAR CELL
HISTOLOGY RCC
Trials of immune checkpoint inhibitors
Courtesy of Moshe Ornstein, MD (Cleveland Clinic)
Presented by Sumanta Pal at 2017 ASCO Annual Meeting.
NON CLEAR CELL HISTOLOGY
RCC: SAVOLITINIB – ORR
MET driven MET independent
Choueiri TK, et al., J Clin Oncol 35(26), 2017: 2993–3001. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
NON CLEAR CELL HISTOLOGY
RCC: SAVOLITINIB: PFS
HR 0.33; 95% CI, 0.20 to 0.52; log-rank P < 0.001)
Choueiri TK, et al., J Clin Oncol 35(26), 2017: 2993–3001. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
EVOLUTION OF SYSTEMIC
THERAPIES IN KIDNEY CANCER
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.
KEY LEARNING POINTS
Cabozantinib and nivolumab have regulatory approval for the treatment of advanced
renal cell cancer
The combination of lenvatinib and everolimus has regulatory approval for the treatment
of advanced renal cell cancer
The introduction of the immune checkpoint inhibitors has altered the profile of toxicity
encountered in treating mRCC
The next generation of clinical trials in mRCC is focused on combination therapy