Maintenance therapy for NSCLC

Federico CappuzzoIstituto Toscano Tumori

Ospedale CivileLivorno-Italy

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The maintenance therapy paradigm

Stratification for EGFR, ALK, histology, response to CT

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No progression after 4 cycles of platinum-based CT, PS=0-1

SD

Continuation maintenance

SCC: Switch maintenance

SCCGemcitabine

EGFR WT/ALK-:Response to CT

/Histology

CR/PR

Non-SCCPemetrexed or beva

Erlotinib or Docetaxel

Non-SCC: cont/switch

maintenance

Pem or beva Erlot or Docetax

Immediate vs. delayed docetaxelas 2nd line NSCLC treatment

CarboplatinPlus

Gemcitabine X 4

RANDOMIZE

ImmediateDocetaxel

DelayedDocetaxel at time of PD

CR, PRSD

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Docetaxel study results

Immediate (n=153)

Delayed (n=154)

LRp-Value

Median PFS months (95% CI)

6.5(4.4, 7.2)

2.8(2.6, 3.4)

<0.0001

12-month PFS, % (95% CI)

20%(13, 26)

9%(5, 14)

PFS

OS

Immediate (n=153)

Delayed (n=154)

LRp-Value

Median OS, months (95% CI)

11.9(10.0, 13.7)

9.1(8.0, 11.2)

0.071

12-mo survival (95% CI)

48.5%(39.9, 57.1)

38.3%(30.0, 46.5)

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TFINE study: multicenter, randomized phase III study of continuation docetaxel

Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV

Docetaxel 60 mg/m2 IV q 3wkUp to six cycles

Docetaxel 60 mg/m2 IV q 3wkUp to six cycles

BSCBSC

IIIB/IVChemo-NaïveNSCLC

N=382

R1

CRPRSD

R2

Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV q

Zhang et al. ASCO 2013, Abstract # 8015

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TFINE study, C-TONG 0904PFS results

Trial Strategy Induction regimen mPFS (months)

Docetaxel dose

Fidias et al. Switch Carbo+Gem 5.7 vs 2.7 (early vs. delayed)

75mg/m2

Zhang et al. Continuation Cis+Doc 5.4 vs 2.7 (Doc vs. BSC)

60mg/m2

Maintenance trials with pemetrexed

Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of gem, doc, or tax +

cis or carb, with CR, PR, or SD

Randomization factors: • gender• PS• stage• best tumor response• non-platinum drug• brain mets

2:1 Randomization

Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*

Placebo (d1, q21d) + BSC (N=222)*

Switch maintenance: JMEN

Continuation maintenance: PARAMOUNT Nonsquamous NSCLC No prior systemic treatment for lung

cancer ECOG PS 0-1

500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d

CR, CP, SD

PD

500 mg/m2 Pemetrexed + BSC, d1, q21d

Placebo + BSC, d1, q21d

2:1 randomization

Stratified for:-PS (0 vs 1)-Disease stage (IIIb vs IV) prior to induction-Response to induction (CR/PR vs SD)

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Progression-free Survival

Switch maintenance: JMEN

Continuation maintenance: PARAMOUNT

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Overall Survival: pemetrexed maintenance data

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Switch maintenance: JMEN

Continuation maintenance: PARAMOUNT

JMEN & PARAMOUNT: OS according to response to first-line chemotherapy

1.2

Favours pemetrexed Favours placeboHR

1.00.80.60.4

*Non-squamous group

HR

Induction response SD* 0.61

Induction response CR/PR* 0.81

Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012

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Induction response SD 0.76

Induction response CR/PR 0.81

Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN

Gefitinib maintenance: INFORM

1:1

Chemonaïve advanced NSCLC

n=1,949Non-PDn=889

4 cycles of 1st-line platinum-

based doublet*

Placebo PD

PD

Mandatory tumor sampling

Erlotinib150mg/day

Stratification factors:• EGFR IHC (positive vs negative vs indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs others)• Smoking history (current vs former vs never)• Region

Gefitinib(250 mg/day)

Placebo(once daily)

1:1 randomization

Patients• Age ≥18 years • Completed 4 cycles of

first-line platinum-based chemotherapy without PD or unacceptable toxicity

• Life expectancy≥12 weeks

• WHO PS 0-2• Measurable

Stage IIIB/IV disease

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Progression-free Survival in ITT population

Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM

HR=0.42 (0.32–0.54)HR=0.71 (0.62–0.82)p<0.0001

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HR=0.81 (0.70–0.95)p=0.0088

Overall Survival in ITT population

Erlotinib maintenance: SATURN

HR = 0.83 (0.61, 1.12) p=0.2109

Gefitinib maintenance: INFORM

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Effect of erlotinib and gefitinib in EGFR wild-type patients: PFS and OS data

PFS and OS in SATURN PFS in INFORM

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OS according to response to first-line chemotherapy*

OS

prob

abili

ty

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

9.6 11.9

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

12.0 12.5

Log-rank p=0.0019

HR=0.72 (0.59–0.89)

Erlotinib (n=252)

Placebo (n=235)

Log-rank p=0.6181

HR=0.94 (0.74–1.20)

Erlotinib (n=184)

Placebo (n=210)

SD CR/PR

*OS is measured from time of randomisation into the maintenance phase

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Observation

IFCT-GFPC 0502 study design

Progression:2nd line

Primary endpoint: PFS

A

C

Maintenancetreatment

PD

*Stratification factors:– gender– histology: adenocarcinoma vs other histology– smoking status: non-smokers vs current/former smokers– center– response vs stabilization to induction chemotherapy

Induction chemo: cisplatin 80mg/m2 d1

+ gemcitabine 1,250mg/m2 d1, d8

Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks

Arm C: erlotinib 150mg daily

N=155

N=154

N=155

EGFR = epidermal growth factor receptorIHC = immunohistochemistry; PD = progressive disease

PD: off

Objectiveresponse or

stable disease

Cisplatingemcitabine

x 4 cyclesN=834

NSCLCStage IIIB wet – IVPS 0-1, 18-70 years

Asymptomatic brainmets allowed

Tumor tissueEGFR IHC

EGFR mutation

R*N=464

BGemcitabine

Erlotinib

PD

PD

Pemetrexed

Pemetrexed

Pemetrexed

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PFS and OS results with continuation gemcitabineIs

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Perol et al. JCO 2012

PFS and OS results with switch erlotinibIs

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Perol et al. JCO 2012

Is continuation maintenance with pemetrexed plus bevacizumab better than beva or pem alone?

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Stratification factors •Gender•Smoking status•Response at randomisation

Avastinn=125

Avastin + pemetrexed

n=128

Avastin‡

+ pemetrexed‡ + cisplatin‡

n=253

CR/PR/SDper RECIST§

First-line induction4 cycles, q3w

PD

Continuation maintenanceq3w until PD

Follow-up

R67%

11

11

Previously untreated

stage IIIB-IVNSCLCN=376

AVAPERL

AVAPERL: PFS from randomisation

0 3 6 9 12 15

1.0

0.8

0.6

0.4

0.2

0

EMCC 2011, ASCO 2013

PFS

estim

ate

Time (months)

Avastin + Pem 7.4mAvastin 3.7mHR: 0.48; p<0.001

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OS for Pem/Bev was better than for Bev (17.1 vs 13.2 months), p=0.29, HR 0.87 (CI 0.63-1.21)

PointBreak: Study Design

Pemetrexed + Carboplatin

+ Bevacizumab

Pemetrexed + Bevacizumab

Paclitaxel+ Carboplatin

+ BevacizumabBevacizumab

Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology

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PointBreak: KM Plot for OS (Intent-to-treat)

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time from Induction (Months)

Su

rviv

al

Pro

ba

bil

ity

HR=1.0 (95% CI: 0.86–1.16)Log-rank P=0.949

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20

40

60

80

100

00

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

PRONOUNCE: Study Design

Stratified for:

PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b)

Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb) Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev)

Bev-Eligible Population

Inclusion:- Chemo-naïve patients- PS 0/1- Stage IV, nonsquam- Stable treated CNS mets

Exclusion:- Uncontrolled effusions

Induction Phaseq21d, 4 cycles

Maintenance Phase q21d until PD

Pemetrexed (folic acid & vitamin B12)

+ Carboplatin

Paclitaxel + Carboplatin + Bevacizumab

R1:1

Pemetrexed (folic acid & vitamin B12)

Bevacizumab

180 patients each

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Zinner ASCO 2013

0 3 6 9 12 15 18 21 24 27

0

20

40

60

80

100

Months

Pro

po

rtio

n

Pem+Cb: median G4PFS = 3.9 (mo)-------- Pac+Cb+Bev: median G4PFS = 2.9 (mo)

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

PC 182 87 44 26 14 7 5 3 1 0PC+Bev 179 75 33 17 9 3 0 0 0 0

Patients at Risk

Primary Endpoint: G4PFS (ITT)Is

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Zinner ASCO 2013

100

00

20

3 6 9 12 15 18 21 24

40

27

60

80

Secondary end-points

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Zinner ASCO 2013

There is any patient unsuitable for maintenance therapy?

Gemcitabine + Carboplatin X 4 cycles

RANDOMIZE

Gemcitabine q 21 days + BSC

N= 128

BSCN= 127

CR, PRSD

Off study

PD

Randomization factors:• PS status• Stage• Best tumour repsonse

Primary Endpoint OS

Belani et al, ASCO 2010

~60% of PS2 Patients

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Overall Survival (months)0 6 12 18 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0Gemcitabine 8.0 mos.

BSC 9.3 mos.

HR=0.97 (95% CI:0.72, 1.30)P =0.838

No benefit with maintenance therapy in PS2 patients

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The maintenance therapy paradigm

EGFR mutated

EGFR-TKI

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No progression after 4 cycles of platinum-based CT, PS irrelevant

HR=0.10 (0.04–0.25)P<0.0001

Time (weeks)

Erlotinib (n=22)

Placebo (n=27)

0 8 16 24 32 40 48 56 64 72 80 88 96

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

PFS

(%)

Time (weeks)

HR=0.17 (0.07–0.42)

20

40

60

80

100

PFS

(%)

Gefitinib (n=15)

Placebo (n=15)

Progression-free Survival in mutated patients

Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM

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The maintenance therapy paradigmIs

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No progression after 4 cycles of platinum-based CT, PS irrelevant ?

ALK+

Pemetrexed Crizotinib

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ALK Fusion not Associated with Sensitivity to Platinum-based Chemotherapy and EGFR –TKIs

• ALK-positive patients display similar sensitivity to platinum-based chemotherapy compared with ALK-negative patients

• Patients with the ALK fusion gene may not benefit from EGFR TKIs

Shaw AT, et al. J Clin Oncol 2009;27:4247‒53

TTP on EGFR-TKI monotherapy

Months

0 12 24 36 48

Prog

ress

ion-

free

(%)

Prog

ress

ion-

free

(%)

p=0.004(ALK vs EGFR)

Months

100

80

60

40

20

0 12 24 36 48 60

TTP on platinum-based chemotherapyTTP on platinum-based chemotherapy

ALK-positiveEGFR mut-positiveWT/WT

ALK-positiveEGFR mut-positiveWT/WT

100

80

60

40

20

ALK fusion predictive for pemetrexed sensitivity

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Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011

Low TS levels in ALK+

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Profile 1007: PFS by Independent Radiologic Review(in overall population and according to chemotherapy)

Treatment mPFS (mos) HR/p value

Crizotinib 7.7 0.49/P<0.001

Chemotherapy 3.0

Treatment mPFS (mos) HR/p value

Crizotinib 7.7

Pemetrexed 4.2 0.59/P<0.001

Docetaxel 2.6 0.30/P<0.001

Shaw AT., Lancet Oncol 2013

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Overall Survival

* 112 patients crossed over to crizotinib

Treatment mOS (mos) HR/p value

Crizotinib 20.3 0.54/P=0.54

Chemotherapy 22.8

Shaw AT., Lancet Oncol 2013

Conclusions

• Maintenance therapy is a relevant option to discuss with patients

• Treatment choice should be based on EGFR, ALK, histology, response to front-line therapy and patient preferences

• In EGFR/ALK wild-type maintenance is not recommended for patients with low performance status

• In EGFR mutated patients EGFR-TKIs are the best option

• In ALK+ any effort should be done for reducing the risk to preclude crizotinib therapy

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