NSCLC : PERSONALISED TREATMENT FOR PS 2PATIENTSimedex.com/lung-cancer-congress-europe/presentations/... · 2013-02-20 · 2/19/13 1 NSCLC : PERSONALISED TREATMENT FOR PS 2PATIENTS

2/19/13

1

NSCLC : PERSONALISED TREATMENTFOR PS 2 PATIENTS

Elisabeth Quoix

Les HôpitauxUniversitairesde STRASBOURG

PS2 patients : what we know PS 2 patients : 30-40% of the patients

PS 0PS

PS3

After D. Cella from BIOQOL/Q-SCORE database (n=493)

Heterogeneous group Comorbidities Stage

Frequently excluded from clinical trials:

PS 1

PS2

very few dedicated trials. Often combined with elderly Subgroup analyses of trials including PS 0-2 patients

Accurate assessment of PS 2 patients? Discrepancies between patients and doctors

(Gebbia V Ann Oncol 2005; 16 (Suppl 4):123-31

2/19/13

2

Performance Satus (PS)Performance Satus (PS)

PS Definitions

0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature

2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up >50% of waking hoursp g

3 Capable of only limited self-care, confined to a bed or a chair >50% of waking hours

4 Completely disabled. Cannot carry on self-care. Totally confined to bed or chair.

5 Dead

Prognostic value of PSPrognostic value of PS

V i bl N 7280 (%) HR (IC 95%)Variable N=7280 (%) HR (IC 95%) p

Age continued 1,00 (1,00-1,01) 0,011

Squamous 2485 (34) 0,95 (0,90-1,00) 0,042

Males 5501 (76) 1,15 (1,09-1,22) <0,001

PS 1 3571 (49) 1,41 (1,34-1,50) <0,001

PS 2 1151 (16) 2,13 (1,97-2,30) <0,001

PS 3-4 517 (7) 3,45 (3,11,3,83) <0,001

Model including biological variables : PS, Age ≥ 75 years, GB, Ca, albumin

Sculier, J Thorac Oncol 2008;3:457-466

2/19/13

3

Impact of PS on OutcomeECOG 1581

Performance Objective Median ToxicPerformance Objective Median ToxicStatus Response (%) Survival (wks) Deaths (%)

0 26 36 3

1 25 26 2

2 - 10 10

Ruckdeschel et al, JCO 1986

Overall survival of PS 2 versus PS 0-1 patientstreated by conventional chemotherapy

European study EORTC 08975 Spanish Lung Cancer Hellenic p y p gGroup Cooperative Group

VdsP vs VP vs V TxlP vs GP vs TxlG GP vs GPV vs GV-IV TxlCb vs TxlG

PS 0-1

n = 486

PS 2

n = 126

PS 0-1

n = 424

PS 2

n = 56

PS 0-1

n = 465

PS 2

n = 92

PS 0-1

n = 418

PS 2

n = 61

8.1 m 4.5 m 8.5 m 3.3 m 9.4 m 4.7 m 11.1 m 5.9 m

Soria, Ann Oncol 2001 ; Smit, JCO 2003 ;Alberola, JCO 2003 ; Kosmidis, JCO 2003 Courtesy of Maurice Pérol

2/19/13

4

Recommendations for treatment of fit patients (PS 0-1)

Evidence supports using a combination of Evidence supports using a combination of 2 cytotoxic drugs

Platinum-based combinations are preferred over nonplatinum doublets

Cisplatin more efficacious thancarboplatincarboplatin

Triplets : more toxic, no survival benefit

Azzoli CG et al. J Clin Oncol 2009;27:6251-65

Chemotherapy or Chemotherapy or Best Supportive Care for PS >=2 pts?Best Supportive Care for PS >=2 pts?

Meta-analysis, 2714 patients , 16 randomized trials 11 Cisplatin + 1 carboplatin-based HR=0,77 (0,71-0,83; p<0.0001)

PS Survivalbenefit

1-yr S

NSCLC Meta-analyses Collaborative Group, J Clin Oncol 2008;26:4617-25

0 + 8 % 26 to 34%

1 + 8 % 18 to 26%

≥2 + 6 % 8 to 14%

2/19/13

5

Platin-based doublets for PS 2 patients?

PS 2 patients in the ECOG 1594 trial

Sweeney CJ Cancer 2001;92:2639-47

2/19/13

6

100

ECOG 1594 : grade 3-5 toxicitiesin PS 2 patients

2030405060708090

Gr 5

Gr 4

Gr 3(% pts, n=64)

010

Taxol/Cis (n=18)

Gem/Cis (n=13)

Docetaxel/Cis (n=18)

Taxol/Para (n=15)CDDP+Tax CDDP + Gem CDDP + Doc Carbo + Tax

n=18 n=13 n=18 n=15

Sweeney CJ Cancer 2001;92:2639-47

No benefit of cisplatin-basedchemotherapy for PS2 patients

612 Patients 612 Patients withwith advancedadvanced NSCLCNSCLCR d i iR d i i bb i lbii lbi ll i l ii l i i d ii d i dd RandomizationRandomization betweenbetween vinorelbinevinorelbine alonealone, , cisplatincisplatin + + vindesinevindesine and and cisplatincisplatin + + vinorelbinevinorelbine

OverallOverall survivalsurvival benefitbenefit for for cisplatincisplatin--vinorelbinevinorelbine arm but….arm but….

PS 0PS 0--11 PS 2PS 2

Vinorelbine + CisplatinVinorelbine + Cisplatin 43 weeks

S1 = 38%

18 weeks

[11-35]

VinorelbineVinorelbine 36 weeks

S1 =34 %

18 weeks

[11-34]

Vindesine + CisplatinVindesine + Cisplatin 33 weeks

S1 = 29 %

18 weeks

[14-32]

Soria JC Ann Oncol 2001S1 = 1-year survival rate

2/19/13

7

Cisplatin gemcitabine Carboplatin paclitaxel

ECOG 1599 randomized phase II trial for PS 2 patients with adapted doses of platin

100 eligible patients

Cisplatin gemcitabine60mg/m² and 1g/m²

Carboplatin paclitaxelAUC 6 and 200 mg/m²

Response rate 23% 14%

Disease control rate 53% 55%

Time to progression 4.8 months 4.2 months

Progression free survival

3 months 3,5 months

Median survival time 6.9 months 6.2 months

1-year survival time 25% 19%

Langer C. J Clin Oncol 2007;25:418-23.

Carboplatin and PS 2Carboplatin and PS 2Paclitaxel Carbo- p

CALGB 9730,1-yr Survival

Paclitaxel

N=561 32% 37 % 0.25

PS 0-1 38% 41 % 0.59

PS 2 (18%) 10% 18 % 0.016

OS for PS2 pts OS for PS0-1 pts

Lilenbaum, J Clin Oncol 2005;23:190-6

PS 2PS 0-1

2/19/13

8

Carboplatin doublet vs single agent in PS2 patients

USOLilly

HCOGKosmidis

CALGB9730

Pts

ORR (%)

PFS ( )

G CG

78 77

12 36

2 8 4 0

G CG

47 43

4 14

3 0 4 0

P CP

50 49

10 24

NA NA

Obasaju et al. ASCO 2007; Kosmidis et al. JTO 2007; Lilenbaum et al. JCO 2005

PFS (mo)

MST (mo)

1-Y Surv (%)

2.8 4.0

5.2 6.9

24 31

3.0 4.0

4.8 6.7

18 20

NA NA

2.4 4.7

10 18

Finally monotherapy or doublet for PS 2 patients?

Gemcitabine Gemcitabine carboplatine P value(n= 47) (n= 43)

Response rate (%) 4 14 0.14

Disease control rate (%) 25 35

MST (months) 4.8 6.7 0.49

1-year survival (%) 17.8 20 0.8

% G3 G4 t i 2 (0) 5 (2 5) < 0 0001% G3-G4 neutropenia 2 (0) 5 (2.5) < 0.0001

% G3-G4 Thrombopenia 0 (0) 5 (2.5) 0.05

% G3-G4 Anemia 2 (0) 7.5 (0) 0.05

% Symptom improvement 64 65 1

Kosmidis P, J Thorac Oncol. 2007

2/19/13

9

Single agent vs combination chemotherapy in PS 2 patients with advanced NSCLC

Lilenbaum R J Thorac Oncol 2009; 4:869-74

Selected adverse events in single agent therapy arm versus combined arm


2/19/13

10

Efficacy parameters


Survival by Number of Risk Factors for All Patients

Risk = 0Risk = 1Risk = 2Risk = 3ct

ion

1.0

0.9

0 8 Risk = 3Risk = 4

urv

iva

l d

istr

ibu

tio

n f

un

c

0.5

0.3

0.8

0.7

0.6

0.4

0 2

Days from randomization to death

0 100 300 500 600 700

S

200 400

0

0.2

0.1

Risk factors : albumin <35 g/l, LDH > 200UI/l, >2 comobidities, extrathoracic metastases

2/19/13

11

Singlet vs. Doublet Therapy in Patients With 0-2 Risk Factors

ctio

n

1.0

0.9

0 8

N Median Survival

1-Year Survival

Doublet 254 8 8 Months 37%

urv

iva

l d

istr

ibu

tio

n f

un

c

0.5

0.3

0.8

0.7

0.6

0.4

0 2

Doublet (PGT303)

254 8.8 Months 37%

Singlet (PGT304) 248 8.8 Months 33%

P = 0.5153

Days from randomization to death0 100 300 500 600 700

S

200 400

0

0.2

0.1


ctio

n

1.0

0.9

0 8

Singlet vs. Doublet Therapy in Patients With 3-4 Risk Factors

N Median Survival

1-Year Survival

D bl t 79 5 8 M th 18%

urv

iva

l d

istr

ibu

tio

n f

un

c

0.5

0.3

0.8

0.7

0.6

0.4

0 2

Doublet (PGT303)

79 5.8 Months 18%

Singlet (PGT304) 105 4.3 Months 13%

P = 0.2033

Days from randomization to death0 100 300 500 600

S

200 400

0

0.2

0.1


2/19/13

12

A randomised Phase III trial in Brazil of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced NSCLC and PS of 2

Pemetrexed alone (500mg/m2) every 3 weeks for 4 cycles

(n=102)Key patient inclusion criteria

• Advanced NSCLC

• Any histology at first, amended to non-squamous only

• PS 2

• No prior chemotherapy

RStratification factors included • stage (IIIB vs IV)• age (≥70 vs <70)• weight loss (≥5 kg vs <5kg)

Lilenbaum et al. J Clin Oncol 30: 2012 (suppl; abstr 7506)

Primary endpoint

OS

Pemetrexed (500mg/m2) + carboplatin (AUC 5) every 3 weeks for 4 cycles (n=103)

• Adequate organ function

(n=217)

Key efficacy data: OS

al

1.0 Pemetrexed Pemetrexed/carboplatin

Median, months 5.6 9.1

Ove

rall

sur

viva 0.8

0.6

0.4

0.2

Pemetrexed

Pemetrexed/carboplatin

OS at 6 months, % 50 65


HR=0.57 (0.41–0.79); p=0.001

O

00 6 12 18 24 30 36

Time (months)


2/19/13

13

Key efficacy and safety: other resultsEfficacy

Pemetrexed Pemetrexed/ carboplatin P

ORR (CR+PR) 10 5% 24 0 <0 029ORR (CR+PR) 10.5% 24.0 <0.029

Median PFS (months) 3.0 5.9 <0.001

PFS at 6 months (%) 17 47 –

Grade 3/4 safety

% Pemetrexed (n=104) Pemetrexed/ carboplatin(n=107)

Anaemia 3.9 11.7

Thrombocytopenia 0 1 0Thrombocytopenia 0 1.0

Neutropenia 1.0 5.8

Febrile neutropenia 2.9 1.9

Nausea/emesis 0 2.9

Diarrhoea 2 1

Dyspnoea 10.8 5.8

Grade 5 events 0 3.9


Conclusions Combination chemotherapy with carboplatin-pemetrexed

significantly improves survival compared with single agent t d i ti t ith d d d PS fpemetrexed in patients with advanced and a PS of 2

The secondary endpoints of response rate and PFS were also met The survival benefit was maintained in subset populations Toxicity was acceptable in this high-risk group


2/19/13

14

What about targeted therapies in PS 2-3 patients as first-line treatment

Randomised Phase II trial : Randomised Phase II trial : Gefitinib vs placebo in PS 2Gefitinib vs placebo in PS 2--33

202 patients G Placebo 202 patients (119 PS2, 83 PS 3)

G Placebo

OR / DCR 6% / 31% 1% / 22.8%

median S 3.7 mo. 2.8 mo.

Goss G, J Clin Oncol 2009; 27:2253-2260

2/19/13

15

EGFREGFR--TKI TKI vsvs Chemotherapy: Chemotherapy: 2 randomized phase II Studies2 randomized phase II Studies

PS 2Lilenbaum, J Clin Oncol 200826:863-869

X 4

GEF 250 mg/D128 Pts

GEM 1250 mg/m2, D1, J8

PS 2

Morère JF, Lung Cancer 2010;70:301-7

g

DOC

PtsStrat: PS 2/3

ADK/other

DOC 75 mg/m², D1

GEF 250 mg/D

RR

Erlotinib Chemo p

Median Gef Gem Doc

PFS 2 1 2 2 2

EGFREGFR--TKI TKI vsvs Chemotherapy: Chemotherapy: Efficacy ResultsEfficacy Results

OR/SD 2%/37% 12%/43%

Med PFS 1.9 mo. 3.5 mo. 0.063

Med OS 6.5 mo. 9.7 mo. 0.018

PFS 2.1 2 2,2

S 2.2 2.4 3.5

S PS 2 3 3.1 5.9

S PS3 1.9 1.8 1.1

All pts(PS2/3: 69%/31%)

Lilenbaum R, JCO 2008 Morère, JF,Lung Cancer 2010

2/19/13

16

Gefitinib in Pts with EGFR Mutated Disease Gefitinib in Pts with EGFR Mutated Disease and no Indication and no Indication for Chemotherapyfor Chemotherapy

Eligibility : 20-74 yrs + PS 3-4 75-79 yrs + PS 2-4 80 yrs + PS 1-4

30 patients including 22 PS 3-4 Gefitinib 250 mg/day

Median PFS 6.5 months Median survival 17.8 months 1-yr survival 63%

Inoue A, J Clin Oncol 2009;27:1394-1400

Changes in PSChanges in PS

79% of patients79% of patients (p<0.00005)

68% of the 22 PS3 pts have changes PS for a PS1

Inoue A, J Clin Oncol 2009;27:1394-1400

2/19/13

17

PS 2 Patients with Advanced NSCLC

SWOG0341

OSI771

USOLILLY

USOLILLY

OSI771

Pts

ORR (%)

PFS (mo)

E

72

7

2.0

E

52

4

1.9

G

78

12

2.8

CG

77

36

4.0

CP

51

12

3.5

Hesketh et al. ASCO 2007; Lilenbaum et al. ASCO 2006; Obasaju et al. ASCO 2007; Lilenbaum et al. JCO 2005

MST (mo)

1-Y (%)

5.0

24

6.6

20

5.2

24

6.9

31

9.5

45

TOPICAL study design

Erlotinib*(150mg/day)

Inclusion criteria

• Histologically/cytologically fi d NSCLC

Primary• Overall survival (OS)

Endpoints

(150mg/day)to PD

Placebo*to PD

1:1 randomization

confirmed NSCLC

• Measurable stage IIIB/IV disease and ≥ 18 yrs

• Chemo-naive and unsuitable for chemotherapy:– ECOG PS 2–3 or– PS 0–1 with impaired renal function CC<60ml/min

• Life expectancy ≥8 weeks

( )

Secondary• Progression-free survival

(PFS)• Objective response rate• Quality of life (QoL)• Disease-related

symptoms • Safety and tolerability

TranslationalBi k l• Biomarker analyses– EGFR mutation– proteomic/genomic

markers

S. Lee J Clin Oncol 28:15s, 2010 (suppl; abstr 7504)

2/19/13

18

TOPICAL StudyPatients characteristics

670 patients were randomised to either erlotinib(350) or placebo (320) from 78 UK centres(350) or placebo (320), from 78 UK centres.

Median age: 77 yrs (range 42-91); 61% male; 38% adenocarcinoma, 39% squamous histology; PS score of 0/1, 2 and 3 were 16%, 55% and 29%

lrespectively; 35% stage IIIB and 65% stage IV disease.


Progression-free survival (PFS)

100

PFS rate (%)

Erlotinib Placebo

Median PFS months 2 8 2 780

60

40

20

HR=0.85 (0.72–0.99); p=0.038

Median PFS, months 2.8 2.7

PFS at 6 months, % 22 13

PFS at 12 months, % 9 4

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (months)


2/19/13

19

Overall survival (OS)100

80

Survival rate (%) Erlotinib Placebo

Median OS, months 3.8 3.6

OS t 6 th % 36 33

HR=0.97 (0.82–1.14); p=0.69

60

40



20

00 4 8 12 16 20 24 28 32 36

Time (months)


PFS: wild-type EGFR by gender

Erlotinib (n=102)Placebo (n=85)

Male100

80

PFS (%)

Erlotinib (n=55)Pl b ( 53)

Female100

80

PFS (%)

HR=1.03, (0.77–1.39), p=0.82

Placebo (n=85)

60

40

20

HR=0.58, (0.39-0.87), p=0.009

Placebo (n=53)

60

40

20

0 4 8 12 16 20 24 28 32 36 40

0

Time (months)

0 4 8 12 16 20 24 28 32 36 40

Time (months)

0


2/19/13

20

Bev in PS 2 Advanced NSCLC: TOPPSRAN

RAN Pemetrexed 500 mg/m2 IV q 21 days

Chemotherapy-naivepatients with stage IIIB (with pleural effusion)

or IV NSCLC and ECOG PS 2

OM

DOMI Carboplatin AUC=5 IV q 21 days

Pemetrexed 500 mg/m2 IV q 21 daysBevacizumab 15 mg/kg IV q 21 days

ZEZE

(max 4 cycles) Pemetrexed 500 mg/m2 IV q 21 daysBevacizumab 15mg/kg IV q 21 days

Primary Objective: PFS

Secondary Objectives:ORRToxicityOS

* Treatment continues until PD or unacceptable toxicity

EML-4 ALK translocations

Camidge Lancet Oncol 2012;13:1011-19

2/19/13

21

Altered PS: ConclusionsAltered PS: Conclusions Available data support the use of single-agent chemotherapy in

PS 2 (ASCO Recos) Data are insufficient to make a recommendation for or against

using a combination of 2 cytotoxic drugs (ASCO Recos) Probable heterogenity of PS 2 patients, some of them might

benefit from doublet treatments See for example the recent positive trial comparing Pem and

Carbo PemCarbo Pem EGFR-TKI or crizotinib in mutated pts, even with altered PS No EGFR-TKI in non-mutated patients as 1st line Need for dedicated trials

Azzoli C, J Clin Oncol 2009;27:6251-66

Documents

NSCLC : PERSONALISED TREATMENT FOR PS 2PATIENTSimedex.com/lung-cancer-congress-europe/presentations/... · 2013-02-20 · 2/19/13 1 NSCLC : PERSONALISED TREATMENT FOR PS 2PATIENTS