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Second-line treatment for advanced NSCLC
Silvia Novello [email protected]
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Life was so simple back in 2008
Di Maio M, EJC 2010
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In 2017, “second line therapy” is no longer as simple
We must now take into consideration:
1.Tumor histology
2.Molecular phenotype (EGFR, ALK, ROS1, etc), Cappuzzo
3.Frontline chemo components (i.e. bevacizumab)
4.Maintenance therapy (continuation, switch)
5. IO in First Line
6.Others (adequacy of tumor tissue, third party reimbursement,
guidelines, “pathways”, etc)
INDUCTION MAINTENANCE 2 nd LINE 3 rd LINE
Di Maio M, JCO 2009
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Clinical Lung Cancer 2014
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Second line therapy Outside Clinical Trials (N=464, 86% of pts progressing after first line)
Gridelli C et al, J Cancer Res Clin Oncol. 2014 De Marinis F et al, Clinical Lung Cancer 2014
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Y Guidelines [ESMO-AIOM]
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Treatment Options Post-platinum Progression: Docetaxel
• Docetaxel was the first treatment to be approved for NSCLC patients with disease progression following first-line chemotherapy1
♦ Patients receiving docetaxel
75 mg/m2 had OS of
7.5 months, compared with
4.6 months for those receiving
BSC2
♦ Docetaxel-treated patients had
a significantly higher 1-year
survival rate compared with
patients receiving vinorelbine
or ifosfamide (32% vs. 19%;
p=.025)3
1. Sanofi Aventis. Taxotere (docetaxel) prescribing information. Nov 2014
2. Shepherd FA et al. J Clin Oncol 2000;18:2095-103
3. Fossella FV et al. J Clin Oncol 2000;18:2354-62
1.0
0.0 0 6 12 18
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Survival (months)
Docetaxel 75 mg/m2 (n=55)
BSC (n=49)
Cu
mu
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rob
ab
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12
• Pemetrexed was approved for patients progressing after chemotherapy after it demonstrated non-inferiority vs. docetaxel, but with a better toxicity profile1-3
Treatment Options Post-platinum Progression: Pemetrexed in nonsquamous NSCLC
♦ In patients with
nonsquamous histology,
pemetrexed treatment
resulted in a median OS of
9.3 months, compared with
8.0 months for docetaxel4
♦ Pemetrexed is only suitable
for patients with
nonsquamous histology1
The increased use of pemetrexed in first-line treatment means docetaxel remains
an option as subsequent therapy for patients of all histologies
1. Eli Lilly and Company. Alimta (pemetrexed) prescribing information. Sep 2013
2. Hanna N et al. J Clin Oncol 2004;22:1589-97
3. Weiss GJ et al. J Clin Oncol 2006;24:4405-11
Survival (months)
4. Scagliotti G et al. Oncologist 2009;14:253-63
Su
rviv
al d
istr
ibu
tio
n
fun
cti
on
0 6
1.0
0.0
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
18 24 30
Pemetrexed
0.78 (95% CI 0.61 ─1.00) Adjusted HR
Docetaxel
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Treatment Options Post-platinum Progression: Erlotinib
• The EGFR TKI erlotinib is approved for use in unselected patients with disease progression after first-line chemotherapy1
1. Astellas Pharma and Genentech. Tarceva (erlotinib) prescribing information. June 2015
2. Garassino MC et al. Lancet Oncol 2013;14:981-8
3. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015
4. Gregorc V et al. Lancet Oncol 2014;15:713-21
♦ However, erlotinib was inferior
to docetaxel for OS and PFS
in patients without an EGFR
mutation; other options may
be preferred in this setting2,3
♦ Erlotinib is not recommended
for patients with a ‘poor’
classification following
proteomic testing in patients
with WT or unknown EGFR
status3,4
100
90
80
70
60
50
40
30
20
10
0
Cox model adjusted HR 0.73 (95% CI 0.53-1.00)
Erlotinib
Docetaxel
Overa
ll s
urv
ival (%
)
0 2 4 6 8 10 12 14 16 18 20
Survival (months)
01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD
*PCR amplification/Sanger sequencing of common mutations
VS-G 96 (72%)
VS-P 38 (28%)
Chemotherapy (129) Erlotinib (134)
VS-G 88 (68%)
VS-P 41 (32%)
3 major protocol violations 19 never received therapy
285 patients randomized 263 included for primary analysis
PROSE Patient Flow
The patient population was 72% male, 63% adenocarcinoma, 14% never smokers, 52% ECOG PS 0, and 41% ECOG PS 1, and was well balanced between arms. Third-line treatment at progression:
– CT arm: 41% overall (48% VS-G and 27% VS-P) – ERL arm: 52% overall (56% VS-G and 39% VS-P)
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SQUAMOUS and NON-SQUAMOUS Carcinoma:
rooms for improvements
SQUAMOUS and NON-SQUAMOUS
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HYPERPLASIA DYSPLASIA CARCINOMA INVASIVE
CARCINOMA
Gene Methylation Mutations Translocations
Promotion of
survival signals and evasion of apoptosis
Tissue invasion and metastasis
Limitless potential for replication
Vascular recruitment
and endothelial cell growth
Cellular proliferation through independent growth signaling
Adapted from Weinberg RA. Sci Am. 1996;275:62-70.
Bronchial Epithelium
Air Space
- Stage IV NSCLC after
one platinum- based chemo +/-
maintenance
- Prior Bev allowed - All histologies
- PS 0 or 1
Treatment until disease progression
or unacceptable toxicity
Ramucirumab 10 mg/kg +
Docetaxel 75 mg/m2 q3wks N=628
Placebo +
Docetaxel 75 mg/m2 q3wks N=625
R A N D O M I Z E
1:1
Stratification factors:
• ECOG PS 0 vs 1
• Gender
• Prior maintenance
• East-Asia vs. ROW
Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes
Median (95% CI) Censoring Rate
RAM+DOC
RAM+DOC vs PL+DOC:
10.5 (9.5-11.2) 31.8% PL+DOC 9.1 (8.4-10.0) 27.0%
Stratified HR (95% CI) = 0.886 (0.75-0.98) Stratified log-rank P = .023
0
20
40
60
80
100
Overa
ll S
urv
ival
(%)
ITT
po
pu
lati
on
RAM+DOC
PL+DOC
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33
527
501
415
386
329
306
231
197
156
129
103
86
70
56
45
36
23
23
11
9
2
0
36
Survival Time (months)
628
625
0
0
RAM+DOC
PL+DOC
Censored
Median (95% CI) Censoring Rate
RAM+DOC vs PL+DOC:
4.5 (4.2-5.4) 11.1%
3.0 (2.8-3.9) 6.7%
Stratified HR (95% CI) = 0.76 (0.68-0.86)
Stratified log-rank P = 0.0001
RAM+DOC
PL+DOC
Pro
gre
ss
ion
-Fre
e S
urv
ival
(%)
ITT
po
pu
lati
on
, In
vesti
gato
r A
ssessm
en
t
RAM+DOC PL+DOC
Number at risk
RAM+DOC
PL+DOC Censored
0 3 6 9 12 15 18 21 24 27 30 33
383 301
204 172
120 95
59 37
38 17
11 9
7 4
3 3
3 2
0 0
0 0
36
Survival Time (months)
628 625
0 0
0
20
40
60
80
100
Responsea, n
(%)
Ramucirumab +
Docetaxel
(n=628)
Placebo +
Docetaxel
(n=625) p value
CR 3 (0.5) 2 (0.3)
PR 141 (22.5) 83 (13.3)
SD 258 (41.1) 244 (39.0)
PD 128 (20.4) 206 (33.0)
Unknown 98 (15.6) 90 (14.4)
ORR
(95% CI)
144 (22.9)
(19.7-26.4)
85 (13.6)
(11.0-16.5) <.001
DCR
(95% CI)
402 (64.0)
(60.1-67.8)
329 (52.6)
(48.6-56.6) <.001
♦ Ramucirumab improved ORR and DCR in nonsquamous and squamous histologies
♦ QoL was
measured using
LCSS and ASBI
♦ A similar increase
in symptom
burden was
observed in both
treatment arms
♦ Addition of
ramucirumab had
no detrimental
effect on QoL
80
100
60
40
20
0 Me
an
LC
SS
To
tal S
co
re
Ramucirumab Placebo
* * * * * * * * * * * * * * * * * *
* * * * * *
0 3 6 7 8 … 10 9 5 2 30-day
follow-up
4 Sum
vis
484 353 233 178 167 111 127 261 422 296 326 366 491 300 196 144 120 86 102 217 433 305 266 367 n =
Cycle
80
100
60
40
20
0 Me
an
AS
BI
To
tal S
co
re
* * * * * * * * * * * * * * * * * *
* * * * * *
0 3 6 7 8 … 10 9 5 2 30-day
follow-up
4 Sum
vis
493 358 240 181 171 112 129 270 457 300 338 375 501 306 199 149 125 87 102 218 443 311 274 372 n =
Randomized (ITT) Population N=1253
PL+DOC (N=625)
Excluded (n=572)
Screened (N=1825)
RAM+DOC (N=627)*
Patients not receiving treatment
(n=4)
Reasons for discontinuation (N=613) PD 341 Adverse event 94 Subject decision 90 Investigator decision 37 Death due to adverse events 30 Death from study disease 12 Other 9 On treatment at data cutoff N=11
RAM+DOC (N=628)
PL+DOC (N=618)*
Patients not receiving
treatment (n=4)
*Three PL+DOC arm patients were inadvertently treated with RAM and are therefore considered part of the RAM+DOC arm for the safety analyses, but the PL+DOC arm for the ITT efficacy analysis.
Safety Population N=1245
REVEL: Patient Disposition
wt 33% mutant 2.4% unknown 64%
wt 31.5% mutant 2.9% unknown 65%
Reasons for discontinuation (N=611) PD 429 Adverse event 55 Subject decision 53 Investigator decision 19 Death due to adverse events 31 Death from study disease 14 Other 10 On treatment at data cutoff N=10
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Forest plot
PFS
SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello
Pembrolizumab - OS by PD-L1 expression - Keynote001
Garon E et al, NEJM 2015
14.9% second line pts
<1% 1-49% ≥50%
SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello Herbst R et al, The Lancet 2016
Pembrolizumab – OS&PFS by PD-L1 expression – Keynote010
OS most impressive in ≥50%, but superior with Pembrolizumab in all groups
PFS benefit was superior in ≥50%,
but not significant for either Pembrolizumab dose in ≥1%
HR 0.53 HR 0.76
Keynote 010: OS by by Subgroups
Pembrolizumab
R Herbst et al., Lancet 2016
Forest plot
PFS
Primary analysis from OAK, a randomized Phase 3 study comparing atezolizumab with docetaxel in 2L/3L NSCLC
• Primary endpoints (first 850 enrolled patients): – OS in the ITT population
– OS in patients with ≥1% PD-L1 expression
• Secondary endpoints: ORR, PFS, DoR,
safety
F. Barlesi, et al. ESMO 2016. Abstract LBA44_PR
• One of the largest studies that tested the role of an anti PDL-1 Mab in the setting of 2/3L NSCLC
R
1:1
Atezolizumab 1200 mg IV q3w
PD or loss of clinical
benefit
Docetaxel 75 mg/m2 q3w
Locally advanced or metastatic NSCLC
• 1–2 prior lines of chemotherapy, including ≥1 platinum based
• Tumor specimen available
• Any PD-L1 status
N=1,225 enrolled
PD
No Cross-Over
Stratification factors • PD-L1 expression
• Histology
• Prior chemotherapy regimens
Primary analysis from OAK, a randomized Phase 3 study comparing atezolizumab with docetaxel in 2L/3L NSCLC
Characteristics Atezolizuma
b n = 425
Docetaxel n = 425
Median age, y 63 64
≥65 y 45% 49%
Male 61% 61%
Nonsquamous 74% 74%
Squamous 26% 26%
ECOG PS, 0/1 37%/64% 38%/62%
No. of prior therapies, 1/2
75%/25% 75%/25%
History of tobacco use
Never 20% 17%
Current/previous
14% / 66% 16% / 67%
Known EGFR status, %
Mutant/WT 10% / 75% 10% / 73%
Atezolizumab Docetaxel
No. at risk Atezolizumab 42
5 407
382
363
342
326
305
279
260
248
234
223
218
205
198
188
175
163
157
141
116
74 54 41 28 15 4 1
Docetaxel 425
390
365
336
311
286
263
236
219
195
179
168
151
140
132
123
116
104
98 90 70 51 37 28 16 6 3
Median 9.6 mo
(95% CI, 8.6, 11.2)
Median 13.8 mo (95% CI, 11.8, 15.7)
Ove
rall
surv
ival
(%
)
Months
HR, 0.73a (95% CI, 0.62, 0.87) P=0.0003 Minimum follow-up = 19 months
3
20
40
60
9 18
80
100
15 6 12 0
0
21 24 27
Overall survival, ITT (n = 850)
F. Barlesi, et al. ESMO 2016. Abstract LBA44_PR
aStratified HR; bUnstratified HR; cP values for descriptive purpose only. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al, Atezolizumab Phase III OAK Study.
Overall survival, PD-L1 expression OS, PD-L1 expression on ≥ 50% TC or ≥ 10% IC
TC3 or IC3; 16% of patients OS, PD-L1 expression on ≥ 1% TC or IC TC1/2/3 or IC1/2/3; 55% of patients
Ove
rall
surv
ival
(%
)
Months
HR, 0.74a (95% CI, 0.58, 0.93) P=0.0102
Minimum follow-up = 19 months
Median 10.3 mo (95% CI, 8.8, 12.0)
Median 15.7 mo (95% CI, 12.6, 18.0)
3
20
40
60
9 18
80
100
15 6 12 0
0
21 24 27
No. at risk Atezolizumab
241
230
215
207
199
190
176
163
150
145
139
133
131
124
119
115
111
104
98 88 71 47 37 28 19 10 3 1
Docetaxel 222
200
185
172
161
148
136
124
116
105
96 89 81 74 72 65 62 59 55 51 41 28 18 15 8 3 1
Atezolizumab Docetaxel
Months
HR, 0.41b (95% CI, 0.27, 0.64) P<0.0001c
Minimum follow-up = 19 months
Median 8.9 mo (95% CI, 5.6, 11.6) Median 20.5 mo
(95% CI, 17.5, NE)
3
20
40
60
9 18
80
100
15 6 12 0
0
21 24 27
No. at risk Atezolizumab
72 69 65 63 61 59 58 55 51 50 49 47 46 46 44 43 43 42 39 34 28 19 16 11 8 6 2
Docetaxel 65 59 57 51 45 40 36 32 32 28 25 24 20 15 14 14 14 13 11 11 9 7 4 3 2
F. Barlesi, et al. ESMO 2016. Abstract LBA44_PR
SQUAMOUS Carcinoma: rooms for improvements
Previous ESMO Guidelines
In studies of nivolumab, a history of smoking in patients with NSCLC was associated with improved clinical response and PFS
HR = hazard ratio; mPFS = median progression-free survival; ORR = objective response rate; PFS = progression-free survival. Hellmann MD, et al. Poster presented at ESMO 2014 (asbtr. 1229PD).
Smoking status and response to immunotherapy in NSCLC
Variable ORR, % (n/N)
[95% CI] P-value
Smoking exposure
≤5 pack-yrs 0 (0/14) [0, 23]
0.018
>5 pack-yrs 30 (20/66)
[20, 43]
14 3 1 1 1 1
75 28 16 12 7 1
≤5 pack-yrs smokers
>5 pack-yrs smokers
0
20
40
60
80
100
PFS
(%
)
0 6 12 18 24 30 Months Since Treatment Initiation
≤5 pack-yrs smokers (mPFS 1.7 months)
>5 pack-yrs smokers (mPFS 2.2 months) HR (95% CI) = 0.41 (0.22, 0.74), P = 0.003
PFS by smoking exposure
SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello
Campbell JD et al, Nat Genet 2016
CheckMate 017 (NCT01642004) - Study Design
• DBL: December 15, 2014
• At time of DBL, 199 deaths (of 272 randomized pts) were reported (86% of 231 deaths required for final analysis)
• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
• Stage IIIb/IV SQ
NSCLC
• 1 prior platinum
doublet-based
chemotherapy
• ECOG PS 0–1
• N = 272
Endpoints
• Primary: OS
• Secondary:
• Investigator-assessed ORR
• Investigator-assessed PFS
• Correlation between PD-L1
expression and efficacy
(ORR, OS, PFS),
• Quality of life (LCSS)
NIVO
3 mg/kg IV
Q2W, until PD or
unacceptable toxicity
n = 135
DOC
75 mg/m2 IV
Q3W, until PD or
unacceptable toxicity
n = 137
Ra
nd
om
ize
1:1
DBL, data base lock; ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenous; LCSS = lung cancer symptom scale; PD = progressive disease; PD-L1 =
programmed cell death ligand 1; SQ = squamous; Q2W = every 2 weeks; Q3W = every 3 weeks
Brahamer J et al, NEJM 2015
Reckamp K et al. , WCLC 2015 ORAL 02.01
Checkmate 017: Updated follow-up
Reckamp K et al. , WCLC 2015 ORAL 02.01
Checkmate 017: Updated follow-up
PD-L1 expression
Patients, n Unstratified
HR(95% Cl)
NIVO DOC
OS
1% 63 56 0.69 (0.45, 1.05)
<1% 54 52 0.58 (0.37, 0.92)
5% 42 39 0.53 (0.31, 0.89)
<5% 75 69 0.70 (0.47, 1.02)
10% 36 33 0.50 (0.28, 0.89)
<10% 81 75 0.70 (0.48, 1.01)
Not quantifiable at baseline 18 29 0.39 (0.19, 0.82)
PFS
1% 63 56 0.67 (0.44, 1.01)
<1% 54 52 0.66 (0.43, 1.00)
5% 42 39 0.54 (0.32, 0.90)
<5% 75 69 0.75 (0.52, 1.08)
10% 36 33 0.58 (0.33, 1.02)
<10% 81 75 0.70 (0.49, 0.99)
Not quantifiable at baseline 18 29 0.45 (0.23, 0.89)
OS and PFS Hazard Ratios by PD-L1 Status
0 1 2
NIVO DOC Spigel DR et al, ASCO 2015
Forest plot
PFS
SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello
Is there a room for targeted therapies (WITHOUT target)
in SQUAMOUS carcinoma
Lux Lung 8: Study design
†Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted ‡Dose reduction to 100 or 50 mg permitted
§Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter.
1. American Joint Committee on Cancer staging manual 7th edition
Key secondary Endpoint:
Overall Survival
Other secondary Endpoints: ORR, DCR,
tumor shrinkage, PRO, safety
1:1
Stratified by East Asian vs. Non-East Asian
Afatinib 40 mg† QD
Erlotinib 150 mg‡ QD
SCC of the lung (Stage IIIB/IV)1
Progressed after ≥4 cycles of a first-line platinum doublet
ECOG PS 0–1
Adequate organ function
Primary Endpoint:
PFS by
Independent Review§
Soria JC et al, ASCO 2015
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LUX LUNG 8: Safety
Goss GD IASLC Geneva 2015; Soria JC et al, ASCO 2015
Afatinib (N=392)
Erlotinib (N=395)
AE category, % All Grade 3 Grade 4 All Grade 3 Grade 4
Total with related AEs 93 25 1 81 16 1 Diarrhea 70 10 1 33 2 <1 Rash/acne* 67 6 0 67 10 0
Stomatitis* 29 4 0 9 0 0
Fatigue* 15 2 0 12 2 0 Nausea 13 1 0 7 1 0 Decreased appetite 13 1 0 10 1 0 Paronychia* 11 1 0 4 <1 0 Dry skin 9 1 0 10 0 0 Pruritus 8 <1 0 12 0 0 Vomiting 8 1 0 3 1 0
Dehydration 4 1 1 1 1 0
Events, % Afatinib (n=392)
Erlotinib (n=395)
Any AE 99.5 97.5
Drug-related AEs 93.4 81.3
AEs leading to dose reduction 26.5 14.2
AEs leading to discontinuations 20.2 17.0
CTCAE grade 3 or higher 57.1 57.4
Serious AEs 44.1 44.1
Drug-related fatal AEs 1.5§ 1.3¶
SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello
Soria JC et al, Lancet Oncol 2015
LUX LUNG 8: Efficacy
PFS
OS
Forest plot
PFS
For Patients and Caregivers
-A 60-page booklet in English, designed as an information guide for patients with SqCLC -The most frequent key questions from a patient with SqCLC
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ADENOCarcinoma (“non-squamous”): rooms for improvements
ADENOCarcinoma
LUME-Lung 1 Study Design
Nintedanib 200mg BID p.o., D2–21,
+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=655)
Placebo BID p.o., D2–21,
+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=659)
N=1314
R
A
N
D
O
M
I
Z
E
Stratification: ECOG PS (0 vs 1)
Prior bevacizumab (yes vs no)
Histology (squamous vs non-
squamous)
Brain metastases (yes vs no)
Stage IIIB/IV
or recurrent
NSCLC patients
after 1st line
chemotherapy
(all histologies)
1:1
PD
PD
Number of docetaxel cycles not restricted
Monotherapy allowed after ≥4 cycles of combination therapy
Primary end point: PFS
Next analysis step only allowed if PFS confirmed
with all PFS events at time point of OS analysis
RECK LBA8011, ASCO 2013
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Reck M et al, Lancet Oncol 2014
LUME1: PFS
TOTAL population
ADENOCARCINOMA
SQUAMOUS CARCINOMA
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Reck M et al, Lancet Oncol 2014
LUME1: OS
Adenocarcinoma <9mo
ADENOCARCINOMA
Total population
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INO
–
DE
PA
RT
ME
NT
OF
ON
CO
LOG
Y
Reck M et al, Lancet Oncol 2014
LUME1: Safety
U
NIV
ER
SIT
Y O
F T
OR
INO
–
DE
PA
RT
ME
NT
OF
ON
CO
LOG
Y
Forest plot
PFS
U
NIV
ER
SIT
Y O
F T
OR
INO
–
DE
PA
RT
ME
NT
OF
ON
CO
LOG
Y
PRETREATED III/IV PS0-1
NIVO 292 PTS
DOC 290 PTS
OS
RR(%) Median (mos) 1-yr (%)
19 12
51
12 9.4 39
NIVOLUMAB NON SQ CHECK-MATE 057
(1)
p= 0.0015 HR 0.73
• Stage IIIB/IV NON-SQUAMOUS
NSCLC
• 1 prior platinum doublet
• ECOG PS 0–1
• Pre-treatment (archival or recent)
tumor samples required for PD-L1
analysis
• Prior maintenance therapy allowed
• Prior TKI therapy allowed for known
ALK translocation or EGFR mutation
N = 582
Nivolumab 3 mg/kg IV Q2W
until PD or unacceptable toxicity
n = 292
Docetaxel 75 mg/m2 IV Q3W
until PD or unacceptable toxicity
n = 290
• Primary Endpoint – OS
• Additional Endpoints – ORRb
– PFSb
– Safety – Efficacy by tumor PD-L1 expression – Quality of life (LCSS)
Patients stratified by prior maintenance therapy
and line of therapy (second- vs third-line)
CheckMate 057: Non Squamous pts
Ran
do
mize 1
:1
Borghaei h et al, NEJM 2015 Sep 27
U
NIV
ER
SIT
Y O
F T
OR
INO
–
DE
PA
RT
ME
NT
OF
ON
CO
LOG
Y
Take Home Messages
• Chemotherapy is still present in second line NSCLC advanced patients
• Antiangiogenic copound found a second youth in second line
• Immunotherapy plays a relevant role in this setting….at least until it will move to first line
• Today even more than yesterday is crucial to design a treatment algorithm for these patients not to waste therapeutic approaches
