maintenance therapy in advanced non-small cell lung cancer. · cielanu et al. 663 pemetrexed better...

Maintenance therapy in advanced

non-small cell lung cancer.

Egbert F. Smit MD PhD

Dept Thoracic Oncology

Netherlands Cancer Institute

[email protected]

Evolution of front line therapy in

NSCLC – unselected pts

• 1970’s – 1980’s: Treatment until progression

• 1990’s: Treatment limited to 6–8 courses

• 2000’s: 3–4 courses of platinum-based therapy.– Provided 2nd-line therapy is considered

• 2010: 4–6 courses of platinum-based therapy + maintenance

Strategies for post Platinum therapy

Concepts of Maintenance

1st-line: Platin-based

Combination Maintenance Monotherapy

with new compound Second Line Treatment

Progression

„Switch“ Maintenance

CR, PR, SD

4 cycles until Progression

bis Progress

JMEN (Pemetrexed)1

SATURN (Erlotinib)2

PARAMOUNT3

AVAPERL4

Selection of patients with good prognosis

Endpoints:

• Quality of Life

• Symptom Control

• Tolerability

ProgressionCR, PR, SD

„Continuation“ Maintenance

1st-line:

Pemetrexed/Cisplatin

Pemetrexed/Cisplatin/Bev

Maintenance Pemetrexed

or Pemetrexed/BevSecond Line

Treatment

4 cycles until Progression

Gemcitabine vs placebo in NSCLC

Primary endpoint:

1. Time to progression

Secondary endpoints:

1. ORR

2. Response duration

3. Overall survival

4. Toxicity

5. Symptom control

Brodowicz et al. Lung Cancer 52,155,2006

Gemcitabine vs Placebo in NSCLC

Brodowicz et al. Lung Cancer

52,155,2006

Progression free survival through study period (left) and maintenance phase (right)

Gemcitabine vs placebo in NSCLC

BSC Gem-BSC P-value

TTP,

overall

5.0

(4.5–5.7)

6.6

(5.9–7.2)

<0.001

TTP,

maintenance

2.0

(1.6–2.6)

3.6

(2.8–4.1)

<0.001

OS 11

(9.7–13.5)

13

(11.0–16.7)

0.195

Brodowicz et al. Lung Cancer 52,155,2006.

Fidias, et al. ASCO 2007; Abstract No. LBA7516

Immediate vs delayed docetaxel (Phase III)

Docetaxel Switch Maintenance: PFS

• Median PFS delayed vs immediate: 2.7 vs 5.7 mos (P = .0001)

Fidias PM, et al. J Clin Oncol. 2009;27:591-598.

DelayedImmediate

Pro

bab

ilit

y o

f P

FS

1.0

0.8

0.6

0.4

0.2

0480 12 24 27 30 33 36 39 42 45

MosPatients at Risk, n

Delayed 156 59 28 18 13 6 1

Immediate 153 106 72 42 26 5 2

3 6 9 15 18 21

HR=0.71

(95% CI: 0.55–0.92)

p<0.0001

Docetaxel Switch Maintenance: OS

Fidias PM, et al. J Clin Oncol. 2009;27:591-598.

DelayedImmediate

Pro

bab

ilit

y o

f O

S

1.0

0.8

0.6

0.4

0.2

0600 6 12 18 24 30 36 42 48 54

MosPatients at Risk, n

Delayed 156 109 65 42 21 6 2

Immediate 153 119 73 49 28 13 2

Median OS delayed vs immediate: 9.7 vs 12.3 mos (P = .0853)

1-yr survival delayed vs immediate: 43.5% vs 51.1%

HR=0.84

(95% CI: 0.65–0.1.08)

p<0.0853

Pem/BSC vs placebo/BSC in NSCLC:

Study design

Stage IIIB/IV NSCLC

PS 0/1

4 prior cycles of gem,

doc, or tax + cis or carb,

with CR, PR, or SD

(NO PEMETREXED)

Randomization factors:

gender

PS

stage

best tumor response to

induction

non-platinum induction

drug

brain mets

Pemetrexed 500 mg/m2

(d1,q21d) + BSC (N=441)*

Primary Endpoint = PFS

Placebo (d1, q21d) + BSC

(N=222)*

*B12, folate, and dexamethasone given in both arms

2:1

Randomization

Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 2008; Chicago, IL.

Pem/BSC vs placebo/BSC in NSCLC:

Progression-free survival

Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 2008; Chicago, IL.

24% censored

N=581

HR=0.599

(95% CI: 0.49–0.73)

p <0.00001

Time (months)

Pro

gre

ss

ion

-fre

e

Pro

bab

ilit

y

1.0

Pemetrexed: 4.04 mos

(95% CI: 3.06–4.44)

Placebo: 1.97 mos

(95% CI: 1.54–2.76)

Maintenance pemetrexed (JMEN):

PFS

(n=581)

OS

(n=663)

Cielanu et al., Lancet 2010

Switch Maintenance: Pemetrexed

Response after induction therapy

Non squamous NSCLC

1,2HR1,00,80,60,4

HR

Induction response SD 0,61

Induction response CR/PR 0,81

Belani CP, et al. ASCO 2009 (Abs. CRA8000).

Favours pemetrexed Favours Placebo

Second Line Pemetrexed after Maintenance

Gemcitabine or Erlotinib. IFCT-GFPC 0502

Perol et al. Proc ESMO 2010

IFCT-GFPC 0502: Treatment Outcomes

OutcomeGemcitabine

(n = 149)

Erlotinib

(n = 153)

Observation

(n = 152)

Median PFS, mos 3.8 2.9 1.9

▪ HR vs observation

(95% CI) 0.55 (0.43-0.70) 0.82 (0.73-0.93)

▪ P value < .0001 .002

Median OS*, mos 12.1 11.8 10.7

▪ HR vs observation

(95% CI) 0.86 (0.66-1.12) 0.91 (0.80-1.04)

▪ P value NS NS

Perol M, et al. ASCO 2010. Abstract 7507.

IFCT-GFPC 0502: Treatment Outcomes

Perol M. Poster presented at ESMO 2010: PD370

Pérol M et al. JCO 2012;30:3516-3524

IFCT-GFPC 0502: OS

Concepts of Maintenance

1st-line: Platin-based

Combination Maintenance Monotherapy

with new compound Second Line Treatment

Progression

„Switch“ Maintenance

CR, PR, SD

4 cykles until Progression

bis Progress

JMEN (Pemetrexed)1

SATURN (Erlotinib)2

PARAMOUNT3

AVAPERL4

Selection of patients with good prognosis

Endpoints:

• Quality of Life

• Symptom Control

• Tolerability

ProgressionCR, PR, SD

„Continuation“ Maintenance

1st-line:

Pemetrexed/Cisplatin

Pemetrexed/Cisplatin/Bev

Maintenance Pemetrexed

or Pemetrexed/BevSecond Line

Treatment

4 cykles until Progression

Primary endpoint: Progression free survival

Inclusion criteria

•Non-squamous

NSCLC

•Stage IIIB/IV

•Chemonaïve

•ECOG PS 0-1

(n=939)Cisplatin

75 mg/m2 iv q21d

Pemetrexed500 mg/m2 iv q21d

R 2:1

Stratification:

• PS (0 vs. 1)

• Stage (IIIB vs. IV) before induction

• Response after induction (CR/PR vs.

SD)

Pemetrexed Continuation-Maintenance

(PARAMOUNT)

Paz-Ares L, et al. Lancet Oncol 2012; 13:247-55;

Paz-Ares L, et al. J Clin Oncol 2013; 31: 2895-902; ClinicalTrials.gov Identifier NCT00789373


Placebo

n=539

n=359

n=180

CR,

PR, SD

PD

Supplementation with Folic acid and

Vitamin B12 in both arms

Maintenance treatment (until PD)Induction treatment (4 cycles)

ProgressionStart of trial

medication21 – 42 days

PS, propensity score; CR, complete response:

vollständiges Ansprechen; PR, partial response: teilweises

Ansprechen; SD, stable disease: Krankheitsstabilisierung;

PD, progressive disease: progressiver Krankheitsverlauf

Time (Months)

0 3 6 9 12 15

Su

rviv

al

Pro

ba

bil

ity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS: Primary Efficacy Endpoint

Pemetrexed

Placebo

Unadjusted HR: 0.62 (0.49-0.79)

Patients at Risk

Pem + BSC 359 132 57 21 4 0

Plac+ BSC 180 52 15 5 0 0

0 3 6 9 12 15 18 21 24 27 30 33

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS: Reassessed at Time of Final OS

Pemetrexed

Placebo

Unadjusted HR: 0.60 (0.50-0.73)

Su

rviv

al

Pro

ba

bil

ity

Time (Months)

Patients at Risk

Pem +BSC 359 215 139 97 67 47 32 22 16 10 5 0

Plac + BSC 180 75 33 16 9 7 6 4 2 0 0 0

PARAMOUNT: Progression free survival

Paz-Ares LG, et al. Lancet Oncology 2012; 13: 247-55

Paz-Ares LG, et al. J Clin Oncol 2013: 31: 2895-902

Paramount: Overall survival

Paz Ares, L. et al J Clin Oncol 2013; 31: 2895 - 902

Hazard Ratio (95% KI)

Favours Pemetrexed Favours Placebo

0,0 0,5 1,0 1,5 2,0 2,5

PARAMOUNT:

OS; Subgroup analysis

Pro

babili

ty o

f surv

ival

0,78

0,79

0,82

0,81

0,76

0,82

0,70

0,75

0,83

0,82

0,73

0,75

0,89

0,82

0,71

0,81

0,44

0,80

Hazard Ratio

All randomized patients (n=539)

Stage IV (n=490)

Stage IIIB (n=49)

Response after induction CR/PR (n=234)

Response after Induction SD (n=285)

PS 1 before randomisation (n=363)

PS 0 before randomisation (n=173)

Neversmoker (n=117)

smoker (n=418)

male (n=313)

female (n=226)

age <70 (n=447)

ager ≥70 (n=92)

age <65 (n=350)

age ≥65 (n=189)

Other histology (n=32)

Large cell histology (n=36)

adenocarcinoma (n=471)

Paz-Ares L, et al. J Clin Oncol 2012; 30(Suppl):LBA7507

0 9 18 27 36

0 9 18 27 36

SD

HR = 0,76

CR/PR

HR = 0,81

Pemetrexed

Placebo

Time since start of

maintenance (monthers)

Pro

babili

ty o

f surv

ival

CR, complete response: vollständiges Ansprechen; PR, partial response: teilweises

Ansprechen; SD, stable disease: Krankheitsstabilisierung; PS, propensity score

Trial N Maintenance drug

PFS HR

(95% CI)

OS HR

(95% CI)

Switch Maintenance

Westeel et al. 181 Vinorelbine 0.77 (0.55-1.07) 1.08 (0.79-1.48)

Fidias et al. 309 Docetaxel 0.71 (0.55-0.92) 0.84 (0.65-1.08)

Capuzzo 889 Erlotinib 0.71 (0.62–0.82) 0.81 (0.70-0.95)

Ciuleanu et al. 663 Pemetrexed 0.60 (0.49-0.73) 0.79 (0.65-0.95)

Continuation Maintenance

Paz-Ares et al 539 Pemetrexed 0.62 (0.49-0.79) NA

Brodowicz et al. 206 Gemcitabine 0.69 (0.56-0.86) 0.84 (0.52-1.30)

Belani et al. 255 Gemcitabine 1.09 (0.81-1.45) 0.97 (0.72-1.30)

Perol et al. 309 Gemcitabine 0.56 (0.44-0.72) 0.89 (0.67-1.15)

Efficacy: PFS & OS

Trial N Maintenance drug

QoL &

Symptom Control

Switch Chemotherapy Maintenance

Westeel et al. 181 Vinorelbine NR

Fidias et al. 309 Docetaxel No differences

Capuzzo 889 Erlotinib Better pain control

Cielanu et al. 663 Pemetrexed Better pain and hemoptisis control

Continuation Chemotherapy Maintenance

Paz-Ares et al 539 Pemetrexed No detrimental effect

Brodowicz et al. 206 Gemcitabine NR

Belani et al. 255 Gemcitabine NR

Perol et al. 309 Gemcitabine NR

Efficacy: QOL

Antibody maintenance

E4599: study design

• Primary endpoint

– overall survival (OS)

CP q3w x6 (n=444) PD*

PD

*No crossover permitted

Previously

untreated

stage IIIB, IV or

recurrent

predominantly non-

squamous

NSCLC (n=878)

Bevacizumab (15mg/kg) +

CP q3w x6 (n=434)

Sandler, et al. N Engl J Med 2006

Bevacizumab

Secondary endpoints

– objective response rate

– progression-free survival (PFS)

– duration of response

– safety

E4599

CP

(n=444)

Bevacizumab

15mg/kg + CP

(n=434)

HR

(95% CI)

0.79(0.67–0.92)

p value 0.003

Median OS

(months) 10.3 12.3

Sandler, et al. N Engl J Med 2006

OS

esti

mate

1.0

0.8

0.6

0.4

0.2

0

Time (months)

0 6 12 18 24 30 36 42

Bev + CP

CP

10.3 12.3

CP=carboplatin/paclitaxel

Pemetrexed or Bevacizumab maintenance?

Primary endpoint

•PFS without Grade 4 AE (G4PFS)

Secondary endpoints

• PFS, OS, RR, DCR

• Safety and tolerability

R

PD

PD

Stratification

• PS (0 vs. 1); sex (M vs. F); disease stage (M1a vs. M1b)

Key patient inclusion

criteria

• No prior systemic

treatment

• ECOG PS 0-1

• Stable IIIB-IV non-

squamous NSCLC

• Stable treated brain

mets

(n=361)

Pac 200 mg/m2 +

Cb AUC6 +

Bev 15 mg/kg

(n=179*)

Pem 500 mg/m2 +

Cb AUC6

(n=182)

Bev 15 mg/kg

(n=95)

Pem 500 mg/m2

(n=98)

Maintenance treatment

q3w

Induction phase

4 cycles, q3w

Zinner et al. J Clin Oncol 31, 2013 (suppl; abstr LBA8003)

Primary Endpoint: G4PFS (ITT)

Pem+Cb: median G4PFS = 3.9 moPac+Cb+Bev: median G4PFS = 2.9 mo

Log-rank p value = 0.176HR (90% CI) = 0.85 (0.70–1.04)

Pem+Cb 182 87 44 26 14 7 5 3 1 0

Pac+Cb+Bev 179 75 33 17 9 3 0 0 0 0

Patients at Risk

Number of

G4PFS events

Pem+Cb

(n=152)

%

Pac+Cb+Bev

(n=144)

%

G4 AE 24.3 44.4

PD 62.5 47.2

Death 13.2 8.3

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27

Pro

po

rtio

n

Zinner et al. J Clin Oncol 31, 2013 (suppl; abstr LBA8003)

Primary Endpoint: Progression free survival

CR,

PR, SD

PD

Inclusion criteria:

•Non-squamous NSCLC

•Stage IIIb/IV

•No prior treatment

n=414

Cisplatin75 mg/m2 iv q21d


Bevacizumab7,5 mg/kg iv q21d

R

Maintenance with Bevacizumab±Pemetrexed (AVAPERL):

Randomised, open phase III trial

Barlesi F, et al. J Clin Oncol 2013, e-published

ClinicalTrials.gov Identifier NCT00961415

Bevacizumab 7,5 mg/kg iv q21d


Bevacizumab7,5 mg/kg iv q21d

Stratification:

• gender

• smoker vs never smoker

• CR/PR vs. SD

n=376

n=253

n=125

n=128

Maintenance therapy until PD)Induction therapy (4 cycles)

ProgressionStart of induction

treatment

AVAPERL: PFS from randomisation

Therapx PFS (Months)

Bev + Pem 7,4 (81 Events)

Bev 3,7 (104 Events)

HR 0,48 (0,35–0,66); p<0,001

Maintenance Bev+Pem (n=128)

Maintenance Bev (n=125)

Patients at risk

Bev + Pem 128 104 67 25 4 0

Bev 125 73 36 13 2 0

Time (months)

Pro

gre

ssio

nsfr

eie

s Ü

be

rle

be

n

ab

de

m T

ag

de

r R

an

do

mis

ieru

ng

(%

)

0 3 6 9 12 15

100

75

50

25

0

Barlesi F, et al. J Clin Oncol 2013, e-published

AVAPERL: Overall survival

Barlesi et al. Ann. Oncol. 2014

Treat

to PD

Treat

to PD

POINTBREAK phase III trial

Bevacizumab

15 mg/kg q3w

+ carboplatin

+ pemetrexed

Bevacizumab

15 mg/kg q3w

Bevacizumab

15 mg/kg q3w

+ pemetrexed

Bevacizumab

15 mg/kg q3w

+ carboplatin

+ paclitaxel

4 cycles

Previously

untreated,

stage IIIB or IV,

non-squamous

NSCLC,

treated CNS mets,

PS 0–1

n=939

PI: J Patel

*Patient numbers excluding those not treated Patel, et al. IASLC 2012 (Chicago)

R1:1

n=442* n=292

n=298

(67%)

(66%)

n=443*

Primary endpoint

– OS

Secondary endpoints

– ORR and DCR

– PFS and TTP

– safety and QoL

POINTBREAK:

OS (primary endpoint) – ITT population

12.6 13.4

HR=1.00 (0.86–1.16)

p=0.949

Pem + Carbo + Bev

Pac + Carbo + Bev

OS

esti

mate

Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39

1.0

0.8

0.6

0.4

0.2

0

Patel, et al. IASLC 2012 (Chicago)

SQUIRE: Study Design

• Primary Objective: Overall survival

• Secondary Objectives: PFS, ORR, safety, QoL

• Exploratory Objective: EGFR protein expression (IHC, DAKO PharmDx)

PD

PD

NECI + Gem-Cis q3w (N=545)

PD

Maximum of 6 cycles

Population

First-Line Stage IV squamous NSCLC

ECOG PS 0-2

NECI q3w

Gem-Cis q3w (N=548)

R

CRPRSD

SQUIRE: G/C + Neci vs G/C in Stage IV

SqCLC

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

OS

(%

)

Mos

G/C + Neci G/C

Stratified HR (95% CI) 0.84 (0.74-0.96)

Stratified P value (log-rank) .01

Median OS, mos (95% CI) 11.5 (10.4-12.6) 9.9 (8.9-11.1)

Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

1093 pts

▪ First-line stage

IV SqCLC

▪ ECOG PS 0-2

G/C (1250 mg/m2;75 mg/m2) +

Neci 800 mg d 1,8

(n = 545)

G/C

(n = 548)

Maximum of 6 cycles

Neci

CR

PR

SD

PD

PD

PD

R


NSCLC –selected pts

• 2005 – 2016: molecular selected patients

• continue treatment until progression:– EGFR

– Alk

– ROS1

– B-RAF

Maintenance in Lung Cancer

“Oncogene Addicted”

Erlotinib in EGFR m+ NSCLC

EURTAC Trial

Rosell R et al., Lancet Oncol 2012

Simulation- EURTAC Trial

4 months treatment

X


NSCLC –selected pts

• 2005 – 2016: molecular selected patients continue treatment until progression

• 2016: PD-L1 positive (>50%) continue pembrolizumab

Key End Points

Primary: PFS (RECIST v1.1 per blinded, independent central review)

Secondary: OS, ORR, safety

Exploratory: DOR

KEYNOTE-024 Study Design (NCT02142738)

Key Eligibility Criteria

• Untreated stage IV NSCLC

• PD-L1 TPS ≥50%

• ECOG PS 0-1

• No activating EGFR mutation or

ALK translocation

• No untreated brain metastases

• No active autoimmune disease

requiring systemic therapy

Pembrolizumab

200 mg IV Q3W(2 years)

R (1:1)

N = 305

Platinum-Doublet

Chemotherapy(4-6 cycles)

Progression-Free Survival

Assessed per RECIST v1.1 by blinded, independent central review.Data cut-off: May 9, 2016.

Events,

n

Median,

mo

HR

(95% CI)

P

Pembro 73 10.3 0.50

(0.37-0.68)<0.001

Chemo 116 6.0

62%

50%

0 3 6 9 12 15 180

10

20

30

40

50

60

70

80

90

100

Time, months

PF

S,%

No. at risk

154 104 89 44 22 3 1

151 99 70 18 9 1 0

48%

15%

Minority received

pemetrexed

maintenance

Overall Survival

Data cut-off: May 9, 2016.

80%

72%

0 3 6 9 12 15 18 210

10

20

30

40

50

60

70

80

90

100

Time, months

OS

,%

No. at risk

154 136 121 82 39 11 0

151 123 106 64 34 7 0

2

1

70%

54%

Events,

n

Median,

mo

HR

(95% CI)

P

Pembro 44 NR 0.60

(0.41-0.89)0.005

Chemo 64 NR


NSCLC – mutation status unknown

• Platin based chemotherapy – Maintenance?

Continuation Gefitinib when EGFR mut

status is unknown

Yang et al. J.Thor. Oncol. 2015

Guidelines

• Maintenance therapy recommended by

– ESMO

– ASCO

Conclusions

• Both switch and continuation maintenance

chemotherapy prolong PFS and OS

• Antibody maintenance prolong PFS and

OS (?)

• Small molecule offered untill PD.

maintenance therapy in advanced non-small cell lung cancer. · cielanu et al. 663 pemetrexed better...

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