First line in mRCC - OverGroup€¦ · Once upon a time… IL‐2 2005 1. Kidney cancer drugs market 2015 –Global Industry analysis, Pipeline Analysis, Size, share, Growth, Trends

First‐line in mRCC

Lisa DerosaPolo Oncologico

Azienda Ospedaliero-Universitaria PisanaUniversità di Pisa

Verona, 5 Marzo 2014

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NormalDiseasedInvasive cancers

RCC is a VEGF driven disease

Once upon a time…

IL‐2

2005

1. Kidney cancer drugs market 2015 – Global Industry analysis, Pipeline Analysis, Size, share, Growth, Trends and Forecast 2014‐2020

Fare clic per modificare lo stile del sottotitolo dello schema

The RECON Analysis: before and after TT

Klepp et al. Presented at: ASCO GU 2015 abstract 443

There will in the storybook…2020’

Personalized decision making:

•Predictive factors will be identified in the next 5‐10 years for each of VEGF, mTOR, and PD1 pathways and other

•Tumor biopsies will be required at each progression to determine next therapeutic step

1. Kidney cancer drugs market 2015 – Global Industry analysis, Pipeline Analysis, Size, share, Growth, Trends and Forecast 2014‐2020

Until then…

1. Escudier B et al. Ann Oncol. 2014; 2. Sonpavde G et al. Eur Urol. 2012;61:307–316.; 3. Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477–2490; 4. Benjamin L et al. Eur J Cancer. 2012;48:912–920; 5. Escudier B et al. Drugs. 2013;73:427–438; 6. Barefoot J et al. Oncol Issues. 2009;May/June:36–39; 7. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. V2.2014.

Disease-specific Factors1-5

Is the primary tumour in place?What is the extent of disease?What are the prognostic factors?

Histological sub-type

Considerations for selection of first‐line therapy

Should nephrectomy or TKI come first?

The role of nephrectomy in mRCC is still controversial because

1. Ramdomized studies are misleading and have been misinterpreted

1. Retrospective data are always biased, and do not account for the most important factors

1. Every urologist and every oncologist think he knows the answer

Is the primary tumour in place?

Courtesy of A Mejean

53‐year‐old ladyGood PSAbdominal mass at examinationSmall lung metastases

Case 1: nephrectomy makes sense

60‐yo ladyPS 2Hb 9.3 g/dlLDH > 2NV

Case 2: nephrectomy is no sense

Case 3: who knows?

mRCC with clear‐cell

component

Randomisation1:1

N = 1134

Arm ANephrectomy

+Sunitinib 50 mg 4/2

Arm B

Sunitinib 50 mg 4/2

CARMENA design

Stratification factors:• MSKCC score• Country

PI A Mejean, Fr






After nephrectomy, do control CT scan, before starting therapy

What is the extent of disease?

Observation and delaying start of treatment

• Try to asses rate of progression• Take into account:

– Fuhrman grade– Size of metastases– Location of metastases (lung, bone, brain)– Patient status (age, comorbidities, wishes…)

To treat or not to treat?






1. AIOM 20142. Escudier B et al. Ann Oncol. 2014. 2. NCCN Guidelines, Kidney Cancer. V1.2013.

SettingRecommended

OptionsOther Options

MSKCC risk: good or

intermediate

• Sunitinib• Bevacizumab + IFN

• Pazopanib

• High‐dose IL‐2• Sorafenib• Clinical trial

MSKCC risk: poor • Temsirolimus• Sunitinib• Clinical trial

Current first‐line mRCCtreatment recommendations1,2,3






Histology and

setting

Risk group Standard Option

NonClear‐cell Temsirolimus [III, B]

Sunitinib [III, B]

Sorafenib [III, B]

Escudier , Porta, Schmidinger et al Ann Oncol 2014

First line

There is no evidence that mTOR inhibition is better that TKIs

Histological subtype?

• Papillary type 1: cMET is a key target

• Chromophobe tumors: some have mTOR pathway activation

• Collecting duct tumors: chemotherapy is the standard. The role of VEGF inhibition is questionable: ongoing phase 2 in France with gemcitabine, CDDP, bevacizumab

• Translocation RCC: more like clear cell

Same histology are different!





Patient-specific Factors1-7

Co-morbidities Age

Patient attitude towards risk

Ability to adhere to therapy

Potential prognostic/predictive markers

Tolerability and QoL issues


Sunitinib Pazopanib Sorafenib Bevacizuma

b

Temsirolimu

s

Hypertension ++ ++ ++ ++

Arterial thrombotic

events+ + + +

Hand‐foot syndrome + + +++

Mucositis + + +

Diarrhoea ++ + +

Cytopenia +++ + +

Rash + ++ +

Fatigue ++ + + + +

Hair colour changes + +

Metabolic changes +1 +1 +1 ++2

Interstitial ++

* +, ++, or +++ based on low-, moderate- or high-grade toxicities; cells left blank indicate no information or no known toxicity. 1Hypothyroidism. 2Hyperlipidaemia/hyperglycaemia. Sonpavde G et al. Eur Urol. 2012;61:307–316.

Considerations for selection of first‐line therapy: toxicity profiles*

Agent Comment

Sunitinib

• Reasonable estimate of PFS (based on 4/2 cycle): ~8‐9 mos in patients with

favourable or intermediate risk

• Suitable for all prognostic groups, particularly those with aggressive disease who

are younger and fitter; less appropriate for elderly patients and/or those with

comorbidities

Pazopani

b

• Based on currently available data, this agent is a good alternative to sunitinib for

patients with good to intermediate risk

Sorafenib

• Reasonable estimate of PFS with sorafenib in the general mRCC population: ~8‐9

mos

• Suitable for patients at all levels of risk, particularly the elderly and those with

comorbidities

BEV + IFN

• The overall estimate of PFS with bevacizumab plus IFN‐α in a general population is

~9 mos, comparable to sunitinib, pazopanib, or sorafenib

• Suitable for patients with a good prognosis or those with indolent disease (ie, likely Escudier B et al. Nat Rev Clin Oncol. 2012;9:327–337.

Expert consensus on overall utility of selected first‐line agents in clinical practice

Assessing the current evidence: completed trials of first‐line

therapies

This presentation is for scientific discussion only – Please do not distribute following this meeting

Motzer RJ et al N Engl J Med 2007;356:115–

Eligibility Criteria mRCC with clear cell histology

No prior systemic treatment

ECOG PS 0 or 1

Sunitinib 50 mg/day4/2 schedule

Primary end point: PFSSecondary end points: ORR, OS, PRO and safety

N = 750

n = 375

IFN-� 3 times/wk(3 MU/dose in wk 1, 6 MU/dose in wk 2, 9 MU/wk thereafter)

n = 375RANDOM I SE

Phase III trial: first‐line sunitinib vs IFN‐α

• Median PFS: 11 mo with SUN vs 5 mo with IFN‐�

• ~90% of patients had good or intermediate MSKCC risk1

• ORR: 31% with sunitinib vs 6% with IFN‐�1

• OS advantage seen with sunitinib vs IFN‐�(26.4 vs 21.8 mo; HR 0.821; 95% CI 0.673–1.001; P=0.051)2

• Grade 3/4 AEs significantly more common with sunitinib: diarrhoea, vomiting, hand‐foot syndrome and hypertension1

• Grade 3/4 AEs significantly more common with IFN‐�: fatigue and lymphopenia1

1. Motzer RJ et al. N Engl J Med. 2007;356:115–124.2. Motzer RJ et al. J Clin Oncol. 2009;27:3584–3590.

Months

Prog

ress

ion-

free

Sur

viva

l

1.00.90.80.70.60.50.40.30.20.10.0

0 1 2 3 4 5 6 7 8 9 10

11

12

13

14

HR 0.42; 95% CI 0.32−0.54; P<0.001

IFN-α

Sunitinib

First‐line sunitinib vs IFN‐α: results

Sternberg CN et al. J Clin Oncol. 2010;28:1061–1068.

Eligibility Criteria Advanced and/or metastatic

RCC

No prior systemic treatment or 1 prior cytokine-based therapy

ECOG PS 0 or 1

Primary end point: PFSSecondary end points: OS, ORR and safety

N = 435

n = 145

n = 290

Pazopanib 800 mg/day

Placebo

RANDOM I SE

Phase III trial: first‐line pazopanib vs placebo

• 233 patients had no prior treatment and 202 patients had 1 prior cytokine-based therapy

• Median PFS: 11.1 mo with pazopanib vs 2.8 mo with placebo (HR 0.40; 95% CI 0.27–0.60; P<0.0001)

• ORR: 32% with pazopanib vs 4% with placebo

• Notable grade 3 hepatotoxicity was observed

Sternberg CN et al. J Clin Oncol. 2010;28:1061–1068.

1.00.80.60.40.2

0 5 10

15

20

Prop

ortio

n Pr

ogre

ssio

n-fr

ee

Time, mo

PazopanibPlacebo

PFS

First‐line pazopanib vs placebo: results

Motzer RJ et al. N Engl J Med. 2013;369:722–731.

Eligibility Criteria Advanced RCC or mRCC

with clear cell histology


Measurable disease

KPS ≥70%

Pazopanib800 mg/day

Sunitinib 50 mg/day(schedule 4/2)

Primary end point: PFSSecondary end points: OS, ORR, PRO, safety and QoL

N = 1110

RANDOM ISE

n = 553

n = 557

Non-inferiority study

Phase III COMPARZ trial: first‐line pazopanib vs sunitinib

*Independent review†Interim analysis

1. Motzer RJ et al. N Engl J Med. 2013;369:722–731.

PFS* OS†

1.00.80.60.40.20

0 4 8 12

16

20

24

28

32

36

40Month

s

Prop

ortio

n Pr

ogre

ssio

n-fr

ee

PazopanibSunitinib

N Median PFS (95% CI)

Pazopanib 557 8.4 mo (8.3–10.9)

Sunitinib 553 9.5 mo (8.3–11.1)

HR 1.05; 95% CI 0.90–1.221.00.80.60.40.20

Estim

ated

Sur

viva

l Fun

ctio

n

0 4 8 12

16

20

24

23

32

36

40

44

PazopanibSunitinib

Months

N Median OS (95% CI)

Pazopanib 557 28.4 mo (26.2–35.6)

Sunitinib 553 29.3 mo (25.3–32.5)

HR 0.91; 95% CI 0.76–1.08; P=0.28

COMPARZ: efficacy of pazopanib is non‐inferior to sunitinib

1. Escudier BJ et al. J Clino Oncol 2014 2. Cella D. et al. Presented at: ESMO Annual Meeting, 28 September–2 October 2012; Vienna, Austria: abstract 792POD.

Pazopanib800 mg/day

Sunitinib 50 mg/day (4/2 schedule)

N = 168

Sunitinib 50 mg/day(4/2 schedule)

Period 1: 10 wk Period 2: 10 wk2-wk

washout

Patient choice of continued treatment

Period 1: 10 wk Period 2: 10 wk2-wk washout

Pazopanib800 mg/day

Patient and physician collected prior to unblinding and disclosure of final tumour assessment

RANDOM I SE

PISCES patient preference study between first‐line pazopanib and sunitinib: study design

Factors Influencing Treatment Choice

70

60

50

40

30

20

10

0

Not report

ed

Less hair colour

change

Less diarrhoea

Less stomach pain

Better appetite

Less hand-foot

syndrome

Less nausea/vomit

ing

Less mucositis/sto

matitis

Less taste change

Less fatigue

Better quality of life

Patients Expressing a Preference, %

PAZ preferred (n =

80)

SUN preferred (n =

25)

Escudier BJ et al. J Clin Oncol 2014, 1–5 June 2012; Chicago, IL: abstract CRA4502.

Patient Preference

0

2

4

6

8

10

12

Pat ie

nts,

%

PISCES patient preference study between first‐line pazopanib and sunitinib: results

Escudier BJ et al. Lancet. 2007;370:2103–2111.

Eligibility Criteria mRCC with predominantly

clear cell histology


KPS �70%

Placebo + IFN-�3 times/wk

(9 MIU)

Primary end point: OSSecondary end points: PFS, ORR and safety

N = 649

n = 322

n = 327

RANDOM I SE

Bevacizumab (10 mg/kg, every 2 wk)

+IFN-� 3 times/wk

(9 MIU)

AVOREN phase III trial: first‐line bevacizumab plus IFN‐α vs placebo plus IFN‐α


• mPFS: 10.2 mo with BEV + IFN-α vs 5.4 mo with IFN-α (HR 0.63; 95% CI 0.52–0.75; P=.0001)1

• ORR: 31% for bevacizumab + IFN-α vs 13% for placebo + IFN-α (P=0.0001)1

• mOS: 23.3 mo with BEV + IFN-α vs 21.3 mo (P=NS)2

• No significant increase or unexpected AEs were reported with combination therapy compared with IFN-α alone

1. Escudier BJ et al. Lancet. 2007;370:2103–2111.2. Escudier BJ et al. J Clin Oncol. 2010;28:2144–2150.

1.0

0.80.6

0.40.20

0 6 12

18

24

Prob

abili

ty o

fPr

ogre

ssio

n-fr

ee S

urvi

val

Time, mo

PFS

BEV + IFN-α

IFN-α

AVOREN: results

Axitinib 5 mg BID*

Sorafenib 400 mg BID

Primary endpoint: PFSSecondary endpoints: OS, ORR, safety, duration of response

N = 288

RANDOM IZE

n = 192Eligibility Criteria Clear cell mRCC

Previously untreated

Measurable disease by RECIST

ECOG 0–1

n = 96

*Titrated stepwise to 7 mg bid, then 10 mg bid without grade 3/4 axitinib-related AEs for a consecutive 2-week period.

Hutson T et al. Presented at: ASCO-GU Symposium; 14–16 February 2013; Orlando, FL: abstract LBA348.

AGILE 1051 phase III trial: study design

• Study did not achieve primary endpoint (HR, 0.77; 95% CI, 0.56–1.05; P=0.038)

Time, mos

PFS

,pro

babi

lity

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

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

AxitinibSorafenib

No. events (%)

111 (58)60 (63)

mPFS, mos (95% CI)

10.1 (7.2–12.1)6.5 (4.7–8.3)

Axitinib censoredSorafenib censored

Hutson T et al. Presented at: ASCO-GU Symposium; 14–16 February 2013; Orlando, FL: abstract LBA348.

AGILE 1051 phase III trial: results

0

2

4

6

8

10

12

Tim

e, m

ont hs


mPFS for selected VEGF-directed therapies observed in phase III trials

1. Motzer RJ et al. Presented at: ESMO Annual Meeting; 28 September–2 October 2012; Vienna, Austria: abstract LBA8_PR; 2. Motzer RJ et al. Presented at: ASCO Annual Meeting; 1–5 June 2012; Chicago, IL: abstract 4501; 3. Rini BI et al. J Clin Oncol. 2010;28:2137–2143;4. Motzer RJ et al. N Engl J Med. 2007;356:115-124. 5. Sternberg CN et al. J Clin Oncol. 2010;28:1061–1068.

Pazopanib1(COMPARZ

)

Sorafenib2

(TIVO‐1)

Sunitinib1(COMPARZ

)

BEV + IFN3

(CALGB)

Sunitinib4

(vs IFN)

Pazopanib5

(vs PBO)

Tivozanib1

(TIVO‐1)

Has PFS reached a plateau, or is there room for improvement?

First‐line combination therapy: emerging data

McDermott D et al. Presented at: ASCO‐GU Symposium; 14–16 February 2013; Orlando, FL: abstract 345.

RANDOM ISE

Eligibility Criteria• Histologically and/or

cytologically confirmed advanced RCC

• ≥75% clear cell histology• Measurable metastatic disease• Prior nephrectomy unless high

burden of disease elsewhere• No prior VEGF, VEGFr or

mTOR inhibitors

BEV

BEV + TEM

BEV + SOR

SOR + TEM

n = 90

n = 90

n = 90

n = 90

Primary end point: PFSSecondary end point: ORR, OS, safety and biomarkers

Phase II E2804 BeST trial: study design

McDermott D et al. Presented at: ASCO‐GU Symposium; 14–16 February 2013; Orlando, FL: abstract 345.

OSPFS

0 10

20

30

40Mont

hs

Prop

ortio

n A

live

and

Prog

ress

ion-

free

1.0

0.8

0.6

0.2

0.0

0.4

BEV (Arm A)BEV + TEM (Arm B)BEV + SOR (Arm C)SOR + TEM (Arm D)

0 10

20

30

40Mont

hs

Prop

ortio

n A

live

1.0

0.8

0.6

0.2

0.0

0.4

HR--1.001.010.98

BEV (Arm A)BEV + TEM (Arm B)BEV + SOR (Arm C)SOR + TEM (Arm D)

BeST: PFS and OS

This presentation is for scientific discussion only – Please do not distribute following this meeting McDermott D et al. Presented at: ASCO‐GU Symposium; 14–16 February 2013; Orlando, FL: abstract 345.

BEV BEV + TEM BEV + SOR SOR + TEMGrade 3 (%) 36 67 67 66Grade 4 (%) 1 7 13 15

Grade 5 (%)2

(obstructed colon; MI)

1 (cardiac

ischaemia)

1 (severe HTN and cerebral

haemorrhage)

1 (pneumonitis)

Grade 3/4 toxicity occurring in >10% of patients in �1 arm, %Hypertension 19/− 17/− 32/3 8/−Fatigue 2/− 15/− 10/− 12/−Hand-foot syndrome −/− 1/− 22/− 3/−

Diarrhoea −/− 6/− 7/− 10/−Hypophosphatemia 1/− 8/− 11/− 33/−

Proteinuria 9/− 23/− 9/− 1/−Hyperglycaemia −/− 10/− 2/− 18/−

BeST: severe toxicity increased with combination therapy

• VEGF‐targeted agents: considered the first‐line standard of care in patients with good or intermediate MSKCC risk1,2

• The mTOR inhibitor temsirolimus is used in patients with poor risk features3

• Selecting the first targeted treatment in mRCC should be a decision weighing disease burden and individualised patient characteristics and preference

• Recommendations change with new agents, clinical development and identification of patient sub‐populations

– The latest clinical evidence should be assessed to ensure the patient achieves the best possible outcome in the first line

1. Escudier B et al. Ann Oncol. 2014.2. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. V2.2014.3. Hudes G et al. N Engl J Med. 2007;356:2271–2281.

Current treatments: an evolving landscape

Promises: the new immunotherapies,new combinations

There will in the storybook…

[email protected]

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First line in mRCC - OverGroup€¦ · Once upon a time… IL‐2 2005 1. Kidney cancer drugs market 2015 –Global Industry analysis, Pipeline Analysis, Size, share, Growth, Trends