Conversatorio con cirugía de tórax sobre NSCLC - 1/3

Tópicos selectos de NSCLC:
Conversatorios con cirugía de tórax
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Medellín, 22/05/2017

Design
• Conference #1
– Selected topics on Early-Stage NSCLC
– Angiogenesis in metastatic NSCLC
• Conference #2
– Selected topics on Locally-advanced NSCLC
– Targeted therapy in metastatic NSCLC
• Conference #3
– Controversies in oligometastatic NSCLC
– Immunotherapy in NSCLC
BREAKING NEWS
INTERDISCIPLINARY MEETINGS ON SYSTEMIC THERAPY FOR NSCLC BEGIN
Cirugía de tórax y oncología 05.2017
Cafetiere de Anita
Medellín
MLM

LUNG CANCER
IASLC: “NEW” TNM CLASSIFICATION FOR LUNG CANCER
Mauricio Lema Medina MD – Hemato-oncólogo 10.2015
ARCHIVE
16th World Conference on Lung Cancer
Denver
8th Edition of the
TNM Classification for
Lung Cancer
MLM

LUNG CANCER
IASLC: “NEW” TNM CLASSIFICATION FOR LUNG CANCER
Mauricio Lema Medina MD – Hemato-oncólogo 10.2015
ARCHIVE
16th World Conference on Lung Cancer
Denver
MLM

T-descriptor
Every cm counts…
Proposed (TNM 8th)
Up to 1 cm: T1a
>1-2 cm: T1b
>2-3 cm: T1c
>3-4 cm: T2a
>4-5 cm: T2b
>5-7 cm: T3
>7 cm: T4
Previous (TNM 7th)
T1a
T1a
T1b
T2a
T2a
T2b
T3
Rami-Porta R, J Thoracic Oncol, 2015
International Association for the Study of Lung Cancer, 2015

T – Primary Tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without evidence
of main bronchus
T1a(mi) Mininally invasive adenocarcinoma
T1a Tumour 1 cm or less in greatest diameter
T1b Tumour more than 1 cm but not more than 2 cm
T1c Tumour more than 2 cm but not more than 3 cm
T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features:
Involves main bronchus (without involving the carina), invades visceral pleura, associated with
atelectasis or obstructive pneumonitis that extends to the hilar region
T2a Tumour more than 3 cm but not more than 4 cm
T2b Tumour more than 4 cm but not more than 5 cm
T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following:
chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s) in the
same lobe as the primary
T4 Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina;
separate tumour nodule(s) in a different ipsilateral lobe to that of the primary

N-descriptor
No changes in the TNM 8th Edition…
Exploratory subgrouping (for future validation)
- N1a: Single N1
- N1b: Multiple N1
- N2a1: Single N2 (skip metastasis)
- N2a2: Single N2 + N1
- N2b: Multiple N2
Asamura H et al. J Thoracic Oncol, 2015, in press

M-descriptor
Eberhardt W et al. J Thoracic Oncol, 2015, in press
• M1a: as it is
• M1b: single metastasis in a single organ
• M1c: multiple metastases in a single organ or
in several organs

N – Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene or supraclavicular lymph node(s)
M – Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastases in one or several organs

STAGE T N M
Occult TX N0 M0
0 Tis N0 M0
IA1 T1a(mi)/T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a-T2b N1 M0
T3 N0 M0
IIIA T1a-T2b N2 M0
T3 N1 M0
T4 N0/N1 M0
IIIB T1a-T2b N3 M0
T3/T4 N2 M0
IIIC T3/T4 N3 M0
IVA Any T Any N M1a/M1b
IVB Any T Any N M1c

STAGE T N M
Occult TX N0 M0
0 Tis N0 M0
IA1 T1a(mi)/T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a-T2b N1 M0
T3 N0 M0
IIIA T1a-T2b N2 M0
T3 N1 M0
T4 N0/N1 M0
IIIB T1a-T2b N3 M0
T3/T4 N2 M0
IIIC T3/T4 N3 M0
IVA Any T Any N M1a/M1b
IVB Any T Any N M1c
NEW

N0 N1 N2 N3 M1
a
M1
b
M1c
T1a IA1 IIB IIIA IIIB IVA IVA IVB
T1b IA2 IIB IIIA IIIB IVA IVA IVB
T1c IA3 IIB IIIA IIIB IVA IVA IVB
T2a IB IIB IIIA IIIB IVA IVA IVB
T2b IIA IIB IIIA IIIB IVA IVA IVB
T3 IIB IIIA IIIB IIIC IVA IVA IVB
T4 IIIA IIIA IIIB IIIC IVA IVA IVB
8th Edition of the TNM Classification
for Lung Cancer

Slideshow created by:
Mauricio Lema Medina (09.2015)
mauriciolema@yahoo.com

ARCHIVE
NEJM: LUNG CANCER SCREENING SAVES LIVES – STUDY SHOWS
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
08.2011
NEJM
NLST
LUNG CANCER
SCREENING
MLM

ARCHIVE
NEJM: LUNG CANCER SCREENING SAVES LIVES – STUDY SHOWS
08.2011
NEJM
NLSTLUNG CANCER
SCREENING
MLM
• ELEGIBILITY
• Eligible participants were between 55 and 74 years of age at the time of randomization,
• Had a history of cigarette smoking of at least 30 pack-years, and,
• If former smokers, had quit within the previous 15 years.
• EXCLUSION
• Persons who had previously received a diagnosis of lung cancer,
• Had undergone chest CT within 18 months before enrollment,
• Had hemoptysis, or
• Had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were
excluded

NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM
High-risk smokers 55-74 yo
(30 ppy, active smokers
within the last 15 years).
No recent CT, weight-loss or
hemoptysis.
Low-dose Chest CT
Every year
For 3 years
Chest X Rays
Every year
For 3 years

NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM

NLST: SCREENING CT SUPERIOR TO CXR FOR NSCLC
ARCHIVE
NEJM
NLST
MLM
Variable Low-dose CT Chest X Ray Comment
Lung cancer (#) 1060 941
Lung cancer incidence, (per
100.000 person-years)
645 572 RR: 1.13 (CI: 1.03-1.23)
Positive screening, then diagnosis 649 279
Negative screening, then diagnosis 44 137
Diagnosis after screening period 367 525

NLST: CT IMPROVES EARLY-STAGE NSCLC DETECTION
ARCHIVE
NEJM
NLST
MLM
Stage Low-dose CT Chest X Ray
Stage I 50% 31.1%
Stage II 7.1% 7.9%
Stage III 20.2% 24.8%
Stage IV 21.7% 36.1%

NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM
Variable Low-dose CT Chest X Ray Comment
Lung cancer deaths (#) 356 443
Lung cancer mortality, (per
100.000 person-years)
247 309 Relative reduction: 20%
(CI: 6.8-26.7%, p=0.004)
NUMBER NEEDED TO SCREEN (TO SAVE ONE LIFE)
320

NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM

MINSALUD
Bogotá
Guía de Práctica Clínica (GPC) para la detección temprana, diagnóstico, estadificación, evaluación pre-quirúrgica y tratamiento de pacientes con
diagnóstico de cáncer de pulmón - http://gpc.minsalud.gov.co/gpc_sites/Repositorio/Conv_563/GPC_c_pulmon/GPC_c_pulmon_profesionales.aspx
MINSALUD (COLOMBIA) RECOMIENDA CRIBADO CON TAC
ARCHIVE
MLM

ARCHIVE
ESMO: ADJUVANT CT SAVES LIVES IN RESECTED STAGES II AND III NSCLC
Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-
small-cell lung cancer consensus on diagnosis, treatment and follow-up. doi:10.1093/annonc/mdu089.
08.2014
Annals of Oncology
ESMO
Adjuvant
chemotherapy for
NSCLC
MLM

NEJM
IALC
Eligible patients had
pathologically documented non–
small-cell lung cancer of stage I,
II, or III (according to the 1986
classification of the American
Joint Committee on Cancer4) and
had undergone a complete
surgical resection.
Adjuvant
Cisplatin-based doublets
(3-4 months)
Control
Group TIALCTC. Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2004;350(4):351-360. doi:10.1056/NEJMoa031644.
IALC: ADJUVANT CHEMOTHERAPY EXPLORED IN STUDY
ARCHIVE
MLM
Other inclusion criteria were an age between 18 and 75 years and
the absence of previous chemotherapy or radiotherapy,
contraindications to chemotherapy, and previous cancer other
than nonmelanoma skin cancer or carcinoma in situ of the cervix.

NEJM
IALC
Group TIALCTC. Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2004;350(4):351-360. doi:10.1056/NEJMoa031644.
IALC: CHEMOTHERAPY REDUCES LUNG CANCER MORTALITY BY 14%
ARCHIVE
MLM
Total study population: 1867

NEJM
JBR.10
Patients 18 years of age or older
with completely resected T2N0,
T1N1, or T2N1 non–small-cell
lung cancer with acceptable
baseline characteristics and an
ECOG performance status of 0 or
1 were eligible
Adjuvant
Cisplatin-Vinorelbin
(16 weeks)
Control
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2005;352(25):2589-2597. doi:10.1056/NEJMoa043623.
JBR.10: ADJUVANT CHEMOTHERAPY EXPLORED IN STUDY
ARCHIVE
MLM
Patients with clinically significant cardiac dysfunction, active
infection, or neurologic or psychiatric disorders were also
ineligible.
Cisplatin 50 mg/m2 d1 and d8
Vinorelbine 25 mg/m2 qw x16

NEJM
JBR.10
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2005;352(25):2589-2597. doi:10.1056/NEJMoa043623.
JBR.10: 15% ABSOLUTE INCREASE IN SURVIVAL WITH CT
ARCHIVE
MLM

NEJM
ANITA
Patients were eligible if they had
stage I (T2N0 only), stage II, and stage
IIIA NSCLC according to the 1986
TNM classification;
Complete resection of the primary
tumour (all margins free of disease:
R0);
Age 18–75 years;
WHO performance status 2 or less;
And adequate biological functions
Adjuvant
Cisplatin-Vinorelbin
(16 weeks)
Control
Douillard J-Y, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-
small-cell lung cancer ANITA: a randomised controlled trial. Lancet Oncol. 2006;7(9):719-727. doi:10.1016/S1470-2045(06)70804-X.
ANITA: ADJUVANT CHEMOTHERAPY EXPLORED IN STUDY
ARCHIVE
MLM
Cisplatin 100 mg/m2 on days 1, 29, 57 and 85
Vinorelbine 30 mg/m2 qw x16

NEJM
ANITA
Douillard J-Y, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-
small-cell lung cancer ANITA: a randomised controlled trial. Lancet Oncol. 2006;7(9):719-727. doi:10.1016/S1470-2045(06)70804-X.
ANITA: ALMOST 3% ABSOLUTE REDUCTION IN MORTALITY WITH
ADJUVANT CHEMOTHERAPY
ARCHIVE
MLM
Total patient population: 840

JCO
LACE
Pignon J-P, Tribodet H, Scagliotti G V., et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol.
2008;26(21):3552-3559. doi:10.1200/JCO.2007.13.9030.
LACE: Adjuvant cisplatin-based chemotherapy should not be
withheld from elderly patients with NSCLC purely on the basis of age.
ARCHIVE
MLM
“No statistically
significant interaction
(P.26) or test for trend (P
.29) between age and
treatment effect for OS
was observed”.

ARCHIVE
08.2014
Annals of Oncology
ESMO
MLM
• Adjuvant chemotherapy should be offered to patients with resected
stage II and III NSCLC [I, A] and can be considered in patients with
resected stage IB disease and a primary tumour >4 cm [II, B]. Pre-
existing comorbidity, time from surgery and postoperative recovery
need to be taken into account in this decision taken in a
multidisciplinary tumour board [V, A].
• For adjuvant chemotherapy, a two-drug combination with cisplatin is
preferable [I, A]. In randomised studies, the attempted cumulative
cisplatin dose was up to 300 mg/m², delivered in three to four cycles.
The most frequently studied regimen is cisplatin–vinorelbine.
• In the current state of knowledge, the choice of adjuvant therapy
should not be guided by molecular analyses such as, e.g. ERCC1 or
mutation testing [IV, B].

Cancer
Canada
Booth, C. M., Shepherd, F. A., Peng, Y., Darling, G., Li, G., Kong, W., … Mackillop, W. J. (2013). Time to adjuvant chemotherapy and survival in non-small
cell lung cancer. Cancer, 119(6), 1243–1250. https://doi.org/10.1002/cncr.27823
TIME TO CHEMOTHERAPY LESS IMPORTANT THAN EXPECTED
ARCHIVE
MLM
1032 patients with NSCLC

ARCHIVE
ESMO: ADJUVANT RT ONLY INDICATED AFTER R1 RESECTION OF NSCLC
08.2014
Annals of Oncology
ESMO
MLM
• Postoperative radiotherapy in completely resected early-stage
NSCLC is not recommended [I, A].
• In case of R1 resection (positive resection margin, chest wall),
postoperative radiotherapy should be considered [IV, B].
• Even if such patients were not included in RCTs, adjuvant
chemotherapy should be given to R1 resection regardless of
nodal status [V, A].
• In case chemotherapy and radiotherapy are administered,
radiotherapy should be administered after chemotherapy [V, C].

ARCHIVE
ESMO: POST-RX SURVEILLANCE IS A MATTER OR OPINION, NOT SCIENCE
08.2014
Annals of Oncology
ESMO
Post-treatment
Surveillance for
NSCLC
MLM

ARCHIVE
ESMO: 6-7% RELAPSE EVERY YEAR FOR THE FIRST 4 YEARS…
08.2014
Annals of Oncology
ESMO
MLM
• Surveillance every 6 months for 2–3 years
with a visit including history, physical
examination and—preferably contrast
enhanced—spiral chest CT at 12 and 24
months is recommended, and thereafter an
annual visit including history, physical
examination and chest CT in order to detect
second primary tumours [III, B].

ARCHIVE
Lou F, Huang J, Sima CS, Dycoco J, Rusch V, Bach PB. Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with
routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013;145(1):75-82. doi:10.1016/j.jtcvs.2012.09.030. 01.2013
J Thorac Cardiovasc Surg
Lou, F
MLM

Surveillance after Early-Stage NSCLC
Year 1
H&P q6mo
Chest CT
Year 2
H&P q6mo
Chest CT
Year 3 and subsequent
Yearly H&P and Chest CT
(Risk of 2nd primary)
ARCHIVE
08.2014
MLM

BREAKING NEWS
Cafetiere de Anita
Medellín
MLM
Angiogenesis in
advanced NSCLC

Lung carcinoma
Non Small-Cell Lung
Cancer (NSCLC)
Small-Cell Lung Cancer
(SCLC)
NSCLC with a “Driver”
NSCLC without a
“Driver”
10%
15% 75%
NSCLC (without a
“driver”)
Squamous-Cell
25%
NSCLC (with a “driver”)
Non-squamous
50%
90%
EGFR: 10%
ALK/EML4: 4%
ROS1: 1%
Mostly Adenocarcimoma
Adenocarcinoma
Squamous
Large-Cell
Lepidic

El Sr. B es un hombre blanco de 69 años de edad, que
actualmente fuma 2 paquetes de cigarrillos a la semana.
Presentó a su médico con una historia de 6 meses de tos
persistente, dificultad para respirar, y, en la última semana,
hemoptisis. Una radiografía de tórax mostró la presencia de
múltiples lesiones en ambos pulmones por lo que se refiere a
un oncólogo. Después de la elaboración adicional, se le
diagnosticó un adenocarcinoma en estadio IV. Las pruebas
moleculares revelaron EGFR de tipo salvaje y ALK y un bajo
nivel de expresión de PD-L1 (1% de las células). Su estado de
desempeño ECOG es 1, y tiene comorbilidades incluyendo la
enfermedad a largo plazo leve pulmonar obstructiva crónica y
disfunción hepática.

ANGIOGENIC THERAPY IS A CONTENTIOUS ISSUE IN NSCLC
Cafetiere de Anita
Medellín
MLM

A world without
anti-angiogenics

Outcomes With First-Line Doublet Therapy:
ECOG 1594
7.8
8.1
7.4
8.1
3.4
4.2
3.7
3.1
0 1 2 3 4 5 6 7 8 9 10
Cisplatin + paclitaxel
Cisplatin + gemcitabine
Cisplatin + docetaxel
Carboplatin + paclitaxel
Chart Title
PFS OS
(N = 288)
(N = 288)
(N = 289)
(N = 290)
Schiller JH, et al. New Engl J Med. 2002;346:92-98.
Months
OS = overall survival; PFS = progression-free survival

Cisplatin + Pemetrexed (C/P) vs Cisplatin + Gemcitabine (C/G)
in Advanced NSCLC: OS by Histology
Survival Time (Mos) in All Patients
With Squamous Histology
SurvivalProbability
SquamousNonsquamous
Survival Time (Mos) in Patients
With Nonsquamous Histology
SurvivalProbability
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
C/P
C/G
C/P vs C/G
Median Survival
11.8 mos
10.4 mos
Adjusted HR: 0.81
(95% CI: 0.70-0.94)
C/P
C/G
C/P vs C/G
Median Survival
9.4 mos
10.8 mos
Adjusted HR: 1.23
(95% CI: 1.00-1.51)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
300 6 12 18 24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
300 6 12 18 24

Revised approach to NSCLC
treatment
Diagnosis Tumour
response or
stable
disease
1st-line Tx
Pt Doublet
(4–6 cycles)
Maintenance
treatment
PD
2nd-line Tx
to PD
Death
• Patients with non-PD receive maintenance therapy
– deferring disease progression
– deferring symptom deterioration
– deferring death

JMEN: Maintenance Therapy with
Pemetrexed - Study Design
 Stage IIIB/IV NSCLC
 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 to
induction
 non-platinum induction drug
 brain mets
Pemetrexed 500 mg/m2
(d1,q21d) + BSC (N=441)*
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC
(N=222)*
*B12, folate, and dexamethasone given in both arms
2:1
Randomization
Ciuleanu et al, The Lancet 2009
Time-to-event endpoints measured from time of randomization into the maintenance phase

Pemetrexed 9.9 mos
Placebo 10.8 mos
Squamous (n=182)
HR=1.07 (95% CI: 0.77–1.50)
p=0.678
Time (months)
Non-squamous (n=481)
Pemetrexed 15.5 mo
Placebo 10.3 mo
HR=0.70 (95% CI: 0.56-0.88)
p=0.002
SurvivalProbability
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SurvivalProbability
Maintenance Therapy with Pemetrexed
Overall Survival by Histology
Ciuleanu et al, The Lancet, 2009

PARAMOUNT: Study Design
Induction Therapy
4 cycles, q21d
Continuation Maintenance Therapy
q21d until PD
Pemetrexed +
BSC
Placebo +
BSC
Pemetrexed
+ Cisplatin
CR/PR/SD
per
RECIST
R
2:1
Stratified for:
• PS (0 vs 1)
• Disease stage (IIIB vs IV) prior to induction
• Response to induction (CR/PR vs SD)
 Randomized, placebo-controlled, double-blind phase III study
 Pemetrexed 500 mg/m2; Cisplatin 75 mg/m2
 Folic acid and vitamin B12 administered to both arms
• Previously
untreated
• PS 0/1
• Stage IIIB-IV
NS-NSCLC

PARAMOUNT: Final OS from Randomization
Patients at Risk
Pem + BSC 359 333 272 235 200 166 138 105 79
43 15 2 0
Placebo + BSC 180 169 131 103 78 65 49 35
Time from Randomization (Months)
0 3 6 9 12 15 18 21 24 27 30 33 36
SurvivalProbability
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)
Log-rank P = 0.0195
Unadjusted HR: 0.78 (95% CI: 0.64–0.96)
1-year 58 (53-63) 45 (38-53)
2-year 32 (27-37) 21 (15-28)

Maintenance treatment - SATURN
1:1
Chemonaïve
advanced
NSCLC
n=1,949
Non-PD
n=889
4 cycles of first-
line platinum
doublet
chemotherapy*
Placebo PD
Erlotinib
150mg/day
PD
Mandatory tumour
sampling
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
Co-primary endpoints:
• PFS in all patients
• PFS in patients with EGFR IHC+ tumours
Secondary endpoints:
• OS in all patients and those with EGFR IHC+
tumours, OS and PFS in EGFR IHC–
tumours; biomarker analyses; safety; time to
symptom progression; QoL
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel
cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel
carboplatin/paclitaxel

El Sr. B se trató con cisplatino más pemetrexed
como terapia inicial, seguida de 4 ciclos de
pemetrexed de mantenimiento, y consigue
enfermedad estable como su mejor respuesta. Sin
embargo, dentro de los 6 meses, su enfermedad
progresaba con múltiples metástasis a hígado,
columna vertebral y las costillas. Sobre la base de la
evidencia disponible en la actualidad, el
tratamiento con un inhibidor de puesto de control
inmunológico es una opción, pero esto puede no
ser la mejor opción para el Sr. B, dado el bajo nivel
de PD-L1 detectado en su muestra de biopsia.

Study Treatment Arms
Median OS
(mos) 1-Year Survival
TAX 317[a]
Docetaxel (N = 103) 7.0 37.0%
Best supportive care (N = 100) 4.6 12.0%
Hanna et al. 2004[b]
Pemetrexed (N = 283) 8.3 29.7%
Docetaxel (N = 288) 7.9 29.7%
INTEREST[c]
Gefitinib (N = 723) 7.6 32.0%
Docetaxel (N = 710) 8.0 34.0%
TITAN[d]
Erlotinib (N = 203) 5.3 26.0%
Chemotherapy (N = 221: 116
docetaxel, 105 pemetrexed)
5.5 24.0%
Second-Line Therapy: Options & Outcomes
a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
c. Kim ES, et al. Lancet. 2008;372:1809-1818.
d. Ciuleanu T, et al. Lancet Oncol. 2012;13:300-308.

Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]
40.2%
Adverse Event
PercentReporting
Second-Line Therapy: Grade 3/4 Toxicities
a. Vamvakas L, et al. ASCO 2010.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

BR.21: trial design
 Primary endpoint = OS
 Secondary endpoints = progression-free survival (PFS), response rate
and duration of response, safety, quality of life
Phase III trial
Advanced
stage IIIB/IV
NSCLC
n=731
Tarceva
150mg daily
(n=488)
Placebo
(n=243)
R
A
N
D
O
M
I
S
E
2
1
Shepherd F, et al. N Engl J Med 2005;353:123–32

Erlotinib significantly
prolongs survival in
relapsed advanced
NSCLC
2004
Shepherd, et al. N Engl J Med 2005
0 5 10 15 20 25 30
HR=0.73, p<0.001
Survivaldistributionfunction
1.00
0.75
0.50
0.25
0
Erlotinib
Placebo
Survival time (months)
“Second” - line therapy BR.21

ARCHIVE
08.2014
Annals of Oncology
ESMO
MLM
En resumen
• Sin angiogénicos (ni inmunológicos), el
manejo óptimo del Sr. B sería:
– Dupleta Platino + Pem
– Mantenimiento con Pem
– Segunda línea con Docetaxel
– Tercera línea con Erlotinib

A world with
antiangiogenic
agents

Empecemos de nuevo…
El Sr. B es un hombre blanco de 69 años de
edad, que actualmente fuma 2 paquetes de
cigarrillos a la semana. Presentó a su médico con
una historia de 6 meses de tos persistente,
dificultad para respirar, y, en la última semana,
hemoptisis…

ECOG 4599: Phase III Trial of
Bevacizumab in Nonsquamous NSCLC
Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
Stratified by RT vs no RT, stage IIIB or IV vs recurrent,
weight loss < 5% vs ≥ 5%, measurable vs nonmeasurable
Treatment-naive patients
with confirmed stage IIIB
or IV cancer; adequate
hematologic, hepatic, and
renal function
(N = 878)
PC
Paclitaxel 200 mg/m2
Carboplatin AUC = 6 mg/mL/min
(once every 3 weeks) x 6 cycles
(n = 433*)
PCB
PC (once every 3 weeks) x 6 cycles +
Bevacizumab 15 mg/kg (once every
3 weeks) until disease progression
(n = 417*)
*Eligible patients included in analysis.

Phase III trials: key entry criteria
Who was treated
• First-line locally advanced,
metastatic, or recurrent NSCLC
• ECOG PS 0 or 1
• Measurable or
nonmeasurable disease
• Centrally located tumors
• Histology not otherwise specified
• Patients receiving ≤325mg aspirin
daily
Who was not treated
• Patients with predominant
squamous histology
• CNS metastases
• Gross hemoptysis (≥0.5 tsp
of red blood) added with Protocol
Amendment 1
• Unstable angina
• Patients receiving therapeutic
anticoagulation
ECOG PS = Eastern Cooperative Oncology Group
performance status
Radiological evidence of tumor
invading or abutting major blood
vessels

Outcomes With First-Line Triplet Therapy:
ECOG 4599
Sandler A, et al. New Engl J Med. 2006;355:2542-2550.
Months
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio

Survival beyond historical benchmark of 12 months
Sandler, et al. NEJM 2006
E4599 overall patient population
Time (months)
OSestimate
0 6 12 18 24 30 36 42
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
CP
(n=444)
Bev 15mg/kg + CP
(n=434)
HR
(95% CI)
p value
0.79
(0.67–0.92)
0.003
Median OS
(months) 10.3 12.3
10.3 12.3
Benefit of 3.9 months OS in adenocarcinoma: pre-planned subgroup analysis
31% reduction in risk of death
E4599 adenocarcinoma patient population
CP
(n=302)
Bev 15mg/kg + CP
(n=300)
HR
(95% CI)
0.69
(0.58–0.83)
Median OS
(months) 10.3 14.2
Sandler, et al. JTO 2010 [in press]
10.3 14.2
Bevacizumab was administered
until disease progression (PD)
1-year survival
51% vs 44%
2-year survival
23% vs 15%

*The analysis corrected for the patients in AVAiL (7%) who received
antineoplastic therapy before documented disease progression
Significant and consistent PFS
benefit in two phase III trials
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time (months)
0 6 12 18 24 30
Probability
Bev 15mg/kg + CP
CP
E45991
6.2 vs 4.5 months
HR=0.66; p<0.001
Bevacizumab 15mg/kg
AVAiL2
Time (months)
0 6 12 18 24 30
Placebo + CG
Bev 7.5mg/kg + CG
Bev 15mg/kg + CG
6.7 vs 6.1 months
HR=0.75; p=0.003
Bevacizumab 7.5mg/kg
6.5 vs 6.1 months
HR=0.82; p=0.03
Bevacizumab 15mg/kg
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median PFS
1. Sandler, et al. NEJM 2006; 2. Reck, et al. JCO 2009
3. Sandler, et al. ECCO 2007
HR=0.68; p<0.0001 HR=0.74; p=0.0021
Pre-planned analysis* applying the
same censoring rules to both trials3

 Primary objective: PFS without grade 4 AE
 Composite endpoint considers the first occurrence of either:
– Grade 4 AE (lower grade AEs are not considered) or disease progression or death (PFS)
PRONOUNCE: Phase III Superiority Trial of
Pem/Carbo → Pem vs Pac/Carbo → Bev
Induction (q21d, 4 cycles) Maintenance (q21d until PD)
Pemetrexed
(folic acid & vitamin B12)
+ Carboplatin
Paclitaxel
+ Carboplatin
+ Bevacizumab
R
1:1
Pemetrexed
(folic acid & vitamin B12)
Bevacizumab
180 patients each
Bev-Eligible Population
Inclusion:
 Chemo-naive patients
 PS 0/1
 Stage IV, nonsquamous
 Stable treated CNS mets
Exclusion:
 Uncontrolled effusions
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.

PRONOUNCE: Primary Endpoint
(G4PFS)
Pem + Cb, median G4PFS: 3.9 mos
Pac + Cb + Bev, median G4PFS: 2.9 mos
Log-rank P = 0.176
HR: 0.85 (95% CI: 0.70-1.04)
Pts at Risk, n
Pem + Cb
Pac + Cb +
Bev
0 3 6 9 12 15 18 21 24 27
0
20
40
60
80
100
Mos
Pts(%)
182
179
87
75
44
33
26
17
14
9
7
3
5
0
3
0
1
0
0
0

PRONOUNCE: OS (ITT)
Pem + Cb, median OS: 10.5 mos
Pac + Cb + Bev, median OS: 11.7 mos
HR: 1.07 (95% CI: 0.83-1.36;
log-rank P = .615)
Pts at Risk, n
Pem + Cb
Pac + Cb +
Bev
0 3 6 9 12 15 18 21 24 42
0
20
40
60
80
100
Mos
Patients,%
182
179
156
151
125
121
102
96
72
73
48
59
33
38
5
0
5
0
5
0
Pem + Cb,
%
(n = 182)
Pac + Cb + Bev,
%
(n = 179)
1 yr 43.7 48.8
2 yrs 18.0 17.6
27 30 33 36 39
20
28
11
10
11
3
5
1
5
1

Possibly Drug-Related Grade 3/4
CTCAE
Event Pem + Cb, %
(n = 171)
Pac + Cb +
Bev, %
(n = 166)
P Value
Anemia 19 5 < .001
Thrombocytopenia 24 10 < .001
Neutropenia 25 49 < .001
Febrile neutropenia 0 2 .118
Hypertension 0 2 .058
Thrombosis/embolism 0 2 .058
Any hemorrhagic events 1 0 .499

Summary
• Study failed to establish that first-line
pemetrexed/ carboplatin superior to
paclitaxel/carboplatin/bevacizumab for PFS
without grade 4 AEs
• PFS, OS, and ORR similar between arms
• AE profiles of each arm differed, but both
tolerable
– Pem + Cb arm with more anemia and
thrombocytopenia
– Pac + Cb + Bev arm with more neutropenia
• No unexpected AEs in either arm
Zinner R, et al. ASCO 2013. Abstract LBA8003.

BREAKING NEWS
Cafetiere de Anita
Medellín
MLM
Bevacizumab + Pemetrexed

79
AVAPERL: Patient
disposition
a RECIST-related end points measured from the preinduction phase.
b Intent-to-treat population
First-line
induction with
Bev-cis-pem
(n=376)
Arm A:
Bevacizumab
(n= 125)
CR/PR/SD by
RECIST
PD
Not eligible for
randomization
(n=123)
Patients randomized
to maintenancea
(n=253)b
Patients
screened
(n=414)
Arm B:
bevacizumab +
pemetrexed
(n=128)
5 patients not treated
3 patients not treated
123 patients not randomized
• 50 discontinued due to AEs
• 49 discontinued due to PD
• 9 patients died
• 7 withdrew consent
• 5 discontinued for other reasons
• 3 did not start treatment
Median follow-up time for this
analysis: 11 months

80
AVAPERL: Patient characteristics:
maintenance population
Bevacizumab
(n=125)
Bevacizumab + pemetrexed
(n=128)
Median age, y
<65 y, no. (%)
60
88 (70)
60
88 (69)
Male, no. (%) 70 (56) 74(58)
ECOG PS, no. (%)
0
1
52 (43)
67 (55)
66 (52)
59 (46)
Current stage IV, no. (%) 110 (88) 121 (94)
Histology, no. (%)
Adenocarcinoma
Large cell
Other
115 (92)
9 (7)
1 (1)
110 (86)
12 (9)
6 (5)
Smoking status, no. (%)
Current smoker
Past smoker
Never smoker
31 (25)
60 (48)
33 (27)
30 (23)
67 (52)
31 (24)

81
AVAPERL: PFS from inductiona
Bev+pem 10.2 months (81 events)
Bev 6.6 months (104 events)
HR, 0.50 (0.37–0.69); P <.001
Progression-freesurvival(%)
Time (months)
128 126 103 66 25 4 0
125 122 73 38 12 2 0
100
75
50
25
0
0 3 6 9 12 15 18
Pts at risk Bev+pem
Bev
Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients.
a Randomized pts, Intent-to-treat population
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)

82
AVAPERL: PFS from randomizationa
Bev+pem 7.4 months (81 events)
HR, 0.48 (0.35–0.66); P <.001
Progression-freesurvival
fromdateofrandomization(%)
Time (months)
128 104 67 25 4 0
125 73 36 13 2 0
100
75
50
25
0
0 3 6 9 12 15
Pts at risk Bev+pem
Bev
a Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm)
bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients.

83
AVAPERL: OS from inductiona
Overallsurvival(%ofpatients)
100
75
50
25
0
0 3 6 9 12 15 18 21
128 127 120 103 56 20 3 0
125 123 110 96 45 17 2 0
Time (months)
Bev+pem NR (34 events)
HR: 0.75 (0.47–1.20); P=0.23
Pts at risk Bev+pem
Bev
Median follow-up time: 11 months (8 months, excluding induction).
30% of events at the time of analysis for overall survival.
bev, bevacizumab; HR, hazard ratio; NR, not reached; pem, pemetrexed; pts, patients.
a Randomized pts, Intent-to-treat population

Phase III First-Line Pem/Carbo/
Bevacizumab in Advanced Non-Sq NSCLC
POINT-BREAK

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)
SurvivalProbability
PointBreak: KM OS
from Randomization (ITT)
Pem+Cb+Bev Pac+Cb+Bev
OS median (mo) 12.6 13.4
HR (95% CI); P value 1.0 (0.86, 1.16); P=0.949
Censoring (%) 27.8 27.2
Survival rate (%)
1-year 52.7 54.1
2-year 24.4 21.2

0 3 6 9 12 15 18 21 24 27 30 33 36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SurvivalProbability
PointBreak: Kaplan-Meier (KM) PFS
from Randomization (ITT)
Pem+Cb+Bev Pac+Cb+Bev
PFS median (mo) 6.0 5.6
HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012
G4 PFS median (mo) 4.3 3.0
HR (95% CI); P value 0.74 (0.64, 0.86) P<.001
TTPD (mo) 7.0 6.0
HR (95% CI); P value 0.79 (0.67, 0.94); P=0.006
ORR (%) 34.1 33.0
Censoring rate for Pem+Cb+Bev was 26.9; for Pac+Cb+Bev was 23.3

0 3 6 9 12 15 18 21 24 27 30 33 36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SurvivalProbability
PointBreak: Prespecified Analysis of KM PFS from
Randomization for the Maint. Population
Pem+Cb+Bev
(n=292)
Pac+Cb+Bev
(n=298)
PFS median (mo) 8.6 6.9
Censoring (%) 24.7 14.1
Prespecified exploratory non-comparative subgroup analyses
Pem-Bev
Bev

Paclitaxel +
Carboplatino +
Bevacizumab
Bevacizumab
Pemetrexed +
Platino +
Bevacizumab
Bevacizumab
+/- Pemetrexed
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Bevacizumab
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Nintedanib
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Ramucirumab
Integración de terapia antiangiogénica en
mNSCLC no escamoso

Paclitaxel +
Carboplatino +
Bevacizumab
Bevacizumab
Pemetrexed +
Platino +
Bevacizumab
Bevacizumab
+/- Pemetrexed
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Bevacizumab
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Nintedanib
Pemetrexed +
Platino
Pemetrexed
Docetaxel +
Ramucirumab
Integración de terapia antiangiogénica en
mNSCLC no escamoso
ECOG 4599
AVaPERL
POINTBREAK
LUME-LUX1
REVEL
ULTIMATE

BREAKING NEWS
Cafetiere de Anita
Medellín
MLM
Conclusion
Angiogenic therapy helps many
patients with NSCLC

“Una conferencia consiste en
un combate cuerpo a cuerpo
con los minutos”
José Ortega y Gasset, Vives, 1940
Gracias, mauriciolema@yahoo.com

Conversatorio con cirugía de tórax sobre NSCLC - 1/3

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