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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut. EGFR –/undetermined
Not eligible bevacizumab
EGFR status
Eligiblefor bevacizumab
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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut. EGFR –/undetermined
Not eligible bevacizumab
EGFR status
Eligiblefor bevacizumab Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed Followed by
Maintenance Pemetrexed orBevacizumab
I nuovi TKI a confronto: caratteristiche, opzioni di
scelta, critiche
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed Followed by
Maintenance Pemetrexed orBevacizumab
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed
Progression Progression Progression Progression
Followed byMaintenance Pemetrexed orBevacizumab
Trasl. ALK +
Progression Progression Progression Progression
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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed
Progression Progression Progression Progression
Followed byMaintenance Pemetrexed orBevacizumab
Trasl. ALK +
Progression Progression Progression Progression
PS-comorbidities
Histology
EGFR status C i ti ib
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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed
Progression Progression Progression Progression
Followed byMaintenance Pemetrexed orBevacizumab
Trasl. ALK +
Platinum-based CT
Progression Progression Progression Progression
PS-comorbidities
Histology
EGFR status C i ti ib
Trasl. ALK -
P t d ( )
2nd line
Platinum based CTEGFR status
ALK status
Crizotinib Pemetrexed (non-squam.)DocetaxelErlotinib
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed
Progression Progression Progression Progression
Followed byMaintenance Pemetrexed orBevacizumab
Trasl. ALK +
Platinum-based CT
Progression Progression Progression Progression
PS-comorbidities
Histology
EGFR status C i ti ib
Trasl. ALK -
P t d ( )
2nd line
Platinum based CT
Progression
EGFR status
ALK status
Crizotinib Pemetrexed (non-squam.)DocetaxelErlotinib
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
PS 0-1 NSCLC PS 2; > 75 years
2015 Advanced NSCLC treatment algorithm
Squamous
M t EGFR Mut EGFR +
Non-squamousPS-comorbidities
Histology
PS 0 1comorbidities
NSCLCStage IV
PS 2; > 75 yearsco-morbidities
Mut EGFRMut. EGFR –/undetermined
Not eligible bevacizumab
Mut. EGFR + EGFR status
Eligiblefor bevacizumab
3rd generation single agent
Mut. EGFR –/undetermined
Eligible bevacizumab
Platinum +GemcitabinePaclitaxelVinorelbineDocetaxel
Platinum +PemetrexedFollowed by Maintenance
GefitinibErlotinibAfatinib
3rd generation single agentaccording to histologyor adapted doublet
Platinum +Pemetrexed orCarboplatin +Paclitaxel +bevacizumabFollowed byDocetaxel
1st linePemetrexed
Progression Progression Progression Progression
Followed byMaintenance Pemetrexed orBevacizumab
Trasl. ALK +
Platinum-based CT
Progression Progression Progression Progression
PS-comorbidities
Histology
EGFR status C i ti ib
Trasl. ALK -
P t d ( )
2nd line
Platinum based CT
Progression
EGFR status
ALK status
Crizotinib Pemetrexed (non-squam.)DocetaxelErlotinib
Erlotinib 3rd lineProgression