Evidencia disponible en subgrupos de pacientes Javier Puente, MD, PhD Hospital Universitario Clinico...

Evidencia disponible en subgrupos de pacientes

Javier Puente, MD, PhDHospital Universitario Clinico San Carlos

Medical Oncology DepartmentComplutense University

Associate Professor of Medicine

Targeted agents currently approved for mRCC in Europe

Sorafenib (oral)Advanced RCC after IFN‑α/IL-2 or if

unsuitable for IFN-α/IL-22

Bevacizumab (+IFN-α) (IV)

First-line mRCC3

Everolimus (oral)Advanced RCC after

VEGF targeted therapy‑ 5

Axitinib (oral)Advanced RCC after sunitinib or a

cytokine7

Temsirolimus (IV)Advanced RCC with 3–6 prognostic

risk factors4

2006 2007 2008 2009 2010 2011 2012 2013 2014

Pazopanib (oral)Advanced RCC6

Sunitinib (oral)Advanced/mRCC1

1. Sunitinib SmPC, Jan 2014; 2. Sorafenib SmPC, Feb 2013; 3. Bevacizumab SmPC, Feb 2014; 4. Temsirolimus SmPC, Oct 2013; 5. Everolimus SmPC, Nov 2013; 6. Pazopanib SmPC, Dec 2013; 7. Axitinib SmPC, Oct 2013.

IFN-α, interferon-alpha; IL-2, interleukin-2; IV, intravenous

Evolution in the first-line treatment of mRCC

Med

ian

su

rviv

al (

mo

nth

s)

PFS OS

3–6

6–15*

13–22

18–32*

After AfterBefore Before

30

25

20

15

10

5

0

Median survival before and after the introduction of targeted agents (TKIs)1–11

1. Coppin et al. Cochrane Database Syst Rev 2005; 2. Gore et al. Lancet 2010; 3. Motzer et al. N Engl J Med 2007; 4. Escudier et al. Lancet 2007; 5. Rini et al. J Clin Oncol 2008; 6. Motzer et al. N Engl J Med 2013; 7. Motzer et al. J Clin Oncol 2009; 8. Escudier et al. J Clin Oncol 2010; 9. Rini et al. J Clin Oncol 2010; 10. Michel et al. ASCO GU 2014; 11. Motzer et al. ASCO 2013.

*With targeted agents as first-line mRCC therapy primarily in favourable/intermediate risk patients

Have we improved OS since 2006?

2007/20131,2 2010/20132,320134

20145 20145 20136

1. Motzer et al. J Clin Oncol 2009; 2. Motzer et al. N Engl J Med 2013; 3. Sternberg et al. Eur J Cancer 2013; 4. Motzer et al. J Clin Oncol 2013; 5. Michel et al. ASCO GU 2014; 6. Motzer et al. ASCO 2013.

Med

ian

OS

, m

on

ths

Please refer to local prescribing information for each treatment option

Median OS for VEGF-targeted therapies in mRCC in clinical studies

Eve. Everolimus; Seq., sequence; Sor, sorafenib; Sun, sunitinib

First-line

Second-line

1. Escudier et al. Ann Oncol 2012; 2. Corrigendum Ann Oncol 2013; 3. Temsirolimus SmPC, Oct 2013.

Second-line targeted treatment options: VEGFR-TKI or mTOR inhibitor?

mRCC1,2

Temsirolimus*

Poor prognosisGood/intermediate prognosis

VEGFR-TKI or mAb-VEGF-A+IFNα

mTOR inhibitorVEGFR-TKI

*Temsirolimus is indicated for the first-line treatment of advanced RCC with 3-6 prognostic risk factors3; mAb, monoclonal antibody

Introduction

With the arrival of targeted therapies, the treatment paradigm for mRCC has become increasingly complex

Maximising the long-term benefit of these agents requires informed decision-making based on both…

Clinical trial data Real-world experience

In this symposium we will explore…

• assess the current treatment paradigm for mRCC

• assess the importance of maximising treatment lines

Clinical evidence, to…

Evidence from the real world, clinical practice, and real-life case studies, to…

• assess how best to optimise the treatment options available

• help make informed treatment decisions for each individual patient

Special subgroups of patients

- ELDERLY PATIENTS

- PERFORMANCE STATUS 2

- BRAIN METASTASES

- COMORBILITIES (CARDIAC DISORDES, RENAL FAILURE, …)

- NON CLEAR CELL CARCINOMA

Percent of New Cases by Age Group: Kidney and Renal Pelvis Cancer

Median age at diagnostic:

64

SEER 18 2007-2011, All Races, Both Sexes

48,3% ≥ 65

23,1% ≥ 75

Percent of new cases by age group

Median age in pivotal studies

Drug Nº patients Benefit (months)

Median age %>70 years

Sunitinib 750 6 62 [27-87] NR

Sorafenib 903 2,7 59 [19-86] 16%

Beva-IFN 649 y 732

4,8 y 3,3

61 [30-82]61 [56-70]

NR

Temsirolimus 626 2,4 58 [32-81] NR

Everolimus 410 2,1 61 [27-85] NR

Pazopanib 435 5 59 [25-85] 35% (>65 a)

Efficacy is mantained regardless of age

Efficacy and safety of sunitinib in elderly patients with mRCC

Hutson TE, et al. Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br J Cancer. 2014 Mar 4;110(5):1125-32.

N= 1059 (19% ≥70 a)


More common (P<0.05) in patients aged ≥70 years:• Fatigue• Cough• Anemia• Peripheral edema• Thrombocytopenia• Decreased weight• Decreased appetite• Dizziness• Hypothyroidism• Dehydration• Urinary tract infection


Expanded Access Program: experience in elderly patients

Drug Nº patients

%≥70 years Median age Efficacy

Sunitinib (Gore) 4564 1418 (32%)(Nota:≥65 a)

59 [19-89] SLP global: 10,9 mSG global: 18,4 m

SLP ≥65 a: 11,3 m SG ≥65 a: 18,2 m

Sorafenib Europeo (Beck)

1159 267 (23%) 62 [18-84] SLP global: 6,6 mTP: 7,9 mSLP ≥70 vs <70 a: 8,0 vs 6,4 m (ns)

SorafenibNorteamericano (Stadler)

2504 736 (29%) 63 [13-93] SLP global: 36 semSG global: 50 semSLP ≥70 vs <70 a: 46 sem vs 50 (ns)

Everolimus (Grünwald)

1367 592 (43.3%)(Nota:≥65 a)

63 [23-87] Median treatment global: 14 sem

Gore et al. Lancet Oncol 2009; Beck et al Ann Oncol 2011; Stadler, et al. Cancer 2010; Bukowski, et al. Oncology 2010

Dosing decisionsTreatment duration

decisionsToxicity management

decisions

Personalising treatment to maximise outcomes with targeted therapy: experience from the real world

How can we select the best treatment for these patients?

Standard vs adapted sunitinib regimen in elderly patients with mRCC

De Giorgi et al. Clin Genitorinary Cancer 2013; 12(3): 182-9

11 meses 25.5 meses

De Giorgi et al. Clin Genitorinary Cancer 2013; 12(3): 182-9

Standard vs adapted sunitinib regimen in elderly patients with mRCC

Why dose titrate?

Dose titration allows treatment to be

personalised with maintenance of

therapeutic drug levels, which are associated with

better outcomes

Efficacy is the main driver in RCC

treatment

RAINBOW study: modified sunitinib scheduling in patients with mRCC

Retrospective observational study of mRCC patients administered sunitinib on a 2/1 schedule*

Group A (n=208)Sunitinib

50 mg/day*Switched from schedule 4/2 to 2/1 due to TEAE

Group B (n=41)Sunitinib

50 mg/day*Schedule 2/1 ab initio due to

poor clinical condition

Objective Evaluate efficacy

and safety of 2/1 vs 4/2 schedule

Eligibility criteria Patients with

advanced RCC

N=276

BASELINE

Group C (n=27)Sunitinib

50 mg/day*Schedule 4/2 (control)

Safety endpoint: Incidence of adverse eventsEfficacy endpoint: PFS and treatment duration *Dose reductions were possible

TEAE, treatment-emergent adverse events

Bracarda et al. ASCO GU 2014

RAINBOW study: AE rate in patients switched from 4/2 to 2/1 schedule

Rat

e (%

)

† ‡ § ¶

*p<0.001; †p=0.008; ‡p=0.063; §p=0.003; ¶p=0.007HFS, hand-foot syndrome

Bracarda et al. ASCO GU 2014

Toxicity evaluation after 2 weeks on first course

Modify dose/schedule

DL-1: Pts than cannot take 50 mg for 28 d- 50 mg individualized # of days / 7 days off

DL-2: Pts than cannot take 50 mg for at least 7 d- 37.5 mg individualized # of days / 7 days off

DL-3: Pts than cannot take 37.5 mg for at least 7- 25 mg individualized # of days / 7 days off

≤ Grade-1 toxicity:Continue Rx

≥ Grade-2 toxicitybefore 4 weeks:Stop Rx for 7 d**

≤ Grade-1 toxicityAt 4 weeks:

Stop Rx for 7 d**

Grade-2 toxicityAt 4 weeks:

Stop Rx for 7 d**

Reduce off-Rx time to 7d**

DL+: 50mg 28/7d

Escalate dose/modify

schedule

DL+1: 62.5 mg 14/7

DL+2: 75.0 mg 14/7

Toxicity evaluation after 4 weeks on first course

≥ Grade-2 toxicity:Stop Rx for 7 d**

Sunitinib Titration Study (Bjarnason et al. ESMO 2014)

** Or until toxicity has resolved

Individually maximize days on Rx during continued therapy based on toxicity

Sub

sequ

ent

Cyc

les

Firs

t cy

cle

Current dose schedule distribution for 91 pts:

Sunitinib dose (mg)

Schedule(d on/off)

# patients currently or when came off study

59.3% of patient with improved dose intensity vs. standard dose criteria

75 14/7 4

18 pts (19.8%)dose escalated

75 10/7 1

62.5 16/7 1

62.5 14/7 11

62.5 7/7 1

50 28/7 19 Many recently entered on study

50 28/14 3

50 24/7 136 pts (39.5%)

50 mg dose maintainedbut for fewer days on

Would have been dose reduced by standard criteria

50 20/7 1

50 16/7 4

50 14/7 18

50 9/7 2

50 7/7 10

37.5 28/7 and 90/7 211 pts (12%) reduced to 37.5 mg

(36 - 63% in rand trials)1-437.5 14/7 5

37.5 5-7/7 4

25 28-42/7 14 pts (4.4%) reduced to 25 mg

(27- 43% in rand trials) 1-425 14/7 1

25 7/7 2

4 pts (4.4%) d/c early due to toxicity (15 - 19% in rand trials) 1-4

1. Motzer RJ, Hutson TE, Olsen MR et al. J Clin Oncol 2012; 30: 1371-1377. 2. Motzer RJ, Hutson TE, Tomczak P et al. J Clin Oncol 2009; 27: 3584-3590.3. Barrios C, Hernandez-Barajas D, Brown M et al. ESMO conference 2009; Abstract 7122.4. Escudier B, Roigas J, Gillessen S et al. J Clin Oncol2009; 27: 4068-4075.

Response data for 65 evaluable pts

Individ Sunitinib

dosing

EFFECT50 mg dose

Sunit data vs. INF

Phase-III

Pazo datavs. Sut

Phase-III

Axitinib data vs. Sorafenib

Phase-III

N 65 146 335 557 192

CR % 4.6 (n=3) 0 0 <1 0

PR % 50.8 (n=33) 32 31 31 32

CR+PR % 55.4* (n=36) 32 31 31 32

SD % 33.8 (n=22) 43 48 39 43

CR+PR+SD 89.2 (n=58) 75 79 70 72

PD % 10.8 (n=7) 25 21 17 10

PFS (mo) n/a 8.5 11 8.4 10.1*Similar to RR for Axitinib dose titration arm (n=56)

Motzer RJ, et al. Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96.

Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27: 5794-5799.

Outcome of patients with mRCC that do not meet eligibility criteria for clinical trials

8,6 vs 5,0 meses28.4 vs 12.5 meses

Heng DY, et al. Annals of Oncology 25: 149–154, 2014.

Gore M, et al. ESMO 2011

Annals of Oncology 23: 973–980, 2012

Retrospectivo: 11157 pacientes

Brain Metastases: Epidemiology

903 TARGET 139

Annals of Oncology 21: 1027–1031, 2010

Cancer. 2011 Feb 1;117(3):501-9

Safety and efficacy of sunitinib for mRCC with brain metastases

Non-clear Cell Renal Cell CarcinomaDescription and Prevalence

• nccRCC represents a diverse group of tumors with varying genetic and histologic characteristics1,2

– Approximately 25% of RCC cases are nccRCC1

• Many nccRCC subtypes have only recently been described as discrete entities; some are considered new and emerging, and others remain unclassified2

32

1. Cohen HT et al. N Engl J Med. 2005;353:2477-2490.2. Srigley JR et al. Mod Pathol. 2009; 22 (suppl 2): S2-S23.

Temsirolimus ARCC Trial: OS and PFS1,2

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ARCC, advanced renal cell carcinoma.

1. Hudes G et al. N Engl J Med. 2007;356:2271-2281.2. Dutcher JP et al. Med Oncol. 2009;26:202-209.

Overall Survival

INF-α Temsirolimus Temsirolimus vs INF-α

Median (mo, 95% CI) Median (mo, 95% CI) HR (95% CI)

ccRCC 8.2 (6.6 – 10.4) 10.7 (8.5 – 13.0) 0.82 (0.64 – 1.06)

nccRCC 4.3 (3.2 – 7.3) 11.6 (8.9 – 14.5) 0.49 (0.29 – 0.85)

Progression-free Survival

INF-α Temsirolimus Temsirolimus vs INF-α

Median (mo, 95% CI) Median (mo, 95% CI) HR (95% CI)

ccRCC 3.7 (2.5 – 4.6) 5.5 (3.8, 7.1) 0.76 (0.60 – 0.97)

nccRCC 1.8 (1.6 – 2.1) 7.0 (3.9 – 8.9) 0.38 (0.23 – 0.62)

Tumor response (per RECIST), n (%)

Number of evaluable patients All (n = 3464) Non-clear cell histology (n = 437)

OR 603 (17) 48 (11)

CR 34 (1) 2 (<1)

PR 569 (16) 46 (11)

SD ≥ 3 months 2029 (59) 250 (57)

PR or SD < 3 months 832 (24) 139 (32)

Clinical benefit* 2632 (76) 298 (68)

Summary of Median PFS and OS

Number of evaluable patients All (n = 4349) Non-clear cell histology (n = 588)

PFS, months (median; 95% CI) 10.9 (10.3 – 11.2) 7.8 (6.3 – 8.3)

OS, months (median; 95% CI) 18.4 (17.4 – 19.2) 13.4 (10.7 – 14.9)

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OR, objective response. *Clinical benefit = OR + SD for ≥ 3 months.

Gore ME et al. Lancet Oncol. 2009;10:757-763.

Safety and efficacy of sunitinib for non clear cell carcinoma (EAP)

SUPAP: Phase 2 Trial of First-Line Sunitinib in Papillary mRCC

35

Primary end point: • objective tumor responseSecondary end points: • safety, OS, PFS, time to response,

duration of response

Eligibility Criteria• Age ≥18 years • Locally advanced or metastatic,

histologically confirmed type1 or 2 papillary RCC

• Measurable disease by RECIST• ECOG PS ≤1• No prior systemic therapy for

mRCC (including sunitinib)

Sunitinib 50 mg/d;4 weeks on/2 weeks off

N = 61

Type 1: n = 15Non-type 1: n = 46

Disease progression or unacceptable

toxicity

Open-label, single-arm phase 2 study

• 61 patients were enrolled (15 with type 1; 46 with non-type 1)

• Two-stage study design based on SIMON 2-step method: 21 patients are included to achieve a 20% ORR. If ≥2 patients achieve this goal, 20 additional patients are added

• A separate, identical study in patients with type 1 or non-type 1 tumors was conducted

Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress;September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis:Patient Characteristics (1)

36

All, n (%)N = 61

Type 1, n (%)n = 15

Non-type 1, n (%)n = 46

Age, y (Median, min-max) 64 (32–81) 69 (53–8-0) 61 (32–81)

Female (%) 10 (16) 1 (7) 9 (20)

Nephrectomy

Yes 53 (87) 115 (100) 38 (83)

No 8 (13) — 8 (17)

Metastatic site

>1 site 55 (90) 13 (87) 42 (91)

Lung 38 (62) 13 (87) 25 (54)

Retroperitoneal lymph nodes 33 (54) 7 (47) 26 (57)

Mediastinum 29 (48) 6 (40) 23 (50)

Bone 17 (28) 6 (40) 11 (24)

Liver 11 (18) — 11 (24)

Other 27 (44) 8 (53) 19 (41)

MSKCC Group

0 Favorable 12 (22) 4 (29) 8 (20)

1-2 Intermediate 33 (61) 7 (50) 26 (65)

≥3 Poor 9 (17) 3 (21) 6 (15)

Undetermined 7 (–) 1 (–) 6 (–)

Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis:Best Response

37

Best Response , n (%) All, n (%)N = 61

Type 1, n (%)n = 15

Non-type 1, n (%)n = 46

Assessable patients 60a (100) 15b (100) 45c (100)

Partial response (PR) 7 (12) 2 (13) 5 (11)

Stable disease (SD) 35 (58) 10 (67) 25 (56)

SD ≥12 weeks 15 (25) 5 (33) 10 (22)

Progression 18 (30) 3 (20) 15 (33)

Objective response rate (95% CI) 12% (3%–20%) 13% (0%–31%) 11% (2%–20%)

Nonprogression rate (95% CI) 70% (58%–82%) 80% (60%–100%) 67% (53%–80%)

aOne patient died before first tumor evaluation from a cause other than disease progression.bOne patient has been reviewed as type 2 (with a PR).cTwo patients have been reviewed as type 1 (both with SD), 1 as a nonpapillary type (with a PR) and 1 as doubtful (with a SD).


SUPAP Interim Analysis:

PFS

38

*Product limit survival estimate with number of patients at risk.PFS, progression-free survival.


SUPAP Interim Analysis: OS

39

Su

rviv

al

Pro

ba

bil

ity

*Product limit survival estimate with number of patients at risk.


Nonrandomized,

single-group assignment

Phase 2 Trial of Everolimus in Patients With mRCC and Non-Clear Cell Histology

Study Design1-3

A total of 49 patients were enrolled from 5 centers; 23 patients had been treated with VEGF-TKI prior to the study enrollment

Median age was 57 years (range 24 ‒ 75 years) and male to female ratio was 37:12 Histology of the patients included papillary (n = 29), chromophobe (n = 8), collecting duct (n = 2),

sarcomatoid (n = 4), and unclassifiable carcinoma (n = 6)

40

Everolimus 10 mg/day orally

Disease progression or unacceptable toxicity

Study start Study end

Primary end point:• PFS

Secondary end points:• Objective response rate• Clinical benefit rate• Disease control rate• Safety

Key eligibility criteria:

≥ 18 years old with mRCC of non clear-cell histology, with or without previous VEGF-TKI therapy

ECOG PS 0 or 1

Key exclusion criteria:

Previous use of an mTOR inhibitor

Clinically uncontrolled CNS metastasis

Interstitial pulmonary disease

ECOG PS, Eastern Cooperative Oncology Group Performance Status.

1. Koh Y et al. J Clin Oncol. 2012;30(suppl):abstract 4544.2. Koh Y et al. Poster presented at the ASCO annual meeting, June 1-5, 2012, Chicago, Illinois.3. ClinicalTrials.gov Identifier: NCT00830895.

Phase 2 Trial of Everolimus in Patients With mRCC and Non-Clear Cell Histology: Efficacy and Safety1,2

Toxicity profiles were commensurate with previous reports of everolimus in patients with mRCC

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Outcomes Everolimus (10 mg/d) N = 49

Best overall response, (n) %

Partial response 5† (10.2)

Stable disease 25 (51.0)

Progressive disease 16 (32.7)

Not eligible for assessment 3 (6.1)

Median PFS, months 5.2

ORR, % 10.2

CBR, % 57.1

DCR, % 61.2

ORR, objective response rate; CBR, clinical benefit rate; DCR, disease control rate.

1. Koh Y et al. J Clin Oncol. 2012;30(suppl.): abstract 4544.2. Koh Y et al. Poster presented at the ASCO annual meeting, June 1-5, 2012, Chicago, Illinois.

Efficacy of EverolimusAccording to Histology

RAPTOR Phase 2 Trial of First-Line Everolimus in Papillary mRCC1,2

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Primary end point: • Proportion of patients progression free at 6 monthsSecondary end points: • DCR, ORR, duration of response, median PFS, safety

Eligibility Criteria• Age ≥18 years • Metastatic papillary RCC• Measurable disease• ECOG PS ≤1• No prior mTOR inhibitor• No prior systemic therapy

for mRCC (including VEGF or mTOR inhibitors

International, multicenter,open-label study

1. ClinicalTrials.gov identifier: NCT00688753.2. Escudier B et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress;

September 28–October 2, 2012; Vienna, Austria.

Trial Sites: Belgium, France, Germany, Italy, Poland, Spain

Everolimus 10 mg/dN = 92

Disease progression or unacceptable

toxicity

RAPTOR Interim Analysis:Patient Characteristics

43

Escudier B et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress;September 28–October 2, 2012; Vienna, Austria.

Sex, n (%)

Female 20 (21.7)

Male 72 (78.3)

Age, y

n 92

Mean (SD) 59.9 (14.9)

Median 62.0

Range 23–84

Patients with PS, n (%)

0 56 (60.9)

1 36 (39.1)

MSKCC, n (%)

Favorable 48 (52.2)

Intermediate 38 (41.3)

Poor 1 (1.1)

Missing 5 (5.4)

Nephrectomized patients, n (%)

No 16 (17.4)

Yes 76 (82.6)

Organs with lesions, n (%)

1 organ 13 (14.1%)

2 organs 23 (25.0%)

>2 lesions 48 (52.2%)

Missing 8 (8.7%)

Time from diagnosis to treatment

n 88

Mean (SD) 788.56 (1218.70)

Median 209.50

Range 14.0–5451.0

Type

Type 1 23 (25.0)

Type 2 39 (42.4)

Missing 30 (32.6)

RAPTOR Final Analysis: PFS, OS (ASCO GU 2014)

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*Kaplan-Meier estimate for the proportion of patients without PFS event (progression or death due to any cause)..

Escudier B et al. Presented at the ASCO GU 2014

ESPN TRIAL Everolimus versus Sunitinib prospective evaluation in metastatic non-clear cell carcinoma1

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1. Tannir E, ASCO 2014 (Abstract 4505)

ESPN TRIAL: PFS in First Line (Primary Endpoint)

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ESPN TRIAL: Overall Survival47


Conclusions: What have we learnt?

What the current treatment paradigm is in mRCC The importance of maximising therapy lines in mRCC That efficacy is the main driver in RCC treatment

Real-world data

Real-life case studies

Strategies to personalise targeted therapy to maximise outcomes

Dosing, treatment duration and toxicity management decisions

Clinical evidence

The value of maximising mRCC therapy in daily clinical practice

THANK YOU

Javier Puente, MD, PhDHospital Universitario Clinico San Carlos

Medical Oncology DepartmentComplutense University

Associate Professor of Medicine

Evidencia disponible en subgrupos de pacientes Javier Puente, MD, PhD Hospital Universitario Clinico...

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