esmo e-learning: maintenance therapy in advanced nsclc...maintenance therapy in advanced nsclc...

Maintenance therapy in advanced NSCLC

Silvia Novello, MD, PhD

University of Torino - Italy

Department of Oncology

1.3.13 1

Diagnosis CR/PR/SD

First-line treatmentPlatinum doublet

chemotherapy(4–6 cycles)

‘Watch and wait’

PD

Second and further lines of treatment

PD

1. Pfister DG et al. J Clin Oncol 2004;22(2):330-353

Is this an historical and outdated approach to NSCLC treatment?

� As a result of cumulative toxicity, patients receive a limited number

of cycles of chemotherapy

� According to ASCO guidelines1, those with stable disease or better

will be observed, with regular follow up to check for disease

progression – ‘watch and wait’ approach

Clinical practice guidelines

� 2011 focused update of 2009 ASCO clinical practice guideline

update on chemotherapy for Stage IV NSCLC1

1.3.13 31. Azzoli CG et al. J Clin Oncol 2011;29(28):3825-3831; 2. Peters S et al. Ann Oncol 2012:23(7);vii56-vii64

� Metastatic NSCLC: ESMO clinical practice guidelines for diagnosis,

treatment and follow-up2

Diagnosis CR/PR/SD

First-line treatmentPlatinum doublet

chemotherapy(4–6 cycles)

‘Watch and wait’

PD

Second and further lines of treatment

PD

Traditional approach

PD

Increased

time to PD

PDMaintenance approach

Diagnosis CR/PR/SD PD PD

What is an ideal maintenance therapy agent?

� Efficacious (PFS & Survival)

� Tolerated well

� No cumulative toxicity

� Ability to administer easily in the outpatient setting

� Affordable

Maintenance therapy: Definition

� Do we really need a definition? The terminology around this issue is

confusing and meaningless

� Some investigators use the term maintenance, others consolidation,

and other sequencing or “extended duration” chemotherapy or

early second line

� Latter is necessarily wrong because the initiation of maintenance

therapy requires the absence of disease progression

Types of Maintenance

� Continuation therapy: Prolonged platinum doublet chemotherapy

� Continuation Maintenance: Continuation of non-platinum agent

used in doublet chemotherapy

� e.g. paclitaxel, gemcitabine, pemetrexed

� Targeted Maintenance: Triplet induction therapy followed of

maintenance with the same targeted agent

� e.g. bevacizumab (EGOC 4599), cetuximab (Flex)

� Switch Maintenance: Introduction of a new cytotoxic agent

� e.g. docetaxel, pemetrexed, erlotinib

1.3.13 9Socinski MA et al. J Clin Oncol 2002:20:1335-1343

Cessation of anti-VEGF therapy results in vascular regrowth

� Rapid tumour vessel regrowth occurs when anti-VEGF therapy is

withdrawn - continuous VEGF inhibition maintains tumour control

Mancuso MR et al. J Clin Invest 2006;116(10):2610-2621

CD31CD31

RIP-Tag2

tumours

RIP-Tag2

tumours

UntreatedUntreated AG-013736, 7 daysAG-013736, 7 days Withdrawal, 2 daysWithdrawal, 2 days Withdrawal, 7 daysWithdrawal, 7 days

PD

PD

PD

PD

Bevacizumab

Placebo + CG x 6 (n = 347)

Bevacizumb(15 mg/kg) every 3

weeks + CG x 6 (n = 351)

Bevacizumab(7.5 mg/kg) every 3

weeks + CG x 6 (n = 345)

Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC

(n = 1043)

Bevacizumab

CP x 6 (n = 444)

Bevacizumab(15 mg/kg) every 3

weeks + CP x 6 (n = 434)

PD

PDBevacizumab

E4599 trial

design

AVAiL trial

design

*No cross over permitted

CP = carboplatin + paclitaxel

CG = cisplatin + gemcitabine

Sandler A et al. N Engl J Med 2006;355(24):2542-2550;

Reck M et al. J Clin Oncol 2009;27(8):1227-1234; Pirker T. Lancet 2009;373:1525-1531

Previously untreatedstage IIIB/IV

non-squamous NSCLC(n = 878)

FLEX trial

design

Cisplatin/vinorelbine(n =568)

Cisplatin/vinorelbine/Cetuximab (n = 557)

PD

Cetuximab

Previously untreatedstage wetIIIB/IV

IHC EGFR expressing NSCLC

PD

PD

PD

PD

Bevacizumab

Placebo + CG x 6 (n = 347)

Bevacizumb(15 mg/kg) every 3

weeks + CG x 6 (n = 351)

Bevacizumab(7.5 mg/kg) every 3

weeks + CG x 6 (n = 345)

Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC

(n = 1043)

Bevacizumab

CP x 6 (n = 444)

Bevacizumab(15 mg/kg) every 3

weeks + CP x 6 (n = 434)

PD

PDBevacizumab

E4599 trial

design

AVAiL trial

design

*No cross over permitted

CP = carboplatin + paclitaxel

CG = cisplatin + gemcitabine

Previously untreatedstage IIIB/IV

non-squamous NSCLC(n = 878)

FLEX trial

design

Cisplatin/vinorelbine(n =568)

Cisplatin/vinorelbine/Cetuximab (n = 557)

PD

Cetuximab

Previously untreatedstage wetIIIB/IV

IHC EGFR expressing NSCLC

42%

41%

53%

80%

Sandler A et al. N Engl J Med 2006;355(24):2542-2550;

Reck M et al. J Clin Oncol 2009;27(8):1227-1234; Pirker T. Lancet 2009;373:1525-1531

ARIES – “Maintenance” data

� This analysis compared post-induction PFS and OS between

patients who did and did not receive bevacizumab (BV)

maintenance after induction treatment with chemotherapy (CT) + BV

in the ARIES NSCLC study

� The induction phase was defined as 12 to 18 weeks of CT (~4-6 cycles)

used within 18 weeks of initial CT + BV

� PFS and OS were calculated from the end of induction therapy to first

progression and death, respectively

Patients in

ARIES NSCLC

(N=1967)

n = 1473

(75%)

n = 494

(25%)

n = 1215

(82%)

n = 540

(44%)

n = 675

(56%)

Completed

4–6 cycles CT

Received

<4 cycles CT

Analysis

populationa

BV maintenance

population

Fischbach N et al. J Thorac Oncol 2009;4(9)(suppl 1):abstr C2.7; Fischbach N et al. ESMO 2010;

Kosty MP et al. ECCO16, ESMO 36, ESTRO 30 Stockholm 2011:abstr 9002

NO randomisation

ARIES: Results

Kosty MP et al. ECCO16, ESMO 36, ESTRO 30 Stockholm 2011:abstr 9002

OutcomesBV maint.

(95% CI)

No BV maint.

(95% CI)

Adjusted hazard ratio

(95% CI)P value

Median post-induction

PFS, mo5.1 (4.7-5.8) 3.8 (3.4-4.1) 0.77 (0.68-0.87) <0.001

6-month PFS, % 44 (40-49) 33 (29-37)

Median post-induction

OS, mo15.7 (14.3-17.6) 11.2 (10.1-12.5) 0.71 (0.62-0.81) <0.001

1-year OS, % 59 (55-63) 47 (44-51)

Real maintenance trial designs containing bevacizumab

Randomised phase III trial: Point Break: Study Design

Primary endpoint:

Overall survival

Patel JD et al. Clin Lung Cancer 2009;10(4):252-256

Patel JD. Chicago IASLC/ASTRO 2012:abstr LBPL1

PointBreak

Randomised phase III trials

ECOG 5508: Study Design

NCT 00948675: Study Design

Dahlberg SE et al. J Clin Oncol 2011;29(15)(suppl):TPS218

IIIB/IV Non squamous NSCLCPS0/1No prior TxN=1288

CarboplatinPaclitaxelBevacizumabx4 cycles

Primary endpoint: Overall survival

CRPRSDN=897

RANDOMISE

Bevacizumab

Pemetrexed

BevacizumabPemetrexed

IIIB/IV Non squamous NSCLCN=360

CarboplatinPaclitaxelBevacizumabx4 cycles

CarboplatinPemetrexedx4 cycles

Bevacizumab

Primary endpoint:PFS without grade 4 toxicity

Pemetrexed

Randomised phase III trials

PI T. Seto

IIIb/IV non squamous NSCLCPS0/1EGFR wild type

CarboplatinPemetrexedBevacizumabx4 cycles

Primary endpoint: Overall survival

CRPRSDN=620

RANDOMISE

Bevacizumab

BevacizumabPemetrexed

N=775

WJOG 5610L: COMPASS

Randomised phase III trials:AVAPERL: Study Design

� Median follow-up time for this analysis was 7.6 months

� Median age of the safety population was 60.0 years, and the

majority of patients (92.2%) had stage IV disease at study entry

IIIB/IV non squamous NSCLC(N=414)(Safety Population=373)

CisplatinPemetrexedBevacizumabX 4 cycles

CRPRSDN=253

Bevacizumab(N=122)

BevacizumabPemetrexed (N=115)

Barlesi F. J Clin Oncol 2011;29(suppl):abstr 7562; Barlesi F et al. ECCO16, ESMO 36, ESTRO 30 Stockholm 2011:abstr LBA34

Primary endpoint: Progression free survival

AVAPERL: Interim safety data

Barlesi F. J Clin Oncol 2011;29(suppl):abstr 7562

AVAPERL: Safety results from Maintenance phase

� First-line therapy with cisplatin,

pemetrexed and bevacizumab was well

tolerated. No new or unexpected toxicity

was observed

� Grade ≥3 adeverse events (AEs) and

serious Aes (SAEs) occurred more

frequently in the bevacizumab +

pemetrexed arm than in the

bevacizumab alone arm

� The most common grade ≥3 AEs with onset during the

maintenance phase were dyspnea and hypertension (2.5%) in the

bevacizumab + pemetrexed arm

� The most common SAEs during the maintenance phase were

pulmonary embolism and hemoptysis (1.7% each) in the

bevacizumab-alone arm and pneumonia and transient ischemic

attack (1.6% each) in the bevacizumab + pemetrexed arm

Barlesi F et al. ECCO16, ESMO 36, ESTRO 30 Stockholm 2011:abstr LBA34

AVAPERL: PFSa from induction

Bev, bevacizumab; cont, continuation; HR, hazard ratio; pem, pemetrexed; pts, patients


CR, complete response; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PR, partial response; SD, stable disease

AVAPERL: PFS subgroup analysis


Bev, bevacizumab; cont, continuation; HR, hazard ratio; NR, not reported; pem, pemetrexed; pts, patientsa Study was not powered for overall survival.

Median follow-up time: 11 months (8 months, excluding induction). 30% of events at the time of analysis for overall survival.

AVAPERL1: OS from induction












Not an answer to this specific question; more data will be

available on bevacizumab and maintenance approach

Phase III trial of “Maintenance” gemcitabine in non progressing advanced NSCLC following - 4 cycles of cis/gem

� Primary endpoint: TTP (OS secondary)

� 352 patients entered

� 257 “non-progressors” after 4 cycles

� 206 randomised (61%)

� TTP significantly increased in those randomised to GEM (6.6 vs. 5.0

months, P<0.001)

� OS not significantly different (13.0 vs. 11.0, P=0.2). In good PS

patients a worse survival in BSC arm (8.3 vs. 22.9, HR=2.1)

� Toxicity: Maintenance GEM well tolerated but more transfusions

required

Brodowicz T et al. Lung Cancer 2006;52(2):155-163

IFCT-GFPC 0502: Study Design

� Primary endpoint: Independent review with 80% power to detect 50% improvement in median PFS. PFS by each comparison (Gem vs. Obs and Erl vs. Obs)

� Secondary endpoints: (OS, safety, symptom control, prognostic and predictive effect of tumour EGFR status (IHC, EGFR mut)

31Perol M et al. J Clin Oncol 2010;28(15)(suppl):abstr 7507; Perol M et al. J Clin Oncol 2012;3516-3524

IFCT-GFPC 0502: Results

� Patients who received 2nd-line pemetrexed: 73% (Obs), 55% (Gem), and

60% (Erl)

� Grade 3-4 treatment-related AEs were more common in Gem (27%) and Erl

(14%) than in Obs (2%)Perol M et al. J Clin Oncol 2010;28(15)(suppl):abstr 7507; Perol M et al. J Clin Oncol 2012;3516-3524

PARAMOUNT: Study Design

� Randomised, placebo-controlled, double-blind phase III study

� Pemetrexed 500 mg/m2; Cisplatin 75 mg/m2

� Folic acid and vitamin B12 administered to both arms

Induction therapy4 cycles, q21d

Continuation Maintenance therapyq21d until PD

Pemetrexed+ BSC

Placebo + BSC

Pemetrexed + cisplatin

R2:1

Stratified for:

� PS (0 vs. 1)

� Disease stage (IIIB vs. IV) prior to induction

� Response to induction (CR/PR vs. SD)

� Previously untreated

� PS 0/1

� Stage IIIB-IV NS-NSCLC

Paz Ares L et al. J Clin Oncol 2011;29(18)(suppl):abstr CR7510

939 pts enrolled

539 pts randomised(2:1 randomisation)

Pemetrexed armn=359

Placebo armn=180

83 pts failed screening

Induction phase

Maintenance phase

1022 patients (pts) screened

400 pts not randomised217 progressive disease62 adverse event (AE)56 death29 study disease15 AE11 drug-related AE1 procedure-related AE65 other reasons

548 patients eligible for maintenance8 discontinued patient decision 1 discontinued physician decision

PARAMOUNT: Initial patient disposition

Paz Ares L et al. J Clin Oncol 2011;29(18)(suppl):abstr CR7510

PARAMOUNT: Patient characteristics

Paz Ares L et al. J Clin Oncol 2011;29(18)(suppl):

abstr CR7510

Paz Ares L et al. J Clin Oncol 2012;30(18)(suppl):abstr LBA7507

PARAMOUNT: PFS from randomisation

Patients at Risk

Pem + BSC 359 333 272 235 200 166 138 105 79 43 15 2 0

Placebo + BSC 180 169 131 103 78 65 49 35 23 12 8 3 0

Time from Randomisation (Months)

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

PARAMOUNT: Final OS from randomisation

Pem Placebo

OS Median (mo)

(95% CI)

13.9

(12.8-16.0)

11.0

(10.0-12.5)

Censoring (%) 28.7 21.7

Survival Rate (%) (95% CI)

1-year 58 (53-63) 45 (38-53)

2-year 32 (27-37) 21 (15-28)


Su

rviv

al

Pro

ba

bil

ity

Time from Induction (Months)0 3 6 9 12 15 18 21 24 27 30 33 36

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

PemetrexedMedian OS =16.9 mos (95% CI: 15.8–19.0)PlaceboMedian OS =14.0 mos (95% CI: 12.9–15.5)Log-rank P=0.0191HR=0.78 (95% CI: 0.64–0.96)

Patients at RiskPem + BSC 359 335 276 234 200 164 138 106 77 42 15 2 0Placebo + BSC 180 168 132 103 78 63 49 35 23 12 8 3 0

PARAMOUNT: Final OS from induction


� The survival results were internally consistent; benefit was seen across all subgroups

PARAMOUNT: Subgroup OS hazard ratiosH

azard

Ratio


Pemetrexed (N=359)

%*

Placebo (N=180)

%*Patients receiving post

discontinuation therapy64 72

Erlotinib 40 43

Docetaxel† 32 43

Gemcitabine 10 8

Vinorelbine 8 6

Investigational drug 6 4

Carboplatin 5 4

Paclitaxel 3 3

Pemetrexed 2 4

Cisplatin 1 2

*Data expressed as % of randomised patients. Systemic therapies used in ≥2% of patients in either arm are shown. †Only

docetaxel usage differed significantly between arms (P=0.013).

PARAMOUNT: Post-discontinuation therapy

1.3.13 42Peters S et al. Ann Oncol 2012;23(7):vii56-vii64

All Randomised Patients (N=539)

Stage IV (n=490)

Stage IIIB (n=49)

Induction Response CR/PR (n=234)

Induction Response SD (n=285)

Pre-randomisation ECOG PS 1 (n=363)

Pre-randomisation ECOG PS 0 (n=173)

Non-smoker (n=117)

Smoker )n=418)

Male (n=313)

Female (n=226)

Age < 70 (n=447)

Age > 70 (n=92)

Age < 65 (n=350)

Age > 65 (n=189(

Other Histologic Diagnosis (n=32)

Large Cell Carcinoma (n=36)

Adenocarcinoma (n=471)

0.78

0.79

0.82

0.81

0.76

0.82

Hazard Ratio

Treatment Hazard Ratio (95%% CI)

Favors Pemetrexed Favors Placebo

� The survival results were consistent across both induction response subgroups

CR/PRHR = 0.81

SDHR = 0.76

Time from Randomisation (Months)

Surv

ival p

rob

ab

ility

Surv

ival p

rob

ab

ility

0 9 18 27 36

0 9 18 27 36

PARAMOUNT: Induction response subgroups OS hazard ratios


PARAMOUNT: Toxicity profile

Pujol JL et al. Ann Oncol 2012;23(suppl 9):abstr 1275P

PARAMOUNT: Cycles administered and QoL

� Long-term maintenance

therapy (>10 maintenance

cycles) was associated

with numerically higher

values for toxicities but

tolerability and QoL were

not impacted

Pujol JL et al. Ann Oncol 2012;23(suppl 9):abstr 1275P

Maintenance therapy and patient perception

Peeters L et al. J Thorac Oncol 2012;7(8):1291-1295

� Answers to the general question

“Do you think maintenance therapy is worthwhile?” T0, time at start of first-line chemotherapy;

T1, after two cycles of chemotherapy;

T2, after four cycles of chemotherapy

� Answers to questions regarding

whether maintenance therapy would

be worthwhile if there would be no survival difference, but benefit in symptom control or imaging findings













A treatment opportunity

Author YearMaintenance

usedPFS mo

(HR)OS mo

(HR)2nd line Rx in control arm

Fidias 2008 Docetaxel5.7 i

2.7 d(0.71)

12.3 i

9.7 d(0.84)

63%

Ciuleanu 2009 Pemetrexed4.0pem

2.0 placebo(0.50)

13.4

10.6(0.79)

67%

Cappuzzo 2009 Erlotinib12.3 wks

11.3 wks(0.71)

12.0

11.0(0.81)

72%

Miller 2009 Erlotinib 0.72 0.90 56%

Perol 2010 Erlotinib2.9

1.9(0.55)

0.86 82%

Takeda 2010 Gefitinib (0.68) (0.86) 72%

Zhang 2011 Gefitinib4.8

2.6(0.42)

18.7

16.9(0.84)

72%

Switch maintenance randomised trials

Erlotinib

150mg/dayPD

Switch maintenance with erlotinib

1:1

Chemonaïveadvanced NSCLC

n=1,949

Non-PD

n=889

(46%)

4 cycles of first-line platinum

doublet chemotherapy*

Placebo PD

Mandatory tumour

sampling

SATURN: trial design

Peters S et al. Ann Oncol 2012;23(7):vii56-vii64

SATURN: OS in the intention-to-treat population and according to response to prior therapy

Erlotinib 12 mo

Placebo 11 mo

Coudert B et al. Ann Oncol 2012;23(2):388-394

Cappuzzo F et al. Lancet Oncol 2010;11:521–29

Conclusions (1)

� There is no evidence to support prolonged administration of doublet

1st line chemotherapy beyond 4-6 cycles

� Even more than in other setting, in maintenance therapy is essential

the selection of the right patient population and “treatment-free

interval” after first line REMAINS an option

� Maintenance approach is ONLY another treatment possibility that

we may consider in those patients who tolerated platinum based

therapy, with PS 0 or 1, without relevant clinical toxicities and who

desire to continue therapy

Conclusions (2)

� Considering Maintenance approach as a treatment for your patient

remember:

� It’s unlikely that all patients will benefit from it

� Fix a second line therapy could be successful

� Monitoring with criteria and timing properly

� Use a drug which works

� Check also grade 1 and 2 toxicities, because it also impacts patients’

QoL in a disease in which the primary goal is palliative and OS remains

modest

Thank you!

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