next generation drugs in kidney cancer€¦ · a phase i study of cabozantinib (xl184) in patients...

NEXT GENERATION DRUGS IN KIDNEY CANCER

Dr Aine O’Reilly

Karolinska Institutet Stockholm, Sweden

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


OVERALL SURVIVAL IN KIDNEY

CANCER


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

CABOZANTINIB

VEGFR

MET

AXL

RET

FLT3

Kit

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



CABOZANTINIB VERSUS

EVEROLIMUS

In advanced RCC: METEOR: PFS



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



OS AND PFS IN SUBGROUPS



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)


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


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


CABOSUN: OS

Cabozantinib Median OS 30.3 months

Sunitinib Median OS 21.8 months

HR, 0.80; 95% CI, 0.50 to 1.26


CABOSUN: TOXICITY

Adverse events


LENVATINIB

VEGF receptor 1, 2 ,3

FGF receptor 1, 2, 3, 4

PDGFR kinase

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


THE COMBINATION

In patients with mRCC: Baseline demographics


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)


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.


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.


THE COMBINATION

In patients with mRCC: ORR




THE COMBINATION

In patients with mRCC: OS

Lenvatinib + everolimus versus everolimus

HR 0.55, 95% CI 0.30–1.01; p=0.062




THE COMBINATION

In patients with mRCC: OS




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



LENVATINIB, EVEROLIMUS & THE

COMBINATION

In patients with mRCC: Toxicity


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


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


*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


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




CHECKMATE 025: ORR


*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




CHECKMATE 025: TOXICITY


No Grade 5 toxicity associated with nivolumab

Discontinuation for AEs: Nivolumab 8%, everolimus 13%



IMMUNE RELATED ADVERSE

EVENTS

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:



Arm N3I3:



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


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


CHECKMATE 214: OVERALL

SURVIVAL: CO-PRIMARY ENDPOINT

OS: IMDC intermediate/poor risk


CHECKMATE 214: PD-L1

EXPRESSION: EXPLORATORY ENDPOINT

PFS by PD-L1 expression: IMDC intermediate/poor risk


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.


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.


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.



JAVELIN Renal 100: ORR



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


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


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

THANK YOU!

next generation drugs in kidney cancer€¦ · a phase i study of cabozantinib (xl184) in patients...

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