Le strategie di sequenzadocumenti.fullday.com/public/BIOLOGIA2015/slides/r)_ROSSI_A.pdffinaaaetonziamento e deirappoappo trti con soggetti popo tatortatori diintete essressi coco e

Le strategie di sequenza terapeutica nella neoplasiaterapeutica nella neoplasia polmonare nell’era biologico

molecolaremolecolare

Antonio ROSSI MDAntonio ROSSI, MDDivision of Medical Oncology,

“S.G. MOSCATI” HOSPITAL, AVELLINO - ITALY

• Dr. Antonio Rossi

• In ottemperanza alla normativa ECM ed al principio di trasparenza delle fonti difinanziamento e dei rapporti con soggetti portatori di interessi commerciali in campoa a e to e de appo t co soggett po tato d te ess co e c a ca posanitario, si informano i discenti che negli ultimi due anni si sono avuti i seguenti rapportianche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario:

Eli Lill• Eli‐Lilly• AstraZeneca• Boehringer‐Ingelheim• Roche• Roche

PS 0-1 NSCLC PS 2; > 75 years

2015 Advanced NSCLC treatment algorithm

Squamous PS-comorbidities

Histology

PS 0 1comorbidities

NSCLCStage IV

PS 2; > 75 yearsco-morbidities

EGFR status

Eligiblefor bevacizumab

Platinum +GemcitabinePaclitaxelVinorelbineDocetaxelDocetaxel

1st line

1st‐Line Platinum‐Based CT in A‐NSCLC Efficacy PlateauEfficacy Plateau

Pacli + carbo (PCb)100 Pacli + cis (PC)

G i (GC)Pacli + carbo (PCb)G i (GC)

1.0

0 9

1.0

0 9Cis + vin (CV)

vival%

80

60

rvival

Gem + cis (GC)Doc + cis (DC) Pacli + carbo (PCb)

Gem + cis (GC) Cis + vin (CV)

0.9

0.6

0.8

0.7

0.9

0.6

0.8

0.7

urvival

Overall surv

40

20Overall su 0.5

0.4

0.3

0.2

0.5

0.4

0.3

0.2

Overall su

00

Months Months305 10 15 20 25

Months0

0.1

0

0.1

0

305 10 15 20 250305 10 15 20 25

Study arm

OS (mo)

1 year (%)

Study arm

OS (mo)

1 year (%)

Study arm

OS (mo)

1 year (%)

PCb 8.6 38

CV 8.1 36

PC 7.8 31

GC 8.1 36

DC 7.4 31

PCb 9.9 43

GC 9.8 37

OS, overall survival

DC 7.4 31

PCb 8.1 34CV 9.5 37

K Kelly et al, JCO 2001 J Schiller et al, NEJM2002 GV Scagliotti et al, JCO 2002

Retrospective Analyses by Histology

ECOG 1594 ILCPECOG 1594 ILCP

Hoang et al, Lung Cancer 2013 Scagliotti et al, J Thorac Oncol 2009

JMDB Trial: Cisplatin/Pemetrexed vsCisplatin/Gemcitabine in Advanced NSCLC

No difference in OS or PFS bability 1.0

0.8 CPCG

Median (95% CI)10.3 (9.8‐11.2)10.3 (9.6‐10.9)

Cisplatin/Gemcitabine in Advanced NSCLC

No difference in OS or PFS between study arms

Survival Prob

0

0.2

0.6

0.4

CG

0 6 12 18 24 30

10.3 (9.6 10.9)

Adjusted HR (95% CI)0.94 (0.84‐1.05)

CP vs CG

Cis/Pem improves OS over cis/gem

Survival Time (Mos) in All Patients0 6 12 18 24 30

Prob

ability

0.6

1.0

0.8 CPCG

Median (95% CI) 11.8 (10.4‐13.2)10.4 (9.6‐11.2)

Adjusted HR (95% CI) CP vs CG

in non‐SCCA (HR: 0.81; P = .005)

Survival Time (Mos) in Patients With N Hi t l

Survival

0

0.2

0.4

0 6 12 18 24 30

j ( )0.81 (0.70‐0.94)

CP vs CG

Cis/Gem improves OS over cis/pem

Nonsquamous Histology

Prob

ability

0.6

1.0

0.8 CPCG

Median (95% CI) 9.4 (8.4‐10.2)10.8 (9.5‐12.1)

Adjusted HR (95% CI) CP vs CG

in SCCA (HR: 1.23; P = .05)

Survival Time (Mos) in Patients With Survival

0

0.2

0.4

0 6 12 18 24 30

j ( )1.23 (1.00‐1.51)

CP vs CG

Scagliotti et al. J Clin Oncol 2008

Squamous Histology

Phase III nab‐P/C vs P/C: ORR & OS by Histology

50% nab P/CSquamous Nonsquamous

41%40%

50% nab-P/CP/C

nses

P < 0.001 P = 0.060 P = 0.808 P = 0.069

n = 228 n = 221 n = 292 n = 310 Nab‐P/C

P/C

37%

26%

37%

24%29%

25%30%

20%

30%

t Re

spon

24%

10%

20%

Percen

t

0%Independent Investigator Independent InvestigatorIndependentRadiologic

IndependentRadiologic

InvestigatorAssessment

InvestigatorAssessmentRadiologic

ReviewAssessment Radiologic

ReviewAssessmentRadiologic

ReviewRadiologicReview

Assessment Assessment

Carboplatin/

paclitaxel

Carboplatin/

nab paclitaxel Hazard

Socinski et al. Ann Oncol 2013

Overall Survival

paclitaxel

(n = 221)

nab paclitaxel

(n = 229)

Hazard

ratio p‐value

Squamous 9.5 months 10.7 months 0.890 0.284*

Nab-Paclitaxel and squamous histology?

Desai et al, Translational Oncology 2009

RA Gemcitabine 1,250 mg/m2, day 1 & 8

N = 60

ND

Carboplatin AUC 5, day 1Q3W Squamous NSCLC

histologyNo prior treatment Up to 6 cyclesO

M Nab‐Paclitaxel 135 mg/m2, day 1 & 8Carboplatin AUC 5, day 1

No prior treatmentStage III-IV not amenable of regional therapyECOG PS 0-1

Up to 6 cycles

IZ

p , yQ3W N = 60

Primary endpoint: ORRE

NCT01236716

Primary endpoint: ORRSecondary endpoints: PFS, OS, Safety, biomarkerparameters (SPARC, caveolin‐1)

NCT02027428

Survival outcomes in unselected patients withadvanced squamous NSCLCadvanced squamous NSCLC

Survival BSC (1) Old drugs(2)

Third generation drugs (3)

Median(months) ≈ 4 ≈ 6 ≈ 10

11-year Survival (%) 10 20 40

2-year Survival (%) 0 < 5 17

1 NSCLC Meta‐Analyses Collaborative Group J Clin Oncol 20082 Delbaldo C, et al. JAMA 20043 Schiller JH, et al. N Engl J Med 2002

SQUIRE trialNecitumumab phase III trial in 1st‐line SCC NSCLC

PDPDPRCRPRCR

Gem-Cis + Neci q3w (N = 545) Necitumumab (800 mg D1 D8)

Neci q3w(800 D1 D8)

PDPRCR

Gem-Cis + Neci q3w (N = 545) Necitumumab (800 mg D1 D8)

Neci q3w(800 D1 D8)

Necitumumab phase III trial in 1st line SCC NSCLC

SDSD

PDPD

Necitumumab (800 mg D1, D8)Gemcitabine (1250 mg/m², D1, D8)Cisplatin (75 mg/m², D1)

Maximum of 6 cyclesMaximum of 6 cycles

ScreeningEntry criteria:Stage IV

(800 mg D1, D8)

RR11

SD

PD

Necitumumab (800 mg D1, D8)Gemcitabine (1250 mg/m², D1, D8)Cisplatin (75 mg/m², D1)

Maximum of 6 cycles

ScreeningEntry criteria:Stage IV

(800 mg D1, D8)

R1

PDPD

Maximum of 6 cyclesMaximum of 6 cyclessquamous NSCLC4,5

ECOG PS 0-2 Gem-Cis q3w (N = 548)Gemcitabine (1250 mg/m², D1, D8)Ci l ti (75 / ² D1)

11

PD

Maximum of 6 cyclessquamous NSCLC4,5

ECOG PS 0-2 Gem-Cis q3w (N = 548)Gemcitabine (1250 mg/m², D1, D8)Ci l ti (75 / ² D1)

1

Cisplatin (75 mg/m², D1)Cisplatin (75 mg/m², D1)

Randomization (R) stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe and Australia; vs. South America, South Africa and India; vs. Eastern Randomization (R) stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe and Australia; vs. South America, South Africa and India; vs. Eastern , p ; , ;Asia)

, p ; , ;Asia)

Primary endpoint: Overall Survival• Patient selection not based on EGFR proteinexpression

Secondary endpoints: PFS, ORR, safety

Exploratory endpoint: EGFR expression

expression• Radiographic tumor asessment (investigator

read) was carried out at baseline and every 6 weeks until PD

(IHC, H-score)• Tissue collection was mandatory

Thatcher et al, Lancet Oncol 2015

SQUIRESQUIRE vs.FLEX

To icitToxicity



Squamous

M t EGFR

Non-squamousPS-comorbidities

Histology

PS 0 1comorbidities

NSCLCStage IV


Mut. EGFR –/undetermined

Not eligible bevacizumab

EGFR status


Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel

Platinum +PemetrexedFollowed by MaintenanceDocetaxel

1st linePemetrexed

Pemetrexed 500 mg/m2 + 2

JMDB: Study Design

Stage IIIB/IV NSCLC

PS 0 - 1

No prior chemo RR

Cisplatin 75 mg/m2 day 1

Primary objective: Overall Survival

15% Non-inferiority margin (HR 1.17)

Gemcitabine 1250 mg/m2 + Cisplatin 75 mg/m2 day 1;

Randomization: gender, PS, stage, histo vs cyto dx, brain mets

RRN = 1700 Patients , Power 80%

Scagliotti GV et al JCO 2008

PARAMOUNT: Study Design

Cisplatin 75 mg/m day 1;Gemcitabine 1250 mg/m2 day 8

Induction Therapy (4 cycles) Maintenance Therapy (Until PD)

500 mg/m2 Pemetrexed + BSC, d1, q21dP ti t ll d if

CR, PR, SD

Placebo + BSC, d1, q21d

g , , q

2:1 RandomizationPatients enrolled if:• Nonsquamous NSCLC• No prior systemic treatment for

lung cancerECOG PS 0/1

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

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

PD

Response to induction (CR/PR vs SD)

Paz‐Ares L et al, Lancet Oncol 2012

PARAMOUNT Trial: ITT population

PDPDPemetrexed500 mg/m2Pemetrexed500 mg/m2

2:1 randomization

Chemonaïveadvanced

NON‐SQUAMOUS NSCLC

Chemonaïveadvanced

NON‐SQUAMOUS NSCLC

Non‐PD randomized pts

n=539

Non‐PD randomized pts

n=539

4 cycles of 1st‐line

CDDP+PEM

4 cycles of 1st‐line

CDDP+PEM

500 mg/m2500 mg/m2

n=939n=939n=539n=539

PlaceboPlacebo PDPD

Progression‐Free Survival Overall Survival

Paz‐Ares L, et al J Clin Oncol 2013

PARAMOUNT Trial: OS outcomes

CR/PRHR: 0.81

SDHR: 0.76

Paz‐Ares L, et al J Clin Oncol 2013

Survival outcomes in patients with advanced non‐squamousNSCLC and not selected for biological biomarkers

Survival BSC (1) Old drugs(2)

Thirdgeneration drugs (3)

PEM- and BEVA-based*

(4, 5)

PEM continuationmaintenanceg ( ) ( , )

(6, 7)Median

(months) ≈ 4 ≈ 6 ≈ 10 ≈ 12 ≈ 171-year

Survival (%) 10 20 40 45 582-year

Survival (%) 0 < 5 17 22 321 NSCLC Meta‐Analyses Collaborative Group J Clin Oncol 20082 Delbaldo C, et al. JAMA 20043 Schiller JH, et al. N Engl J Med 2002, g4 Sandler A, et al. N Engl J Med 2006 5 Scagliotti GV, et al J Clin Oncol 2008 6 Paz‐Ares L, et al. Lancet Oncol 20127 Paz Ares L, et al. J clin Oncol 2013



Squamous

M t EGFR


Histology

PS 0 1comorbidities

NSCLCStage IV




EGFR status

Eligiblefor bevacizumab Eligible bevacizumab


Platinum +PemetrexedFollowed by Maintenance

Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel

1st linePemetrexed Followed by

Maintenance Pemetrexed orBevacizumab

Bevacizumab in NSCLCBevacizumab in NSCLCE4599 trial design1

CP x 6 (n=444) PD*

g

Previously untreatedstage IIIB/IV

non-squamous NSCLCAvastin (15mg/kg)

every 3 weeks + CP x6 (n=434) PD

Avastinq

(n=878)

PD*Placebo + CG x 6 (n=347)

AVAiL trial design2

PD AvastinAvastin (15mg/kg)

every 3 weeks + CG x 6 (n=351)

Previously untreated, stage IIIB, IV or recurrent non-

squamous NSCLC (n=1 043)

PD Avastin (7.5mg/kg)

every 3 weeks + CG x 6 (n=345)

(n=1,043)

Avastin

*No cross over permittedpCP=carboplatin + paclitaxelCG=cisplatin + gemcitabinePD=progression of disease

1. Sandler, et al. N Engl J Med 2006;355:2542-25502. Reck, et al. J Clin Oncol 2009;27:1227-1234

Bevacizumab in Non-squamous NSCLCKey Results

ECOG 4599 AVAIL

PCB PC CGB (7.5) CGB (15) CG

RR 35% 15% 34.1% 30.4% 20.1%<0 0001 (7 5)p-value <0.001 <0.0001 (7.5)0.0023 (15)

PFS (m) 6.2 4.5 6.7 6.5 6.1

HR / p-value 0.66 (<0.001) 0.75 (0.003) / 7.50.82 (0.03) / 15

OS (m) 12.3 10.3 13.6 13.4 13.1

HR / p-value 0.79 (0.003) 0.93 (ns) / 7.51.03 (ns) / 15( )

Sandler, et al. N Engl J Med 2006;355:2542-2550Reck, et al. J Clin Oncol 2009;27:1227-1234Reck, et al Ann Oncol 2010



Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV




Mut. EGFR + EGFR status

Eligiblefor bevacizumab Eligible bevacizumab



GefitinibErlotinibAfatinib




I nuovi TKI a confronto: caratteristiche, opzioni di

scelta, critiche



Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV


Mut EGFRMut. EGFR –/undetermined




3rd generation single agent


Eligible bevacizumab




3rd generation single agentaccording to histologyor adapted doublet






Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV














1st linePemetrexed

Progression Progression Progression Progression

Followed byMaintenance Pemetrexed orBevacizumab

Trasl. ALK +


PS-comorbidities

Histology

EGFR status C i ti ib

Trasl. ALK -

2nd line

EGFR status

ALK status

Crizotinib

I nuovi TKI a confronto: caratteristiche, opzioni di

scelta, critiche



Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV














1st linePemetrexed



Trasl. ALK +


PS-comorbidities

Histology


Trasl. ALK -

P t d ( )

2nd line

EGFR status

ALK status

Crizotinib Pemetrexed (non-squam.)DocetaxelErlotinib

Second‐Line Therapy: Grade 3/4 Toxicities

Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]

40 2%40.2%

ing

t Re

port

Percen

Adverse Eventa. Vamvakas L, et al. Cancer. 2013;119:2754‐2764.b. Hanna N, et al. J Clin Oncol. 2004;22:1589‐1597.

Selecting Second‐Line Therapy in U l t d NSCLC P ti tUnselected NSCLC Patients

Patient Factors

• Performance Status

First‐Line Treatment History

• First‐line regimen• Duration of

Tumor Characteristics

• Tumor burden• Smoke• Age• Patient co‐morbidity

P ti t f

• Duration of response to first‐line treatment

• Tolerability

• Histology• Targetable

alterations• Patient preference • Tolerability

Erlotinib

??

NintedanibNintedanib 200 mg BID 200 mg BID p.op.o., D2., D2‐‐21 21 ++R

Treatment until disease progression

Treatment until disease progression

++Docetaxel 75 Docetaxel 75 mg/mmg/m22 IV, D1, q3wksIV, D1, q3wks

N=655N=655

RANDO

‐ Stage IIIB/IV or recurrent NSCLC

ti t ft 1st li

‐ Stage IIIB/IV or recurrent NSCLC

ti t ft 1st li 1:1 progression or unacceptable

toxicity

progression or unacceptable

toxicityPlacebo BID Placebo BID p.op.o., D2., D2‐‐2121++

D t lD t l 7575 // 22 IV D1 3 kIV D1 3 k

OMIZE

patients after 1st‐line chemotherapy (All histologies)

patients after 1st‐line chemotherapy (All histologies)

1:1

Docetaxel Docetaxel 75 75 mg/mmg/m22 IV, D1, q3wksIV, D1, q3wksN=659N=659

E

N = 1314

Stratification factors:• ECOG PS 0 vs 1Stratification factors:• ECOG PS 0 vs 1 Primary endpoint: Progression‐Free SurvivalPrimary endpoint: Progression‐Free Survival

• Prior bevacizumab• Histology (squamous vs non‐squamous) • Brain metastases (yes or no)

• Prior bevacizumab• Histology (squamous vs non‐squamous) • Brain metastases (yes or no)

Secondary endpoints:OS, ORR, safety, patient‐reported outcomesSecondary endpoints:OS, ORR, safety, patient‐reported outcomes

All histologies Adenocarcinoma

SquamousProgression‐

Free Survival

Nintedanib/

Docetaxel

(months)

Placebo/

Docetaxel

(months) HR p‐value( ) ( ) p

All histologies 3.4 2.7 0.79 0.0019

Adenocarcinoma ‐ ‐ 0.77 0.002

Squamous ‐ ‐ 0.77 0.002

Adenocarcinoma9 months within

All adenocarcinoma

start of 1st‐line

All histologiesOverall

Survival

Nintedanib/

Docetaxel

(months)

Placebo/

Docetaxel

(months) HR p‐value( ) ( ) p

ADK 9 mos

within 1st‐line10.9 7.9 0.75 0.0073

Ad i 12 6 10 3 0 83 0 059Adenocarcinoma 12.6 10.3 0.83 0.059

All histologies 10.1 9.1 0.94 0.27

Nintedanib EMA Approval

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_‐_Initial_authorisation/human/002569/WC500173607.pdf

R i bR i b 1010 /k/k

1:1

‐ Stage IV NSCLC after one platinum‐ based

‐ Stage IV NSCLC after one platinum‐ based Treatment Treatment

Ramucirumab Ramucirumab 10 10 mg/kg mg/kg ++

Docetaxel 75 Docetaxel 75 mg/mmg/m22 qq3wks3wksN=628N=628

RAN

chemo +/‐maintenance

‐ Prior Bev allowedAll hi t l i

chemo +/‐maintenance

‐ Prior Bev allowedAll hi t l i

until disease progression

or unacceptable toxicity

until disease progression

or unacceptable toxicityPlacebo Placebo

NDOMI‐ All histologies

‐ PS 0 or 1‐ All histologies‐ PS 0 or 1

++Docetaxel Docetaxel 75 75 mg/mmg/m22 qq3wks3wks

N=625N=625

ZE

Stratification factors:• ECOG PS 0 vs 1Stratification factors:• ECOG PS 0 vs 1 Primary endpoint: Overall SurvivalPrimary endpoint: Overall Survival

• Gender • Prior maintenance• East‐Asia vs. ROW

• Gender • Prior maintenance• East‐Asia vs. ROW

Secondary endpoints:PFS, ORR, safety, patient‐reported outcomesSecondary endpoints:PFS, ORR, safety, patient‐reported outcomes

100Median (95% CI) Censoring Rate

RAM DOC PL DOC

4.5 (4.2-5.4) 11.1%3.0 (2.8-3.9) 6.7%

RAM+DOCPL+DOC

(%)

men

t 80

RAM+DOC vs PL+DOC:Stratified HR (95% CI) = 0.76 (0.68-0.86)Stratified log-rank P = 0.0001

ee S

urvi

val

igat

or A

sses

sm

60

essi

on-F

reul

atio

n, In

vest

i

40

Prog

reIT

T po

p

RAM+DOCPL+DOCCensored0

20

Number at risk

Censored

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

0

RAM+DOCPL+DOC

Number at risk383301

204172

12095

5937

3817

119

74

33

32

00

00

628625

00

Median (95% CI) Censoring Rate100

Median (95% CI) Censoring RateRAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5‐11.2) 31.8%PL+DOC 9.1 (8.4‐10.0) 27.0%80

RAM+DOC vs PL+DOC:Stratified HR (95% CI) = 0.886 (0.75‐0.98)Stratified log‐rank P = .02360

urvi

val (

%)

pula

tion

40

Ove

rall

SuIT

T po

p

0

20RAM+DOCPL+DOCCensored

0

Number at risk

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

RAM+DOCPL+DOC

Number at risk

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

628625

00

First anti-angiogenetic approved for NSCLCsquamous NSCLC

https://investor.lilly.com/releasedetail.cfm?releaseid=887944



Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV














1st linePemetrexed



Trasl. ALK +

Platinum-based CT


PS-comorbidities

Histology


Trasl. ALK -

P t d ( )

2nd line

Platinum based CTEGFR status

ALK status




Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV














1st linePemetrexed



Trasl. ALK +

Platinum-based CT


PS-comorbidities

Histology


Trasl. ALK -

P t d ( )

2nd line

Platinum based CT

Progression

EGFR status

ALK status


Erlotinib 3rd lineProgression

T-cell activation and therapeutic opportunities in lung cancers

Anti-CTLA-4:Ipilimumab

Anti-PD-L1MPDL3280A

Anti-PD-1Nivolumab

opportunities in lung cancers

Ipilimumab Tremelimumab

MPDL3280AMEDI4736

BMS-935559

NivolumabPembrolizumab

Il futuro dell’inibizione di PD‐1 e PD‐L1 nella neoplasia

polmonare non a piccole cellule

LYMPH NODE

Intlekofer & Thompson, JLB 2013



Squamous

M t EGFR Mut EGFR +


Histology

PS 0 1comorbidities

NSCLCStage IV














1st linePemetrexed



Trasl. ALK +

Platinum-based CT


PS-comorbidities

Histology


Trasl. ALK -

P t d ( )

2nd line

Platinum based CT

Progression

EGFR status

ALK status


Erlotinib 3rd lineProgression

Documents

Le strategie di sequenzadocumenti.fullday.com/public/BIOLOGIA2015/slides/r)_ROSSI_A.pdffinaaaetonziamento e deirappoappo trti con soggetti popo tatortatori diintete essressi coco e