1-line treatment of advanced-nsclc wt cesare gridelli division of medical oncology “s.g....

1-line Treatment of Advanced-NSCLC WT1-line Treatment of Advanced-NSCLC WT

Cesare GridelliDivision of Medical Oncology

“S.G. Moscati” Hospital – Avellino (Italy)[email protected]

mailto:[email protected]

First-Line Treatment of A-NSCLC in EUFirst-Line Treatment of A-NSCLC in EU

EGFR-mutation analysis

Non-squamous cell carcinoma

Metastatic NSCLC, PS 0-2

Squamous cell carcinoma

EGFR mutation (del 19 or L858R in exon 21)

EGFR wild type (or not done)

EGFR-TKI Radiotherapy• CNS• Central airways• Bone• Soft tissue

Platinum plus• Pemetrexed or gemcitabine or taxanes or

vinorelbine

OR Platinum combination plus

• Bevacizumab* (PS 0,1)

Elderly/PS 2• Platinum combination (preferred in fit elderly) or• Monotherapy (preferred in unfit elderly)

Platinum plus• Gemcitabine or taxane or vinorelbine

Elderly/PS 2• Platinum combination (preferred in fit elderly) or • Monotherapy (preferred in unfit elderly)

1

2

2

3

First-Line Treatment of Advanced NSCLCFirst-Line Treatment of Advanced NSCLCNCCN GuidelinesNCCN Guidelines

• Adenocarcinoma• Large cells• NSCLC NOS


EGFR mutation and ALK negative

EGFR mutation positive

ALK positive

PS 0-1

PS 2

PS 3-4

Erlotinib

Crizotinib

Doublet chemotherapy (category 1)

ORCetuximab/vinorelbine/ cisplatin (category 2B)

Chemotherapy

Best supportive care

PS 0-1

PS 2

PS 3-4

Doublet chemotherapy (category 1) OR

Bevacizumab + chemotherapy (if criteria met)

ORCisplatin/pemetrexed (category 1)

(if criteria met)OR

Cetuximab/vinorelbine/cisplatin(category 2B)

Chemotherapy

Best supportive care only

First-Line Treatment of Advanced NSCLCFirst-Line Treatment of Advanced NSCLC









vinorelbine


• Bevacizumab PS 0,1)




BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin.The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the chemotherapy-alone group.Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550.

Hazard ratio, 0.79; P=0.003

100

80

60

40

20

0

Ove

rall

Surv

ival

, %

423024181260

Month

36

BPC group(305 events in 417 patients)

PC group(344 events in 433 patients)

• Avastin-based therapy (n=602)– extends OS to 14.2 months– 31% reduction in the risk of death (HR=0.69)

Duration of OS (months)

Pro

bab

ility

of O

S

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48

Avastin + CP (n=300)

CP (n=302)

10.3 14.2

First-Line Treatment of Advanced NSCLCFirst-Line Treatment of Advanced NSCLCESMO GuidelinesESMO Guidelines









vinorelbine


• Bevacizumab PS 0,1)




Cisplatin With Pemetrexed or GemcitabineJMDB Trial

Cisplatin/pemetrexed provides similar efficacy with better tolerability andmore convenient administration than cisplatin/gemcitabine in NSCLC

CP, cisplatin-pemetrexed.Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551.

Surv

ival

Pro

babi

lity

CG 10.4; 9.6, 11.2

CP 11.8; 10.4, 13.21.00.80.60.40.20.0

0 6 12 18 24 30

Survival Time (months) in PatientsWith Squamous Cell Carcinoma

Surv

ival

Pro

babi

lity

1.00.80.60.40.20.0

0 6 12 18 24 30PF

S Pr

obab

ility 1.0

0.80.60.40.20.0

0 6 12 18 24 30

PFS (months) in PatientsWith Squamous Cell Carcinoma

PFS

Prob

abili

ty 1.00.80.60.40.20.0

0 6 12 18 24 30

Survival Time (months) in PatientsWith Non-squamous Histology

PFS (months) in PatientsWith Non-squamous Histology

CP vs CG Adjusted HR; 95% CI 0.81; 0.70, 0.94

Median; 95% CI

CG 4.7; 4.4, 5.4

CP 5.3; 4.8, 5.7


Median; 95% CI

CG 5.5; 4.6, 5.9

CP 4.4; 4.1, 4.9


Median; 95% CI

CG 10.8; 9.5, 12.1

CP 9.4; 8.4, 10.2


Median; 95% CI

Maintenance TherapyContinuation vs Switch

QoLSymptom control

Toxicities

‘Continuation’ maintenance with the chemo drug X

‘Switch’ maintenance with a new chemo drug

‘Continuation’ maintenance with TT(eg, bevacizumab)

P + X ± TT× 4 cycles

50%

Selection of patients with a

better prognosis

Stabilisation orobjective response

‘Switch’ maintenance with a new drug TT (EGFR TKI for SD patients)

Maintenance Therapy in NSCLCPatient Selection

Histology• Adenocarcinoma subtypes• Squamous cell carcinoma

Clinical Features

• Age: Adults 18-70 years (fit, elderly)• Gender: Any• ECOG PS 0-1, KPS>80• ECOG PS 2 (selected cases for TKI)

Genetics

• EGFR Wild type – chemotherapy • EGFR Mutant – TKI

(TKI responders; Asian, women, never smoker, having adenocarcinoma)• k-ras mutation – chemotherapy• EML4-ALK – Crizotinib

Suitable Subset of Patients

• Clinical benefit; stable disease or regression after induction chemotherapy• Well-preserved organ function• No major comorbidity

SATURN: Sequential Tarceva in unresectable NSCLC

No progression (n=899)

Progression

Tumour samples

(mandatory)

Erlotinib 150mg/day Placebo

Until PD, death or unacceptable toxicity

Randomisation with stratification

EGFR protein expression

(IHC) results

Stu

dy

Pe

rio

dS

cre

enin

g

Pe

rio

d

Until PD, death or unacceptable toxicity

TITAN

Stage IIIb/IV NSCLC 4 cycles of a first-line standard

platinum-based doublet

Planned Recruitment

= 1,700

OS from randomization in all patientsOS from randomization in all patients

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

OS

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=438)

Placebo (n=451)

11.0 12.0

*OS is measured from time of randomisation into the maintenance phase;ITT = intent-to-treat population

HR=0.81 (0.70–0.95)Log-rank p=0.0088

Cappuzzo et al,WCLC 2009

OS

pro

bab

ilit

y

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

Measured from time of randomisation into the maintenance phase

OS according to response to first-line chemoOS according to response to first-line chemo

Multivariate HR for OS in SD population 0.71, p=0.0019

PARAMOUNT: Study DesignPARAMOUNT: Study DesignStudy Treatment Period

Progression

Induction Therapy (4 cycles)

Maintenance Therapy (Until PD)

21 to 42 Days

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

q21d

CR, PR, SD

PD

Placebo + BSC, d1, q21d

500 mg/m2 Pemetrexed + BSC, d1, q21d

2:1 Randomization

Patients enrolled if:•Nonsquamous NSCLC•No prior systemic treatment for lung cancer•ECOG PS 0/1 Stratified for:

•PS (0 vs 1) •Disease stage (IIIB vs IV) prior to induction•Response to induction (CR/PR vs SD)

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

PARAMOUNT: Investigator Assessed PFS (from Maintenance)

Pemetrexed: median =4.1 mos (3.2-4.6)Placebo: median =2.8 mos (2.6-3.1)Log-rank P=0.00006Unadjusted HR: 0.62 (0.49-0.79)

Patients at Risk

Pem + BSC N=359 132 57 21 4 0

Placebo + BSC N=180 52 15 5 0 0

Pem + BSC

Placebo + BSC

PARAMOUNT: Final OS from Randomization

Patients at RiskPem + BSC 359 333 272 235 200 166 138 105 79

43 15 2 0Placebo + BSC 180 169 131 103 78 65 49 35

23 12 8 3 0

Time from Randomization (Months)

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

Su

rviv

al

Pro

bab

ilit

y

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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)

Log-rank P = 0.0195 Unadjusted HR: 0.78 (95% CI: 0.64–0.96)

PARAMOUNT: Final OS from InductionS

urv

ival

Pro

bab

ilit

y

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

Pemetrexed Median OS =16.9 mos (95% CI: 15.8–19.0)Placebo Median 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

Surv

ival

Pro

babi

lity

Time From Randomisation, months

CR/PRHR=0.81 (0.59–1.11)

Stable DiseaseHR=0.76 (0.57–1.01)

Time From Induction, months

Surv

ival

Pro

babi

lity

1.0

Pemetrexed + BSCMedian OS=16.9 months (95% CI, 15.8–19.0)

HR=0.78 (95% CI, 0.64–0.96)Log-rank P=0.0191

0.8

0.6

0.4

0.2

0.0

Placebo + BSCMedian OS=14.0 months (95% CI, 12.9–15.5)

3633302724211815129630

3633302724211815129630

3633302724211815129630

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

65

70

75

80

1 2 3 4 5 6

EQ-5D, EuroQol 5-dimensional questionnaire; VAS, visual analog scale.*P≤0.05, comparing the difference in mean changes from baseline between treatment arms.Gridelli C, et al. J Thorac Oncol. 2012;7(11):1713-1721.

0.65

0.70

0.75

0.80

0.85

0.90

1 2 3 4 5 6

Top of bar=mean value at that cycle for pemetrexed

Top of bar=mean value at that cycle for placebo

Impr

ovem

ent

Mea

n Sc

ore

(Sca

le -0

.59

to +

1.00

)

N=265 132 241 129 160 83 149 66 108 48 98 36

Maintenance Cycles

∆0.01

∆0.01∆0.01

∆0.00∆0.00

∆0.03∆-0.01

∆0.02

∆0.01

∆0.01

∆-0.02∆0.04

Mean value at baseline (Cycle 0)

Mean change from baseline∆

Impr

ovem

ent

Mea

n R

atin

g (S

cale

0 to

100

)

N=266 126 239 127 162 81 147 65 107 48 98 36

Maintenance Cycles

∆1.65∆1.42

∆3.15∆1.24

∆1.82∆4.90

∆0.69

∆6.15

∆1.55

∆5.99

∆3.01

∆5.76

*

* *

EQ-5D UK population-based index score EQ-5D VAS

Change in ECOG Performance Status from Baseline to Last Maintenance Treatment

7.8% 9.0%

76.2% 78.6%

16.0% 12.4%

PARAMOUNT: Long Term SafetyPARAMOUNT: Long Term Safety

CTCAE Grade 3/4/5 term

>10 cycles Pemetrexed*

n = 84(%)

≤10 cycles Pemetrexed

n = 275(%)

P-value

All laboratory 13.1 8.0 0.194

All non-laboratory 8.3 9.1 1.00

Neutropenia† 8.3 2.2 0.015

Infections 1.2 2.9 0.691

* 10 cycles = 10 total cycles (4 induction cycles + 6 maintenance cycles) † Although incidence of G 3-4 neutropenia higher with long-term use; this did not translate into increased G 3-4

infections.

Grade 1-4 Adverse EventsGrade 1-4 Adverse Events

Event (%)

≥70 Yrs Subgroup <70 Yrs Subgroup

Gr 1 Gr 2 Gr 3/4 Gr 1 Gr 2 Gr 3/4

pem plc pem plc pem plc pem plc pem plc pem plc

Fatigue 8 5 15 5 6 5 9 6 9 5 5 0

Anemia 8 5 10 8 12 0 4 0 10 2 6 0.7

Neutropenia 6 0 8 0 17 0 1 0 3 0.7 4 0

Febrile Neutropenia 0 0 0 0 0 0 0 0 0 0 2 0

Leukopenia 2 0 4 0 4 0 1 0 1 0 2 0

Thrombocytopenia 6 0 0 0 2 0 1 0 0.7 0 2 0

Renal* 4 5 6 0 0 0 3 0.7 4 0.7 1 0

Rash 0 3 0 0 0 0 3 2 0.7 0 0 0

Edema 6 3 4 0 0 0 4 4 4 0 0 0

Palliative radiation during pemetrexed plus cisplatin first-line treatment for advanced non-small cell lung cancer (NSCLC): Patient safety in the JMDB and PARAMOUNT trials

1Giorgio V Scagliotti, 2Cesare Gridelli, 3Filippo de Marinis, 4Bonne Biesma, 5Martin Reck, 6Belen San Antonio, 7Annamaria Hayden Zimmermann, 8Carla Visseren-Grul, 9Nadia Chouaki, 10Luis Paz-Ares

1University of Torino, San Luigi Hospital, Orbassano (Torino), Italy; 2San Giuseppe Moscati Hospital, Avellino, Italy; 3San Camillo - Forlanini Hospital, Rome, Italy; 4Jeroen Bosch Hospital, Hertogenbosch, Netherlands; 5Hospital Grosshansdorf, Grosshansdorf, Germany; 6Eli Lilly and Company, Madrid, Spain; 7Eli Lilly and Company, Indianapolis, IN, USA; 8Eli Lilly and Company, Houten, Netherlands; 9Eli Lilly and Company, Paris, France; 10Seville University Hospital, Seville, Spain

J Thorac Oncol, in press

*In JMDB two patients experienced AEs; 1 Grade 2 (Gr 2) anemia and 1 Gr 2 radiation dermatitis.*In Paramount 10 patients experienced AEs during the induction phase of treatmentOther events commonly associated with the administration of chemotherapy and XRT, such as lung toxicities (e.g. pneumonitis) and esophagitis, were not reported.

Patients Receiving Palliative XRT During Pem/Cis Treatment (N=65)

Patients with adverse events n=12 (18.5%)CTCAE Gr 1, n (%) Gr 2, n (%) Gr 3-4, n (%)

Hematologic

Anemia 1 (1.5) *4 (6.1) 3 (4.6)

Leukocytes 0 2 (3.1) 0

Platelets 0 1 (1.5) 0

Nonhematologic

Rash/dermatitis 1 (1.5) 1 (1.5) 0

Rash/desquamation 1 (1.5) 1 (1.5) 0

Radiation dermatitis 0 *1 (1.5) 0

• Dose range for 12 patients with AEs 8-34 Gy• Half of patients with adverse events received palliative radiation within 7 days of the

last chemotherapy• Of the patients with brain metastases (n=5) none reported adverse events related to

palliative XRT

1-line treatment of advanced-nsclc wt cesare gridelli division of medical oncology “s.g....

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