ESMO E-Learning Advances in Systemic Treatment …...ADVANCES IN SYSTEMIC TREATMENT OF ADVANCED/METASTATIC RENAL CELL CARCINOMA Defining new standards of care from Phase III trials

ADVANCES IN SYSTEMIC TREATMENT OF ADVANCED/METASTATIC RENAL CELL CARCINOMA

Defining new standards of care

from Phase III trials

Rosa Nadal1 & Joaquim Bellmunt Molins2

1. National Cancer Institute. National Institutes of Health.

Bethesda, Maryland, USA

2. Dana-Farber Cancer Institute/Brigham and Women’s Hospital.

Harvard Medical School, Boston, USA ; PSMAR and IMIM-

Hospital del Mar Medical Research Institute, Barcelona, Spain

I. Epidemiology fact sheet

II. Nephrectomy and/or metastasectomy in advanced renal cancer

III. 1st, 2nd and 3rd line systemic therapy in advanced cancer

IV. New agents, selected new combinations

V. adjuvant systemic therapy

VI. Conclusions

CONTENT:

RENAL CELL CARCINOMA

EPIDEMIOLOGY

Europe estimated numbers of new cancer cases and deaths (thousands) for 2012*

115.2 new cases/49.0 deaths

US estimates for 2013

63,999 new cases/14,400 deaths

3.8% of all cancers

7th most common cancer in men, 9th most common in women

85% or more: clear cell RCC

2/1 Male/Female ratio

Smoking, obesity and hypertension are established risk factors

Median age at diagnosis: 65 years (2000-2004)

Median age at death: 71 years (2000-2004)

5-year survival has improved:

50.9% in 1975-1977; 70.6% in 2002-2008

*Ferlay J, et al. Eur J Cancer 2013;49:1374-1403; National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed

2017; Cho E, et al. Hematol Oncol Clin North 2011;25(4):651-665.

Around 20% of patients present with metastatic disease

Around 30% of individuals undergoing curative therapy eventually experience disease

recurrence.

Value of Metastasectomy:

No Phase III data, to be considered in highly selected cases of single/oligo metastases

Value of Cytoreductive Nephrectomy in patients with metastatic disease:

No mature data on the additive value of nephrectomy in patients treated with a first line

Tyrosine Kinase Inhibitor. A randomised prospective trial by the EORTC ( NCT

01099423), which evaluates this question for the sunitinib case, has recently reached

its intended accrual and results are awaited.

SURGERY FOR ADVANCED RCC

Flanigan RC, et al. N Engl J Med 2001;345:1655; Mickisch GH, et al. Lancet 2001;358:966; Choueiri,TK, et al. J Urol 2011;185:60–66.

SYSTEMIC THERAPY FOR

ADVANCED RCC

EMA AND FDA REGULATORY

APPROVED DRUGS

Approval Agent EMA and FDA Indications

1992 Intereukin-2 Metastatic

2005 Sorafenib Advanced

2006 Sunitinib Advanced

2007 Temsirolimus Advanced

2009 Bevacizumab (+ IFN-α) Metastatic

2009 Everolimus After failure of sunitinib or sorafenib

2009 Pazopanib Advanced

2012 Axitinib Failure of prior systemic therapy

2015 Nivolumab Failure of prior systemic therapy

2016 Cabozantinib Failure of prior systemic therapy

2016 Lenvatinib plus everolimus Failure of prior systemic therapy

TREATMENT OPTIONS

for patients with mRCC* have been revolutionised in a short period of

time…

1. Fyfe G, et al. J Clin Oncol 1995;13:688-96; 2. Escudier B, et al. N Engl J Med 2007;356:125-34; 3. Motzer RJ, et al. N Engl J Med 2007;356:115-24;

4. Hudes G, et al. N Engl J Med 2007;356:2271-81; 5. Escudier B, et al. Lancet 2007;370:2103-111; 6. Motzer RJ, et al. Lancet 2008;372:449-56;

7. Sternberg CN, et al. J Clin Oncol 2010;28:1061-8; 8. Rini BI, et al. Lancet 2011;378:1931-9; 9. Motzer RJ, et al. N Engl J Med 2015;373:19;

10. Choueiri TK, et al. N Engl J Med 2015;373:19; 11. Motzer RJ, et al. Lancet Oncol 2015;16:1473-82.

1992-2005 2005 2006 2007 2008 2009 2010 2011 2012 2015 2016

*mRCC: metastatic Renal Cell Carcinoma

IFN-α Bevacizumab

+ IFN-α5

High-dose

interleukin-21

Sorafenib2

Sunitinib3

Temsirolimus4 Pazopanib7

Everolimus6 Axitinib8

Nivolumab9

Cabozantinib10

Lenvatinib plus

everolimus11

MECHANISM OF ACTION OF

TREATMENTS FOR RCC

CTLA4=cytotoxic T-lymphocyte-associated antigen 4; HGF=hepatocyte growth factor; PDGF=platelet-derived growth factor; PDGFR=platelet-derived growth factor receptor;

PD-1=programmed cell death 1; PDL-1=programmed cell death ligand 1; VEGF=vascular endothelial growth factor; VEGFR=vascular endothelial growth factor receptor

Greef B, et al. Br J Cancer 2016;115:505–16. Available at: https://www.nature.com/articles/bjc2016230, under Creative Commons CC-BY-NC-SA 4.0 licence;

https://creativecommons.org/licenses/by-nc-sa/4.0/ .

https://www.nature.com/articles/bjc2016230

TARGETED AGENTS SELECTED

TOXICITIES

VEGF TKI Bevacizumab mTOR inhibitors

Fatigue/Asthenia o o o

Hypertension o o

Diarrhea/mucositis o o

Rash o o

Hand Foot Skin Reaction o

Thyroid abnormalities o

Heme toxicities (minimal overall) o o o

Hyperlipidemia/Hyperglycemia o

Dyspnea/pneumonitis o

Infections o

Thrombosis/bleed/CHF o o

Adapted and modified from Appleby LA, et al. Hematol Oncol Clin North Am 2011;25(4):893-915

ROLE OF NEPHRECTOMY AND METASTASECTOMY IN THE MANAGEMENT OF RCC

Randomized clinical trials have shown a benefit of cytoreductive nephrectomy

as compared to cytokine therapy alone

Several targeted therapies have demonstrated efficacy in treating metastatic

RCC.

Retrospective studies and meta-analysis have suggested a benefit for

cytoreductive nephrectomy

BACKGROUND

Flannigan R, et al. N Engl J Med. 2001; 345:1655.

Mickish G, et al. Lancet. 2001; 358:966

Bamias A, et al. Oncologist. 2017; 22:667

Garcia-Perdomo H, et al. Investig Clin Urol. 2018; 59:2

Bhindi B, et al. J Urol. 2018, Mar 21. pii: S0022-5347(18)42718-8. doi: 10.1016/j.juro.2018.03.077.

SUNITINIB ALONE OR AFTER NEPHRECTOMY IN METASTATIC RENAL-CELL CARCINOMA

CARMENA: Prospective, multicenter,

open-label, randomised, Phase III

non-inferiority study

Méjean A, et al. N Engl J Med. 2018; 379: 417- 427.

CARMENA: PROSPECTIVE, MULTICENTRE,

OPEN-LABEL, RANDOMISED, PHASE III NON-

INFERIORITY STUDY

Study design and conduct

▪ Confirmed metastatic clear cell

RCC/Biopsy

▪ Amenable to nephrectomy

▪ Eligible for sunitinib

▪ Brain metastases absent or

controlled by treatment

▪ No prior systemic therapy for RCC

R1:1

nephrectomy

Sunitinib

50 mg QD 4 wks on / 2 wks off

Sunitinib

50 mg QD 4 wks on / 2 wks off

3-6 wksARM A

ARM B

Primary endpoint:

Overall Survival

Primary endpoint:

Progression-free survival, objective response rate, clinical benefit, safety

Stratification

- MSKCC risk group

- Centre location

MSKCC: Memorial Sloan Kettering Center; QD: once daily; R: randomisation; RCC: renal cell carcinoma


OVERALL SURVIVAL

KAPLAN-MEIER ESTIMATES OF

SURVIVAL

PROGRESSION-FREE SURVIVAL

From N Engl J Med, Méjean A, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma 2018; 379, 417-427. Copyright © 2018

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

OVERALL SURVIVAL

Median OS, months

(95% CI)

Arm A:

Nephrectomy +

Sunitinib

(n=226)

Arm B:

Sunitinib Alone

(n=224)

HR

(95% CI)

Overall 13.9

(11.8-18.3)

18.4

(14.7-23.0)

0.89

(0.71-1.10)

MSKCC intermediate

risk

19.0

(12.0-28.0)

23.4

(17.0-32.0)

0.92

(0.6-1.24)

MSKCC poor risk 10.2

(9.0-14.0)

13.3

(9.0-17.0)

0.86

(0.62-1.17)

OVERALL SURVIVAL (ITT)

Non-inferiority study ≤ 1.20


Sunitinib alone is non-inferior to cytoreductive nephrectomy followed by sunitinib for

overall survival, both in intermediate- and poor-risk patients with metastatic RCC

Clinical benefit was also significantly better in the sunitinib alone arm

Cytoreductive nephrectomy should no longer be considered standard of care in

intermediate- and poor-risk MSKCC groups of metastatic RCC, at least when

medical treatment is required

CONCLUSIONS

RESORT TRIAL:STUDY DESIGN

Key eligibility criteria

• Histological diagnosis of predominantly clear

cell RCC

• Maximum 3 metastatic lesions

(independently if the site)

• Absence of radiological residual lesions

following removal of metastatic disease

• Histologically proven disease free margins of

resected surgical specimens

• No more than three months from radical

resection of metastases

• ECOG Performance Status of 0-2

Randomised

1:1

Stratification according to:

• Time from nephrectomy

( > or < 12 months)

• Site of disease ( lung vs.

others)

• Number of lesions ( single

vs. multiple)

Sorafenib *

for 52 weeks

Observation

for 52 weeks

Primary endpoint:

Recurrence-free

survival

Primary endpoint:

Overall survival and safety profile

Exploratory endpoint:

Translational analyses and tumour

samples

Sorafenib dose: Sorafenib 400 mg once a day for 3 weeks. After 21 days, the dose should be increased to the standard dose

(400 mg bid) if the patient has not experienced greater than grade 1 skin toxicity or greater than grade 2 of any other toxicities.

Procopio G, et al. A randomized, open label, multicenter phase 2 study, to evaluate the efficacy of sorafenib (So) in patients (pts) with metastatic renal cell carcinoma

(mRCC) after a radical resection of the metastases: RESORT trial. J Clin Oncol 36, 2018 (suppl; abstr 4502).

Courtesy of Prof G Procopio

RESORT TRIAL

Recurrence-free survival

n. of

patientsn. of events

Median

(months)

Arm=OSB** 36 12 35.0

Arm=Sorafenib 32 14 29.0

12 months

RFS (%, 95% CI)

24 months

RFS (%, 95% CI)

Arm=OSB** 74 (59-91) 59 (42-82)

Arm=Sorafenib 62 (46-84) 52 (35-76)

OBS: observation; RFS: Recurrence-free Survival; N: number;

CI: Confidence Interval.

Procopio G, et al. A randomized, open label, multicenter phase 2 study, to evaluate the efficacy of sorafenib (So) in patients (pts) with metastatic renal cell carcinoma

(mRCC) after a radical resection of the metastases: RESORT trial. J Clin Oncol 36, 2018 (suppl; abstr 4502).

Courtesy of Prof G Procopio

RESORT trial did not meet its primary endpoint

Sorafenib did not improve recurrence-free survival over observation in patients with

metastatic RCC after radical metastasectomy

The limited sample size and the heterogeneity of the study population suggest to

consider the efficacy of the results with caution.

CONCLUSIONS

CHOICE OF TARGETED AGENT IN FIRST-LINE TREATMENT

FIRST-LINE TREATMENT OF RCC:

OVERVIEW OF PIVOTAL TRIALS

LEADING TO APPROVAL

Study nResponse

vs. IFN-α, %

MedianProgression-free

Survivalvs. IFN-α, mo

Median Overall Survival

vs. IFN-α, mo

Sunitinib vs. IFN-α1 750 47 vs. 1211 vs. 5P <0.01

26.4 vs. 21.8P = 0.051

Bevacizumab+ IFN-α vs. IFN-α2 649 31 vs. 12

10.4 vs. 5.5P <0.01

23.3 vs. 21.3P = 0.1291

Pazopanib vs. placebo3 233 30 vs. 311.1 vs. 2.8

P <0.01NA

Temsirolimus vs. IFN-α4

(Poor Risk)626 9 vs. 5

5.5 vs. 3.1P <0.01

10.9 vs. 7.3 P < 0.01

1. Motzer RJ, et al. J Clin Oncol 2009;27:3584-3590; 2. Escudier B, et al. J Clin Oncol 2009;27:1280-1289;

3. Sternberg CN, et al. J Clin Oncol 2010;28:1061-1068; 4. Hudes G, et al. N Engl J Med 2007;356:2271-2281

MSKCC CRITERIA DIVIDE PATIENTS

IN 3 GROUPS WITH POOR, INTERMEDIATE

OR FAVOURABLE OUTCOME

Risk Group by No. of Risk Factors

Favourable 0

Intermediate 1 or 2

Poor 3-5

MSKCC Criteria

Karnofsky Performance Status

<80%

Time from diagnosis to treatment with IFN-α

<12 months

Haemoglobin <LLR

LDH >1.5 x ULR

Corrected serum calcium >10.0 mg/dL

IFN = interferon; KPS = Karnofsky PS; LDH = lactate dehydrogenase; LLR = lower limit of laboratory’s reference range;

MSKCC = Memorial Sloan-Kettering Cancer Center; ULR = upper limit of laboratory’s reference range.

Motzer RJ, et al. J Clin Oncol 2002;20:289-296

No. at Risk

Interferon 207 126 80 42 15 3 0

Temsirolimus 209 159 110 56 19 3 0

Combination 210 135 93 50 17 7 2

IMPROVED SURVIVAL WITH

TEMSIROLIMUS COMPARED TO IFN IN POOR

RISK PATIENTS

1.00

0.75

0.50

0.00

0.25

0 5 10 15 20 25 30

Temsirolimus (n = 209) Temsirolimus + IFN (n = 210)IFN (n = 207)

Pro

bab

ility

of

surv

ival

Months

From N Eng J Med, Hudes G, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma, 356(22):2271-81. Copyright © 2007,


nMedian OS, months

(95% CI)

IFN 207 7.3 (6.1–8.8)

Temsirolimus 209 10.9 (8.6–12.7)

Temsirolimus + IFN 210 8.4 (6.6–10.3)

PHASE III TRIAL OF

SUNITINIB VS. IFN-Α

PFS independent central review

Sunitinib: 11 months (95% CI, 8 to 14)

Interferon alfa: 4 months (95% CI, 4 to 5)

From N Engl J Med, Motzer RJ, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma, 356(2):115-124. Copyright © 2007 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

PAZOPANIB VS. SUNITINIB

PAZOPANIB VS. SUNITINIB FOR

1ST-LINE TREATMENT OF CLEAR-CELL

MRCC (COMPARZ)

Primary endpoint: PFS (non-inferiority)

Secondary endpoints: OS, ORR, safety, QoL

Pazopanib 800 mg/day

Sunitinib 50 mg/day (Schedule 4/2)

N=1110

Eligibility criteria:

Metastatic RCC

or mRCC

Clear-cell histology

No prior systemic therapy

Measurable disease

RANDOMISATION

Phase III study

Motzer RJ, et al. ESMO 2012 oral presentation; Abst LBA8_PR; Motzer R, et al. N Engl J Med 2013;369(8):722-731.

PRIMARY ENDPOINT:


(INDEPENDENT REVIEW)

Pazopanib

Sunitinib

N Median PFS (95% CI)

Pazopanib 557 8.4 mo (8.3, 10.9)

Sunitinib 553 9.5 mo (8.3, 11.1)

HR (95% CI ) = 1.047 (0.898,1.220)

The upper bound of 95% CI hazard

ratio <1.25 indicates pazopanib is

non-inferior compared to sunitinib

From N Engl J Med, Motzer R, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma 2013;369(8):722-731. Copyright © 2013. Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

Hair colour change

Weight decreased

Serum ALT increased

Alopecia

Upper abdominal pain

Serum AST increased

Fatigue

Rash

Pain in extremity

Constipation

Taste alteration

LDH increased

Serum creatinine increased

Peripheral oedema

Hand-foot syndrome

Dyspepsia

Pyrexia

Leukopenia

Hypothyroidism

Epistaxis

Serum TSH increased

Mucositis

Neutropenia

Anaemia

Thrombocytopenia

Relative risk (95% CI)

Favours Votrient Favours sunitinib

Adverse event

Log10

RELATIVE RISK IN AEs

AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1

Courtesy of ESMO. Motzer R, et al. ESMO 2012 oral presentation;Abst LBA8_PR.

PRECLINICAL DATA SUGGEST HIGHER POTENCY OF NEW VEGF-R INHIBITORS TIVOZANIB AND AXITINIBIN FIRST-LINE TREATMENT

IN VITRO POTENCY OF TIVOZANIB

AND AXITINIB COMPARED TO OTHER TKIS1

VEGFR-1 VEGFR-2 VEGFR-3

More potent

Less potent

Sunitinib1 Sorafenib1

Axitinib*,1

(AG13736)

Pazopanib1

(GW-786034)

Tivozanib2,3

(AV-951)

Approximate: adjustment in

consideration of 2.3% BSA

Note: Reported potencies* are either biochemical- or cell-based IC50s (nM); cell-based data are shown when available.

*Axitinib data for VEGFR-2 are from an ELISA assay; all other axitinib data are from an immunoprecipitation essay.

In addition, Chow LQM, Eckhardt SG reported an axitinib IC50 of 1.2, 0.25, and 0.29 nM for VEGFR-1, -2, and -3 (J Clin Oncol 2007;25:884-95)

1. Axitinib FDA Oncologic Drugs Advisory Committee briefing document. 12/7/2011; 2. Eskens FALM et al. Proceedings of the 99th Annual Meeting of the

AACR 2008:Abst LB-201; 3. Nakamura K, et al. Cancer Res 2006;66:9134-9142;

Courtesy of Prof Tim Eisen.

AXITINIB FOR FIRST-LINE

METASTATIC RCC

Overall efficacy and pharmacokinetic analyses from a randomised

Phase II study: Study design

1:1

Arm CAxitinib ≤5 mg BID(no dose titration)

Arm BAxitinib 5 mg BID

+Placebo dose titrationb

(blinded therapy)

Arm AAxitinib 5 mg BID

+Axitinib dose titrationb

(blinded therapy)

R

A

N

D

O

M

I

S

EDuring Cycle 1

(subset of patients)

ABPMc

6-h PK samplingd

Randomisation criteriaa

BP ≤150/90 mmHg

and

≤2 concurrent anti-HTN medications

andNo grade 3 or 4

axitinib-related toxicities

and

No dose reduction

Lead-in period(Cycle 1)

Axitinib 5 mg BID(4 wks)

aFor at least 2 consecutive weeksbTitrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomisation to dose titration were metcAmbulatory blood pressure monitoring performed at baseline and on Cycle 1 Days 4 and 15; d6-hr PK sampling performed on

Cycle 1 Day 15Rini B, et al. Lancet Oncol 2013;14:1233–42

Yes

No

CLINICAL EFFICACY OF 1ST LINE

AXITINIB IN ADVANCED RCC

Totala

(N = 213)

Arm C

Not eligible for dose titration

(n = 91)

Arms A + B

Eligible for dose titration

(n = 112)

mPFS, mo

(95% CI)b

14.5

(11.5, 17.4)

16.4

(11.0, 19.0)

14.5

(11.0, 19.3)

ORR

(95% CI)b

48%

(41%, 55%)

59%

(49%, 70%)

43%

(34%, 53%)

aIncludes 10 patients who discontinued study treatment prior to decision for dose titrationbAs of April 30, 2012

CI, confidence interval; mPFS, median progression-free survival

Rini B, et al. Lancet Oncol 2013;14:1233–42

Axitinib versus sorafenib as first-line therapy in patients with

metastatic renal cell carcinoma (mRCC)

TE Hutson1, J Gallardo2, V Lesovoy3, S Al-Shukri4,

VP Stus5, A Bair6, B Rosbrook6, P Bycott6, J Tarazi6,

S Kim6, NJ Vogelzang7

1. GU Oncology Program, Baylor Sammons Cancer Center, Dallas, TX and US Oncology Research, Houston, TX; 2. Instituto de Terapias

Oncológicas, Providencia, Santiago, Chile; 3. Kharkiv Regional Clinical Center of Urology and Nephrology, Kharkiv, Ukraine; 4. Department

of Urology, Saint-Petersburg State Medical University, Saint-Petersburg, Russian Federation; 5. Department of Urology, Municipal

Institution “Dnipropetrovs’k Regional Clinical Hospital n.a. I.I. Mechnikov”, Dnipropetrovsk, Ukraine; 6. Clinical Development, Pfizer

Oncology, San Diego, CA; 7. Comprehensive Cancer Centers of Nevada, Las Vegas, NV, and US Oncology Research, Houston, TX.

Hutson TE, et al. Lancet Oncol. 2013 Dec;14(13):1287-94

STUDY DESIGN

Previously untreated

metastatic RCC

R

A

N

D

O

M

I

S

E

Axitinib 5 mg BID†

(n=192)

2:1

Sorafenib 400 mg BID

(n=96)

Randomisation stratified by ECOG PS (0 vs. 1)

†Titrated stepwise to 7 mg BID and then 10 mg BID in patients without grade 3 or 4 (CTCAE v3.0) axitinib-related AEs

for a consecutive 2-week period, unless BP >150/90 mmHg.

Hutson TE, et al. Lancet Oncol. 2013 Dec;14(13):1287-94


(IRC ASSESSMENT)

*Stratified by ECOG PS; assuming proportional hazards, HR <1 indicates a reduction in favour of axitinib and HR >1 indicates a reduction in

favour of sorafenib.

IRC = independent radiology committee; mPFS = median progression-free survival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10

Time (months)12 14 16 18 20

PF

S (

pro

bab

ility

)

22 24

1-sided P=0.038

Stratified HR, 0.77*(95% CI 0.56–1.05)

192 154 132 114 91 78 63 54 19 6 0

96 73 60 43 34 24 20 19 10 0 0

Patients at risk, n

Axitinib

Sorafenib

34

13

1

0

= censored for axitinib

= censored for sorafenib

10.1 (7.2–12.1)6.5 (4.7–8.3)

AxitinibSorafenib

No. events (%)

111 (58)60 (63)

mPFS, mo (95%CI)

Reprinted from The Lancet Oncol., 14(13), Hutson TE, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a

randomised open-label phase 3 trial, 1287-94. Copyright 2013, with permission from Elsevier.

CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell

carcinoma (mRCC) of poor and intermediate risk groups

ALLIANCE A031203 Trial

Toni K. Choueiri MD, Susan Halabi PhD, Ben Sanford

MS, Olwen Hahn MD, M. Dror Michaelson MD, Meghara

Walsh RN, Thomas Olencki MD, Joel Picus MD, Eric

Small MD, Shaker Dakhil MD, Daniel George MD, and

Michael J. Morris MD

Choueiri TK, et al. J Clin Oncol 2017;35:591-7

STUDY DESIGN1

Advanced RCC (N=150)

Clear cell component

Measurable disease

No prior systemic therapy

ECOG PS 0-2

IMDC intermediate or poor risk groups

Cabozantinib

60 mg qd orally(6 week cycles)

Sunitinib

50 mg qd orally(4 weeks on/2 weeks off)

Randomisation 1:1

No cross-over allowed

Tumour assessment by

RECIST 1.1 every other

cycle

Treatment until disease

progression or

intolerable toxicity

Stratification

IMDC risk group2: intermediate, poor

Bone metastases: yes, no

Endpoints

Primary: PFS

Secondary: OS, ORR and safety

1. Choueiri TK, at al. J Clin Oncol. 2017;35:591–7

2. Heng D, et al. J Clin Oncol 2009

Arm PFS Events Median PFS (95% CI), mo HR (95% CI)*

CabozantinibSunitinib

6461

8.2 (6.2, 9.0)5.6 (3.4, 8.1)

0.69 (0.48-0.99)p-value (one-sided) = 0.012

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30

Pro

gre

ssio

n-f

ree

surv

ival

(pro

bab

ility

)

Cabozantinib

Sunitinib

No. at risk

Cabozantinib 79 50 26 15 3 1

Sunitinib 78 32 17 7 1 0

Time since randomisation (months)


*Adjusted for bone metastases and IMDC risk groupChoueiri TK, et al. J Clin Oncol 35, 2017;:591–7. Reprinted with permission © 2017 American Society of Clinical Oncology. All rights reserved.

Sunitinib, pazopanib, bevacizumab (plus IFN), tivozanib and cabozantinib show

improved PFS

Pazopanib shows similar efficacy, a different safety profile and higher quality of life

scores compared to sunitinib

Tivozanib improves PFS compared to sorafenib

Benefit compared to other VEGFR TKIs undefined.

Axitinib is active, but Phase III trial did not meet primary endpoint of superiority

over sorafenib

Cabozantinib is active in first line for intermediate and poor risk patients, but only

Phase II data and OS still not mature

1ST LINE TREATMENT:

MAIN CONCLUSIONS

N Median PFS (95% CI)

Pazopanib 557 8.4 mo (8.3, 10.9)

Sunitinib 553 9.5 mo (8.3, 11.1)

HR (95% CI) 1.047 (0.898, 1.220)

SECOND-LINE TREATMENT AFTER FAILURE OF ANTI-VEGF

2ND LINE EVEROLIMUS VS.

PLACEBO

Study design and conduct

N = 416

Stratification

Prior VEGFR-TKI: 1 or 2

MSKCC risk group:

favourable, intermediate,

or poor

RANDOMISATION

Placebo + BSC

(n = 139)

Upon Disease

Progression

Safety interim

analysis

Everolimus 10 mg/day +

best supportive care (BSC) (n = 277)

416 patients randomised between December 2006 and November 2007

Analysis cut-off: February 28, 2008, based on 266 PFS events

Second interim analysis based on cut-off: October 15, 2007, efficacy boundary crossed with 410

patients/191 PFS events,complete study unblinded on February 28, 2008

Second interim

analysis data cut-

off: October 15,

2007, N = 4101

End of double- blind

analysis data cut-off:

February 28, 20082

Study

Unblinded

2:1

1. Motzer RJ, et al. Lancet 2008;372(9637):449-456

2. Motzer RJ, et al. Cancer 2010;116(18):4256-65

EVEROLIMUS VS. PLACEBO:

OUTCOME

Number of Patients at Risk

Everolimus 277 192 115 51 26 10 1 0

Placebo 139 47 15 6 2 0 0 0

Analysis on Feb 2008 Data Cutoff. Analysis on Nov 2008 Data Cutoff.

Number of Patients at Risk

Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0

Placebo 139 131 117 100 86 74 56 43 27 13 3 0 0

Pro

bab

ility

(%

)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 20 22 24

Hazard ratio = 0.87

95% CI [0.65, 1.71]

Kaplan-Meier Medians

Everolimus : 14.78 mo

Placebo: 14.39 mo

Log rank P value 0.177

Hazard ratio = 0.33

95% CI [0.25, 0.43]

Medians PFS

Everolimus : 4.90 mo

Placebo: 1.87 mo

Log rank P value < 0.001

Everolimus (n = 277)

Placebo (n = 139)

Progression-free survival

central radiology review Overall survival

Everolimus (n = 277)

Placebo (n = 139)

Months Months

Motzer RJ, et al. Cancer 2010;116(18):4256-65. With permission from John Wiley & Sons. Copyright © 2010 John Wiley & Sons, Inc. All rights reserved

100

80

60

40

20

0

2ND LINE AXITINIB VS. SORAFENIB

Primary endpoint: Compare PFS of patients receiving axitinib vs. sorafenib in mRCC after disease

progression to 1 prior systemic first-line regimen containing 1 of the following agents: Sunitinib,

bevacizumab + IFN-α, temsirolimus or cytokine(s)

Secondary endpoint: OS, ORR, evaluate safety and tolerability, DR, compare symptoms severity

Patients after disease

progression to 1 prior

systemic first-line

treatment

(N=723)

R

A

N

D

O

M

I

S

A

T

I

O

N

Sorafenib (2 x 200 mg) BID (n=362)

Axitinib 5 mg BID (n=361)

1:1

Rini BI, et al. Lancet 2011;378:1931-9

2ND LINE AXITINIB VS. SORAFENIB:

PFS

Months of PFS

Pro

bab

ility

Axitinib

Sorafenib

Stratified HR 0.665 (95% CI: 0.544-0.812)

P<0.0001 (log-rank, 1-sided)

Median PFS 95% CI

6.7 months 6.3 – 8.6

4.7 months 4.6 – 5.6

Reprinted from The Lancet, 378, Rini BI, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised

phase 3 trial, 1931-39., Copyright 2011, with permission from Elsevier.

Patients with mRCC and PD on 1st-line sunitinib (N=512)

Stratification factors:

Duration of sunitinib therapy

(≤ or >6 mo)

MSKCC risk group

Histology (clear cell or

non–clear cell)

Nephrectomy status

R

A

N

D

O

M

I

S

E

1:1

Temsirolimus

25 mg IV weekly†

(n=259)

Sorafenib

400 mg oral BID†

(n=253)

Treat until PD, unacceptable toxicity, or

discontinuation for any other reason

Primary end

point: PFS

(per IRC)

*ClinicalTrials.gov Identifier: NCT00474786†Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg), sorafenib (to 400 mg/day then every other day).

2ND LINE TEMSIROLIMUS VS.

SORAFENIB

Hutson TE, et al. J Clin Oncol 2014;32(8):760-7

TEMSIROLIMUS VS. SORAFENIB:

PFSP

FS

(p

rob

abili

ty)

252 72 22 11 6 0

259 96 28 9 5 0

Sorafenib

Temsirolimus

Time (months)

0 5 10 15 20 25

TemsirolimusSorafenib

P=0.1933 (log-rank)

Stratified HR: 0.87

(95% CI: 0.71, 1.07)

Median PFS,months 95% CI

4.283.91

4.01, 5.432.80, 4.21

Patients at risk, n

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

IRC, Independent Review Committee

Reprinted with permission. © 2014, American Society of Clinical Oncology. All rights reserved. Hutson TE, et al. J Clin Oncol 32(8), 2014:760-7

TEMSIROLIMUS VS. SORAFENIB:

OSO

vera

ll S

urv

ival

(p

rob

abili

ty)

0 10 20 30 40 50

253 158 74 34 13 0

259 132 54 22 8 0

Sorafenib

Temsirolimus

Patients at risk, n

Time (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

TemsirolimusSorafenib

P=0.014 (log-rank)

Stratified HR: 1.31(95% CI: 1.05, 1.63)

12.2716.64

10.13, 14.8013.55, 18.72

Median OS,months 95% CI

Reprinted with permission. © 2014, American Society of Clinical Oncology. All rights reserved. Hutson TE, et al. J Clin Oncol 32(8), 2014:760-7

BMS-936558 (ANTI-PD-1, MDX-1106)

A monoclonal antibody that increases immune surveillance

against tumours

Ag, antigen; APC, antigen-presenting cell; MHC, major histocompatibility molecule; PD-1, programmed death-1; TCR, T-cell receptor

Reprinted from Inman BA, et al. Eur Urol 2013;63(5):Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma, 881-89. Copyright (2013),

with permission from Elsevier.

2ND LINE NIVOLUMAB (ANTI-PD1

ANTIBODY) VS. EVEROLIMUS

FOLLOWING VEGF TARGETED

THERAPY

Primary endpoint: Compare overall survival

Secondary endpoint: PFS, ORR, safety, quality of life

Patients after disease progression

to 1 or 2 prior VEGF systemic

treatment (N=860)

Stratification

MSKCC risk group

Number of prior therapies (one or

two)

R

A

N

D

O

M

I

S

A

T

I

O

N

Everolimus

10 mg qd orally

Nivolumab

10 mg per kilogram of body weight

intravenous every 2 weeks

1:1

Motzer RJ, et al. N Engl J Med 2015;373(19):1803–13

KAPLAN-MEIER ESTIMATES OF

OVERALL SURVIVAL

No. of patients at risk

Nivolumab 410 230 145 116 81 66 48 29 11 4 0

Everolimus 411 227 129 97 61 47 25 16 3 0 0

0 3 6 129 15

Time (months)

18 21 24 27 30

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ssio

n-f

ree

surv

ival

(p

rob

abili

ty)

Nivolumab

Everolimus

Median OS 95% CI

25.0 months 21.8– NE

19.6 months 17.6–23.1

---- Nivolumab

---- Everolimus

HR, 0.73 (98.5% CI, 0.57-0.93)

p=0.002

From N.Engl J Med, Motzer RJ, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373 (19): 1803-1813. Copyright © 2015, Massachusetts


2ND LINE CABOZANTINIB VS.

EVEROLIMUS

Clear cell histology

Measurable disease

Patients after disease progression on

prior VEGF treatment within 6 months

Antibodies targeting PD-1/PD-L1 allowed

Brain metastases allowed if treated

(N=650)

Stratification:

MSKCC risk groups: favourable,

intermediate, poor

Number prior VEGFR-TKIs: 1, 2 or more

R

A

N

D

O

M

I

S

A

T

I

O

N

Everolimus

10 mg qd orally

Cabozantinib

60 mg qd orally

1:1

No cross-over allowed

Tumour assessment by RECIST

1.1 every 8 weeks

Treatment until loss of clinical

benefit or intolerable toxicity

Primary endpoint: PFS

Secondary endpoint: OS, ORR by IRC

Choueiri TK, et al. N Engl J Med 2015;373:1814-23

CABOZANTINIB VS. EVEROLIMUS:

OS

Interim analysis (49% information fraction)

The interim boundary to reach significance (P=0.0019) was not reached

Survival follow up is continuing to the planned final analysis

From N.Engl J Med, Choueiri TK, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma, 373:1814-1823. Copyright © 2015, Massachusetts


2ND LINE LENVATINIB VS.

EVEROLIMUS VS. COMBINATION

Everolimus

10 mg qd orally (n=50)

Clear cell histology

Measurable disease

Patients after disease progression on

prior 1 VEGF systemic treatment

within 9 months

Stratification

Hemoglobin (low vs. normal)

Corrected serum calcium

(≥ vs. <10 mg/dl) (N=153)

R

A

N

D

O

M

I

S

A

T

I

O

N

Lenvatinib

24 mg qd orally (n=52)

Lenvatinib 18 mg qd + everolimus 5 mg

qd orally (n=51)

1:1

Patients were treated until progressive disease or unacceptable toxicity

Primary endpoint: PFS with lenvatinib± everolimus vs. everolimus alone

Secondary endpoints: PFS with combination vs lenvatinib, ORR, OS, safety

vs: versus; qd: every day

Motzer RJ, et al. Lancet Oncol 2015.

2ND LINE OPTIONS AFTER VEGF

TREATMENT

Sunitinib or

Pazopanib

mTOR (Everolimus)

VEGF TKI (Axitinib)

PROGRESSION PD-1 inh (Nivolumab)

MET and VEGF TKI (Cabozantinib)

VEGF TKI (Lenvatinib) +

mTOR (Everolimus)

THERAPY DECISIONS FOR 2ND

AND 3RD LINE TREATMENT IN RCC

SunitinibPazopanib

Longer progression free survival (and overall survival)

Progression

NivolumabCabozantinibLenvatinib + everolimus

Progression

EverolimusAxitinib

1st Line

2nd Line

3rd Line

Setting Patients Level 1* > Level 2*

1st line

Good or intermediate

risk

Pazopanib

Sunitinib

Bevacizumab + IFN-α

High-dose IL-2

Sorafenib

Poor riskTemsirolimus

(Sunitinib)**

2nd (or 3rdl)

Line

Prior cytokineSorafenib

Pazopanib

Sunitinib

Bevacizumab

Prior VEGF-TKI

Nivolumab

Cabozantinib

Lenvatinib+Everolimus

Axitinib

Everolimus

Sorafenib

Prior mTOR

Nivolumab

Cabozantinib

Axitinib

Sorafenib

TREATMENTS FOR ADVANCED

CLEAR-CELL RCC

*Guide to clinical preventative services: National Library of Medicine (web site). http//www.ncbi.nlm.nih.gov

**Included in phase 3 trial but comprised <10% of study population.

NEW AGENTS - SELECTED NEW COMBINATIONS

CHECKMATE 214

Nivolumab + ipilimumab versus sunitinib for first-line treatment in

metastatic RCC

Treatment-naïve advanced or metastatic

clear-cell RCC

Measurable disease

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) (N=1096)

R

A

N

D

O

M

I

S

A

T

I

O

N

Sunitinib 50 mg orally once daily

for 4 weeks (6-week cycles)

Nivolumab 3 mg/kg IV +

ipilimumab 1 mg/kg IV 3QW for four

doses, then

nivolumab 3 mg/kg IV Q2W

1:1

Patients were treated until progressive disease or unacceptable toxicity

Primary endpoints: ORR, PFS, and OS for intermediate- and poor-risk patients

Secondary endpoints: ORR, PFS, and OS in the intent-to-treat population

IMDC: International Metastatic RCC Database consortium; vs.US: United States Q2W: every 2 weeks; Q3W: every 3 weeks

Motzer R.J, et al. N Engl J Med. 2018 Apr 5;378(14):1277-1290

IMDC Intermediate/poor risk Intention to treat

OutcomeNIVO+IPI

N=425

SUN

N=422PD-L1< 1% PD-L1 >=1% PD-L1< 1% PD-L1 >=1%

NIVO+IPI

N=284

SUN

N=278

NIVO+IPI

N=100

SUN

N=114

NIVO+IPI

N=386

SUN

N=376

NIVO+IPI

N=113

SUN

N=127

Confirmed ORR, %

(95%CI)42 (37-47) 27(22-31) 37 (32-43) 28(23-43) 58 (48-68) 22 (15-31) 36 (31-41) 35 (31-40) 53 (44-63) 22 (15-30)

p < 0.0001 p = 0.0252 p < 0.0001 p = 0.8799 p = 0.0001

BOR, %

Complete Response

Partial Response

Stable Disease

Progressive Disease

NA

9

32

31

20

8

1

25

45

17

12

7

30

36

20

7

1

27

47

13

12

16

42

19

14

9

1

21

40

25

13

9

27

39

18

7

2

33

43

11

11

14

39

25

14

8

1

21

43

23

13

Duration of ResponseNot reached

(21.8-NE)

18.2

(14.8-NE)- - - - - - - -

CHECKMATE 214

ANTITUMOUR ACTIVITY

Motzer R.J, et al. N Engl J Med. 2018 Apr 5;378(14):1277-1290

CHECKMATE 214

OVERALL SURVIVAL

From N Engl J Med., Motzer RJ, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma, 378(14): 1277-1290. Copyright © 2018.


ADJUVANT TREATMENT FOR CLEAR CELL RCC

SUMMARY OF PHASE III ADJUVANT

TRIALS IN RENAL CELL

CARCINOMA

1. Haas NB, et al. Lancet 2016; 387: 2008–16

2. Ravaud, A, et al. New Engl J Med 2016 Dec 8;375(23):2246-2254

3. Motzer RJ, et al. J Clin Oncol. 2017 Dec 10;35(35):3916-3923

4. NCT00492258

5. NCT01599754

n Risk Groups

Patients with

clear cell

histology

Dosing

Intended starting

dose

Proportion of

patients receiving

intended starting

dose

Duration of treatment

ASSURE1 1943

pT1bN0/NxM0 g 3-4

pT2-4NxM0 any g

pT(any)N+M0 any g

79%

Sunitinib 50 mg/d

Sorafenib 400 mg

BID

Sunitinib:69.6%

Sorafenib: 69.8%

Median cycle of treatment

sunitinib/sorafenib:

8 Cycles (IQR:2-9)

Placebo: 9 Cycles (IQR:7-9)

S-TRAC2 615pT3-4NxM0 any g

pT(any)N+M0 any g>99% Sunitinib 50 mg/d Sunitinib: 100%

Median (range, months

Sunitinib: 12.4 (0.1-14.9)

Placebo: 12.4 (0.03-13/7)

PROTECT3 1540

pT2N0/NxM0 g3-4

pT3-4N0/NxM0 any g

pT(any)N+M0 any g

>99% Pazopanib 800 mg/d Pazopanib: 25%

Median, months

Pazopanib 600 mg: 10.6

Pazopanib 800 mg: 10.2

SORCE4 1656

Intermediate-or-high-

risk (Leibovich score,

3-11)

PredominantlySorafenib 400 mg

BIDNA NA

ATLAS5 700pT2-4N0M0

pTxN1M0Predominantly Axitinib 5 mg BID NA NA

UISS: UCLA integrated staging system; TNM: tumour/node/metastasis;

g: grade; d:day; BID: twice daily, NA: no available

Disease-free Survival

S-TRAC TRIAL HAS LED TO FDA-APPROVAL

FOR ADJUVANT SUNITINIB IN STAGE III AND/OR

NODE-POSITIVE CLEAR CELL RENAL CANCER

Sunitinib 6.8 years

Placebo 5.6 years

HR 0.76 (95% CI, 0.59-0.98; p 0.03

From New Engl J Med, Ravaud, A, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy, 8;375(23):2246-2254. Copyright © 2016,


Sunitinib 6.8 years

Placebo 5.6 years

HR 0.76 (95% CI, 0.59-0.98; p 0.03

Cytoreductive nephrectomy should no longer be considered standard of care in

intermediate- and poor-risk MSKCC groups of metastatic RCC, at least when

medical treatment is required.

Radical metastasectomy followed by observation is a commonly used strategy in

selected patients with oligometastatic RCC. There is no clear role for systemic

targeted therapy after surgical metastasectomy.

Sunitinib has been FDA approved for adjuvant therapy in high risk clear cell renal

cancer

Standard of care for advanced renal cancer has dramatically changed in the era of

targeted therapy and immune-checkpoint inhibitors

Standard 1st line therapy for most patients is a VEGF-TKI for patients with

favorable-risk metastatic RCC or unfit for nivolumab plus ipilimumab combination,

likely pazopanib, sunitinib or tivozanib.

CONCLUSIONS

Nivolumab and ipilimumab in combination were granted FDA approval in April 2018

for the treatment of intermediate or poor risk, previously untreated advanced renal

cell carcinoma.

Standard 2nd line therapy and beyond for most patients is either nivolumab or

cabozantinib , both drugs have not been compared head to head.

Additional combination therapies are under investigation.

CONCLUSIONS

THANK YOU!

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ESMO E-Learning Advances in Systemic Treatment …...ADVANCES IN SYSTEMIC TREATMENT OF ADVANCED/METASTATIC RENAL CELL CARCINOMA Defining new standards of care from Phase III trials