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Tratamientos locorregionales
en el NSCLC
Tratamiento combinado QT/RT
B.Massutí
Hospital General Universitario Alicante

HO...
Agenda
•
•
•
•

Situación actual y resultados terapéuticos
Cuestiones abiertas
Presentaciones en WCLC 2013
Perspectivas de...
7th IASLC Staging System
T and M

N0

N1

N2

N3

UICC6 and descriptor

New
T/M

Stg

Stg

Stg

Stg

T1 (2 cm)

T1a

IA

...
7th IASLC Staging System
T and M

N0

N1

N2

N3

UICC6 and descriptor

New
T/M

Stg

Stg

Stg

Stg

T1 (2 cm)

T1a

IA

...
7th IASLC TNM Staging System:
Survival according to N status and single/multiple nodal zones
NSCLC stages at presentation and
treatment outcomes
STAGE
I

60 – 70%

II

40 – 55%

IIIA

10 – 25%

IIIB

5%

IV

30%

St...
Evolución de los resultados
terapéuticos tto QT/RT
• Medianas sup EC aleatorizados:
– 80´s:
– 90´s:
– 2000´s:
– 2010´s:

9...
Metanálisis QT-RT secuencial vs concomitante /
JCO 2010;38:2181-2190
Rowell N; O’Rourke N
Cochrane Database Syst Rev 2004
RT vs QTRT (R.R)

QTRTvs QTRT (R.R)

Risk of death (2a)

0.93

Risk ...
Tratamientos combinación: selección
pacientes
Bajo riesgo

Riesgo intermedio

Alto riesgo

PS 0-1
No comorbilidades
Edad <...
Pacientes elegibles para tto QT/RT concomitante
 Registro población de Maastricht (853.553 habitantes)
 711 pacientes Es...
Cuestiones abiertas
• Secuencia QT/RT:
– QT Inducción
– QT Consolidación

• Esquemas QT concomitante:
– Dosis plenas
– Dos...
RTOG 0617: Phase III Trial of 74 Gy vs 60
Gy RT in Unresectable Stage III NSCLC
Stratified by RT technique,
Zubrod status,...
RTOG 0617: Survival
Efficacy Outcome

Standard-Dose RT
(n = 213)

High-Dose RT
(n = 206)

HR
(95% CI)

Median OS, mos

28....
RTOG 0617: Safety
• Grade 3 esophagitis occurred significantly more often with highdose vs standard-dose RT (20.9% vs 7.0%...
Resultados
• HR PFS 0.96 (0.77-1.19)
• HR OS 0.99 (0.78-1.27)
Summary
• High-dose RT (74 Gy) associated with
higher risk of death, locoregional
recurrence, and incidence of fatal AEs v...
WCLC 2013:
RTOG 0716: Cetuximab analysis
- Compare the overall survival of patients
treated with concurrent chemo-radiothe...
Toxicidades comparativas
Toxicidades

Cetuximab (237 p)
Grado 3

No-Hematol.

130
(54.9%)

Conjunto
Maxima
toxicidad

No C...
Overall survival
Tecemotide (L-BLP25):
Novel Lipopeptide Cancer Vaccine
MUC1 mucin

GSTAPPAHGVTSAPDTRPAP

S T A P P A H G V T S A P D T R P...
START: Study Design
Randomized 2:1; stratified by disease
stage, response
to chemoradiotherapy, concurrent vs
sequential c...
START: Overall Survival
100

L-BLP25
(n = 829)
25.6

90
Median OS, mos

70
Survival (%)

80

Adjusted HR

60

Placebo
(n =...
START: OS Analyses by
Randomization Strata
Median OS, Mos
L-BLP25 vs Placebo

27.6 vs 23.1

0.86 (0.67-1.11)

23.7 vs 20.9...
START: OS in Patients With
Concurrent Chemo/RT
100

L-BLP25
(n = 538)
30.8

90
Median OS, mos

70
Survival (%)

80

HR

Pl...
START: Safety
AE, %

Tecemotide
(n = 1024)

Placebo
(n = 477)

100

Most frequent AEs
(> 10% in tecemotide arm)

91.6 90.6...
Summary
• Study did not meet primary endpoint of
significant improvement in OS with use of
tecemotide maintenance
• Prespe...
#2658: Interim analysis of the Spanish Lung Cancer Group (SLCG)
randomized phase II trial of thoracic radiotherapy (RT) co...
STUDY DESIGN
Multicentric randomized phase II trial
Patients with non-resectable stage IIIA – IIIB NSCLC
PS ECOG 0-1, Age ...
PATIENT CHARACTERISTICS
ARM A
OVNR + CDDP

ARM B
E + CDDP

N=34

N=34

64 (45-75)

60 (43-71)

Gender, %: Male
Female

91....
RESPONSE RATE
ARM A

ARM B

OVNR + CDDP

E + CDDP

N=22

N=24

CR

4.5 %

4.2 %

PR

63.7 %

50 %

OR (CR + PR)

68.2 %

5...
TOXICITY Grade ¾
HEMATOLOGICAL
TOXICITIES

ARM A

ARM B
E + CDDP
N = 56 cy

NONHEMATOLOGICAL
TOXICITIES

ARM A

ARM B

Neu...
Safety Data from a Phase II Study of Pemetrexed (PEM) and Cisplatin
(CIS) with Concurrent Thoracic Radiation after PEM+CIS...
Background
• Concurrent chemo- and radiotherapy (CT+RT) is standard of care
for most patients with locally advanced unrese...
Objectives
• Primary objective: To assess the antitumor activity of
PEM+CIS as induction, followed by PEM+CIS with concurr...
Study Design
Treatment Period
Induction CT (2 cycles)

Concurrent CT (2 cycles) + RT

Patients enrolled if:
• Non-squamous...
Summary of CT and RT Exposure
Cycles received, n (%)

All patients (N = 90)

Completed 2 cycles of induction CT

85 (94.4)...
Progression free survival
PFS Probability

1.0
0.8
0.6
0.4
0.2
0.0
0

6

12

18

Time (months)

24

30
Proximity of Disease Progression to
Radiation Field
All patients (N = 90)
n (%)
With documented disease progression

53 (5...
Tumor Response (RECIST 1.0)
All patients (N = 90)
Best overall response
n (%)
Complete response (CR)
Partial response (PR)...
Safety Data – Overview
All patients (N = 90)
n (%) with event
Any treatment-emergent adverse event (TEAE)
Grade 3/4 TEAEs
...
Grade 3/4 Toxicities (CTCAE)
Number (%) of patients with G3/4 CTCAEs
During Induction
CT
N = 90

During conc. CT+RT
N = 75...
Conclusions
In this study of PEM+CIS induction, followed by concurrent full-dose
PEM+CIS plus RT in patients with locally ...
Comentarios a futuro:
¿Denver 2015?
• Es necesario realizar estudios en subgrupos
específicos de los estadios IIIA-IIIB
• ...
Albert Camus (1913-1960)
• Adquirimos la costumbre de vivir antes que la
de pensar". (El mito de Sísifo).
• “Lo que más di...
bmassutis@seom.org
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón
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09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón

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Autor/a Dr. Bartomeu Massutí
V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón.
ARCO MEDITERRANEO. Valencia 8-Nov-2013

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09 Tratamiento combinado de quimio y radioterapia en Cáncer de Pulmón

  1. 1. Tratamientos locorregionales en el NSCLC Tratamiento combinado QT/RT B.Massutí Hospital General Universitario Alicante HOSPITALS DÍLLES BALEARS
  2. 2. Agenda • • • • Situación actual y resultados terapéuticos Cuestiones abiertas Presentaciones en WCLC 2013 Perspectivas de futuros
  3. 3. 7th IASLC Staging System T and M N0 N1 N2 N3 UICC6 and descriptor New T/M Stg Stg Stg Stg T1 (2 cm) T1a IA IIA IIIA IIIB T1 (>2-3 cm) T1b IA IIA IIIA IIIB T2 (5 cm) T2a IB IIA IIIA IIIB T2 (>5-7 cm) T2b IIA IIB IIIA IIIB IIB IIIA IIIA IIIB IIB IIIA IIIA IIIB T4 (same lobe nodules) IIB IIIA IIIA IIIB T4 (extension) IIIA IIIA IIIB IIIB IIIA IIIA IIIB IIIB IV IV IV IV IV IV IV IV IV IV IV IV T2 (>7 cm) T3 invasion M1 (ipsilateral lung) T3 T4 T4 (pleural effusion) M1 (contralateral lung) M1 (distant) M1a M1b
  4. 4. 7th IASLC Staging System T and M N0 N1 N2 N3 UICC6 and descriptor New T/M Stg Stg Stg Stg T1 (2 cm) T1a IA IIA IIIA IIIB T1 (>2-3 cm) T1b IA IIA IIIA IIIB T2 (5 cm) T2a IB IIA IIIA IIIB T2 (>5-7 cm) T2b IIA IIB IIIA IIIB IIB IIIA IIIA IIIB IIB IIIA IIIA IIIB T4 (same lobe nodules) IIB IIIA IIIA IIIB T4 (extension) IIIA IIIA IIIB IIIB IIIA IIIA IIIB IIIB IV IV IV IV IV IV IV IV IV IV IV IV T2 (>7 cm) T3 invasion M1 (ipsilateral lung) T3 T4 T4 (pleural effusion) M1 (contralateral lung) M1 (distant) M1a M1b
  5. 5. 7th IASLC TNM Staging System: Survival according to N status and single/multiple nodal zones
  6. 6. NSCLC stages at presentation and treatment outcomes STAGE I 60 – 70% II 40 – 55% IIIA 10 – 25% IIIB 5% IV 30% Stage I Stage II Stage III Stage IV 5-year SURVIVAL < 1% Approximately 10-15% of newly diagnosed NSCLC p. will be classified as stage IIIA-N2
  7. 7. Evolución de los resultados terapéuticos tto QT/RT • Medianas sup EC aleatorizados: – 80´s: – 90´s: – 2000´s: – 2010´s: 9m 14 m 18 m 20 m
  8. 8. Metanálisis QT-RT secuencial vs concomitante / JCO 2010;38:2181-2190
  9. 9. Rowell N; O’Rourke N Cochrane Database Syst Rev 2004 RT vs QTRT (R.R) QTRTvs QTRT (R.R) Risk of death (2a) 0.93 Risk of death (2a) ↑PFS (LR)2a 0.84 ↑PFS (LR)2a 0.86 0.84 ↑ PFS 0.90 1.13 3.19 3.12 1.58 1.72 1.19 1.15 Absolute risk death 1.60 Neutropenia Acute esophagitis 1.07 6.77 PNeumonitis 0.66 Absolute risk death Anemia Neutropenia Acute esophagitis Late esophagitis Pneumonitis Lung fibrosis
  10. 10. Tratamientos combinación: selección pacientes Bajo riesgo Riesgo intermedio Alto riesgo PS 0-1 No comorbilidades Edad < 70 a PFR buenas V20<35% PS 0-1 Pocas comorbil. Edad < 80 a PFR aceptables 35 < V <45% PS >1 Comorbilidades Cualquier edad PFR afectadas V > 45% RT-QT concomitante QT-RT secuencial Tratamiento paliat.
  11. 11. Pacientes elegibles para tto QT/RT concomitante  Registro población de Maastricht (853.553 habitantes)  711 pacientes Estadio III (81% CPNM, 18% CPCP) (2002-2005).  Características clínicas: ◦ 545 (76.7%) < 75 años ◦ Comorbilidades: 63.1% (> 75 a) versus 47.1% (< 75 a )  Resultados: ◦ En el grupo de edad 60 – 69 a, solamente 50% se considerarían elegibles para tto concomitante ◦ Entre 70 – 74 a, < 50% ◦ 60% de la población ineligible para tto concomitante De Ruysscher D. Ann Oncol 2009
  12. 12. Cuestiones abiertas • Secuencia QT/RT: – QT Inducción – QT Consolidación • Esquemas QT concomitante: – Dosis plenas – Dosis frecuentes • • • • • Dosis RT Integración agentes biológicos Reducción toxicidad Estrategias inmunoterapia Heterogeneidad estadios IIIA-IIIB
  13. 13. RTOG 0617: Phase III Trial of 74 Gy vs 60 Gy RT in Unresectable Stage III NSCLC Stratified by RT technique, Zubrod status, PET staging, histology Consolidation Treatment Standard-Dose RT + concurrent CT* (n = 125) Consolidation CT* High-Dose RT + concurrent CT* (n = 121) Consolidation CT* Standard-Dose RT + concurrent CT* + Cetuximab† (n = 108) Consolidation CT* + Cetuximab† High-Dose RT+ concurrent CT* + Cetuximab† (n = 110) Patients with newly diagnosed, unresectable stage IIIA/IIIB NSCLC (N = 464) Concurrent Treatment Consolidation CT* + Cetuximab† *CT consisted of carboplatin/paclitaxel. †400 mg/m2 loading dose on Day 1, followed by weekly dose of 250 mg/m 2  Primary endpoint: OS Bradley JD, et al. ASCO 2013. Abstract 7501.
  14. 14. RTOG 0617: Survival Efficacy Outcome Standard-Dose RT (n = 213) High-Dose RT (n = 206) HR (95% CI) Median OS, mos 28.7 19.5 1.56 (1.19-2.06) .0007 18-mo PFS, % 36.6 26.3 1.30 (1.04-1.63) .0116 18-mo local failure, % 25.1 34.3 1.37 (0.99-1.89) .0319 18-mo distant failure, % 42.4 47.8 1.15 (0.87-1.51) .1576 Bradley JD, et al. ASCO 2013. Abstract 7501. P Value
  15. 15. RTOG 0617: Safety • Grade 3 esophagitis occurred significantly more often with highdose vs standard-dose RT (20.9% vs 7.0%; P = .0003) Standard-Dose RT (n = 213) High-Dose RT (n = 206)  Grade 3 46.0 46.1  Grade 4 9.9 11.2  Grade 5 0.9 4.9  Grade 3 46.5 41.7  Grade 4 26.8 31.6  Grade 5 0.9 4.9 Adverse Events Definitely, Probably, or Possibly Related to Treatment, % Worst nonhematologic events Worst overall Bradley JD, et al. ASCO 2013. Abstract 7501.
  16. 16. Resultados • HR PFS 0.96 (0.77-1.19) • HR OS 0.99 (0.78-1.27)
  17. 17. Summary • High-dose RT (74 Gy) associated with higher risk of death, locoregional recurrence, and incidence of fatal AEs vs low-dose RT (60 Gy) when administered with concurrent CT in patients with newly diagnosed, unresectable stage III NSCLC • Analysis of the addition of cetuximab to high- and low-dose RT with concurrent CT is ongoing Bradley JD, et al. ASCO 2013. Abstract 7501.
  18. 18. WCLC 2013: RTOG 0716: Cetuximab analysis - Compare the overall survival of patients treated with concurrent chemo-radiotherapy plus cetuximab versus chemo-radiotherapy alone
  19. 19. Toxicidades comparativas Toxicidades Cetuximab (237 p) Grado 3 No-Hematol. 130 (54.9%) Conjunto Maxima toxicidad No Cetuximab (227 p) Grado 4 Grado 5 26 (11%) 11 (4.6%) Grado 3 91 (40.1%) 167 (70.5%) 117 (49.4%) Conjunto P> 0.0001 74 (31.2%) 202 (85.2%) Grado 4 Grado 5 18 (7.9%) 6 (2.6%) 115 (50.7%) 11 (4.6%) 93 (41%) 57 (25.1%) 157 (69.2%) 7 (3.1%)
  20. 20. Overall survival
  21. 21. Tecemotide (L-BLP25): Novel Lipopeptide Cancer Vaccine MUC1 mucin GSTAPPAHGVTSAPDTRPAP S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G Antigen = BLP25 lipopeptide The amino acids of the lipopeptide provide antigenic epitopes for T cells Adjuvant = Monophosphoryl lipid A The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation) Structural lipids = cholesterol, DPPC, and DMPG Further enhancement of antigen delivery/uptake into APCs and immune reaction Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
  22. 22. START: Study Design Randomized 2:1; stratified by disease stage, response to chemoradiotherapy, concurrent vs sequential chemoradiotherapy, geographic region Patients with unresectable stage IIIA/B NSCLC without disease progression following chemoradiotherapy (N = 1239) Tecemotide 806 µg SC weekly for 8 wks, then every 6 wks thereafter + Best Supportive Care (n = 829) Treated until PD Placebo + Best Supportive Care (n = 410) 1 dose of cyclophosphamide 300 mg/m2 or saline given 3 days prior to first tecemotide or placebo dose, respectively. Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
  23. 23. START: Overall Survival 100 L-BLP25 (n = 829) 25.6 90 Median OS, mos 70 Survival (%) 80 Adjusted HR 60 Placebo (n = 410) 22.3 0.88 (95% CI: 0.75-1.03; P = .123*) Median follow-up, mos 39.9 37.7 50 40 30 L-BLP25 Placebo 20 10 *2-sided, strata and multiplicity adjusted 0 0 6 12 18 24 30 36 42 48 54 60 66 33 73 18 33 4 8 0 0 Mos Pts at Risk, n Placebo 410 353 285 188 127 108 88 59 L-BLP25 829 757 617 429 301 255 204 128 Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
  24. 24. START: OS Analyses by Randomization Strata Median OS, Mos L-BLP25 vs Placebo 27.6 vs 23.1 0.86 (0.67-1.11) 23.7 vs 20.9 0.90 (0.74-1.09) NA and Aus. (n = 321) 34.1 vs 21.7 0.79 (0.58-1.09) W. Europe (n = 475) 24.2 vs 22.3 0.91 (0.71-1.17) Rest of world (n = 443) Region Stage IIIA (n = 487) Stage IIIB (n = 752) Stage HR* (95% CI) 21.8 vs 22.7 0.95 (0.73-1.22) 20.4 vs 17.8 0.85 (0.65-1.11) 27.8 vs 23.9 0.91 (0.75-1.10) Concurrent (n = 806) 30.8 vs 20.6 0.78 (0.64-0.96) Sequential (n = 433) 19.4 vs 24.6 1.11 (0.86-1.43) Response SD (n = 396) to chemo/RT Obj. response (n = 843) Chemo/ RT type *Not adjusted for strata. 0.5 1.0 Favors L-BLP25 Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission. 2.0 Favors Placebo
  25. 25. START: OS in Patients With Concurrent Chemo/RT 100 L-BLP25 (n = 538) 30.8 90 Median OS, mos 70 Survival (%) 80 HR Placebo (n = 268) 20.6 0.78 (95% CI: 0.65-0.95; P = .016*) 60 50 40 30 20 L-BLP25 Placebo 10 *2-sided, adjusted for strata 0 0 6 12 18 24 30 36 42 48 54 60 66 40 89 26 51 16 24 4 7 0 0 Mos Pts at Risk, n Placebo 268 227 186 118 73 62 54 L-BLP25 538 499 412 295 205 176 147 Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
  26. 26. START: Safety AE, % Tecemotide (n = 1024) Placebo (n = 477) 100 Most frequent AEs (> 10% in tecemotide arm) 91.6 90.6 90 33.0 27.9 80  Dyspnea 23.2 23.5 70  Fatigue 19.2 21.4  Back pain 14.3 11.1  Nausea 13.7 8.2  Chest pain 13.2 9.4  Nasopharyngitis 12.5 9.2  Headache 12.1 11.3 20  Decreased appetite 10.6 9.2 10  Arthralgia 10.5 7.1 0 Patients (%)  Cough Tecemotide (n = 1024) Placebo (n = 477) 60 50 33.4 35.8 40 30 4.5 Any AE  Influenzalike symptoms • Any 38.2 33.1 • Grade 3/4 1.5 29.6 31.7 1.7 Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission. Any Grade 3/4 AE 7.3 Any Any AE Serious Leading AE to Death
  27. 27. Summary • Study did not meet primary endpoint of significant improvement in OS with use of tecemotide maintenance • Prespecified subgroup analysis identified significant 10.2-mo OS benefit with tecemotide in patients who received concurrent initial chemotherapy and radiotherapy • Tecemotide therapy was well tolerated – AE incidence similar to placebo
  28. 28. #2658: Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine (OV) or etoposide (E) for unresectable locally advanced (LA) stage III non-small cell lung cancer (NSCLC). (GECP10/02). Dolores Isla1, Ramon De Las Peñas, Natividad Martinez-Banaclocha, Bartomeu Massuti, Maria Angeles Sala, Isabel Bover, Raquel Marse, Amelia Insa, Teresa Moran, Angel Artal, Pilar Diz, Jose Gomez-Codina, Ana Laura Ortega, Vanesa Gutierrez, Jose Muñoz, Melchor Alvarez De Mon, Carlos Camps, Ramon GarciaGomez, Jose M. Jurado, Santiago Ponce-Aix, Mariano Provencio
  29. 29. STUDY DESIGN Multicentric randomized phase II trial Patients with non-resectable stage IIIA – IIIB NSCLC PS ECOG 0-1, Age ≤ 75 years, Weight loss < 5% / 3 m., Adequate lung function Arm A: 2 cycles Induction CT: Vinorelbine Oral 80 mg/m2 (1st cycle 60 mg/m2) D1 D8 CDDP 80 mg/m2 D1 Every 3 weeks 2 cycles Concomitant CT-RT: Vinorelbine Oral 40 mg/m2 D1 D8 CDDP 80 mg/m2 D1 RT 66 Gy Every 3 weeks Arm B: 2 cycles Concomitant CT-RT: Etoposide 50 mg/m2 D1 to D5 CDDP 50 mg/m2 D1 D8 RT 66 Gy Every 4 weeks Thoracic RT: Standard 3D conformal RT by linear accelerator with >6 MV rays, Total dose: 66 Gy / 33 daily fractions / 2 Gy (5 dy/w) Total sample size: 67 patients per arm Accrual start date: August 2011 # 2658: Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine
  30. 30. PATIENT CHARACTERISTICS ARM A OVNR + CDDP ARM B E + CDDP N=34 N=34 64 (45-75) 60 (43-71) Gender, %: Male Female 91.2 8,8 88.2 11.8 ECOG PS, %: 0 1 58.8 41.2 32.4 67.6 Smokers, %: Current Never Former 47.1 2.9 50 50 0 50 Histology, %:Squamous Adenocarcinoma Large cell 55.9 41.2 2.9 52.9 44.1 2.9 Stage, %: IIIA IIIB IV* 52.9 44.1 2.9 47.1 52.9 0 CHARACTERISTIC Median age, yr (range) N of Participating Sites: 25 N of Patients Analized: 68 (total of 134) * 1 inclusion failure, who did not receive study treatment but included in the ITT analysis. # 2658: Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine
  31. 31. RESPONSE RATE ARM A ARM B OVNR + CDDP E + CDDP N=22 N=24 CR 4.5 % 4.2 % PR 63.7 % 50 % OR (CR + PR) 68.2 % 54.2 % SD 22.7 % 29.1 % PD 9.1 % 16.7 % RESPONSE * * Evaluable population # 2658: Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine
  32. 32. TOXICITY Grade ¾ HEMATOLOGICAL TOXICITIES ARM A ARM B E + CDDP N = 56 cy NONHEMATOLOGICAL TOXICITIES ARM A ARM B Neutropenia E + CDDP N = 56 cy Asthenia/fatigue 1.02 1.79 Diarrhoea 1.02 0 0 8.93 1.02 7.14 Mucositis Anemia OVNR + CDDP N = 98 cy Infection % of cycles OVNR + CDDP N = 98 cy 1.02 1.79 Alopecia (grades 1/2) 6.12 37.5 % of cycles 0 3.57 6.12 12.50 Esophagitis Febrile neutropenia Leucopenia Thrombocytopenia 3.06 2.04 0 1.79 8.93 5.36 # 2658: Interim analysis of the Spanish Lung Cancer Group (SLCG) randomized phase II trial of thoracic radiotherapy (RT) concurrent with cisplatin (P) plus oral vinorelbine
  33. 33. Safety Data from a Phase II Study of Pemetrexed (PEM) and Cisplatin (CIS) with Concurrent Thoracic Radiation after PEM+CIS Induction in Patients with Unresectable Locally Advanced (LA) Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC) P. Garrido1, M. Serke2, S. Novello3, P. Giraud4, C. Visseren-Grul5, S. Ameryckx6, V. Soldatenkova7, N. Chouaki8, W. Engel-Riedel9 1University Hospital Ramon Y Cajal, Madrid, Spain; 2Hemer Lung Clinic, Hemer, Germany; 3S. Luigi Hospital, University of Turin, Orbassano, Italy; 4Georges Pompidou European Hospital, Paris, France; 5Medical Oncology, Eli Lilly and Company, Houten, The Netherlands; 6Global Clinical Trial Management, Lilly S.A. Eli Lilly Benelux N.V., Brussels, Belgium; 7European Statistics, Oncology, Lilly Deutschland GmbH, Bad Homburg, Germany; 8Medical Oncology, Lilly France, Neuilly sur Seine, France; 9Lung Clinic Merheim, Hospital of Cologne, Cologne, Germany
  34. 34. Background • Concurrent chemo- and radiotherapy (CT+RT) is standard of care for most patients with locally advanced unresectable NSCLC, but no specific CT regimen is recommended1,2 • PEM synergizes with ionizing radiation and CIS in preclinical models3,4 • PEM+CIS doublets showed efficacy and favourable toxicity profiles in Phase I/II studies of locally advanced NSCLC when combined with thoracic RT5,6 • Concurrent CT+RT preceded by induction has been tested in Phase III, using a CARBO-based regimen1,7 1Vansteenkiste et al., Ann Oncol 2013 [epub]; 2Auperin et al., J Clin Oncol 2010;28:2181-90; 3Wagner and Yang, Curr Drug Targets 2010;11:67-73 4 Bischof et al., Int J Radiat Oncol Biol Phys 2002;52:1381-88 5 Brade et al., Int J Radiat Oncol Biol Phys 2011;79:1395-401 6 Gadgeel et al., J Thorac Oncol 2011;6:927-33 7 Vokes et al., J Clin Oncol 2007;25:1698-704
  35. 35. Objectives • Primary objective: To assess the antitumor activity of PEM+CIS as induction, followed by PEM+CIS with concurrent thoracic RT, as measured by 1-year progression-free survival (PFS) rate • Secondary objectives: – Objective tumor response rate (RR) – Overall survival (OS) – Safety and tolerability
  36. 36. Study Design Treatment Period Induction CT (2 cycles) Concurrent CT (2 cycles) + RT Patients enrolled if: • Non-squamous NSCLC • Stage IIIA/IIIB (AJCC Version 6)1 • ECOG PS 0/1 FU Concurrent CT + RT started if: • CR, PR, SD 2 • ECOG PS 0/1 500 mg/m2 pemetrexed + 75 mg/m2 cisplatin, d1, q21d 500 mg/m2 pemetrexed + 75 mg/m2 cisplatin, d1, q21d ≥ 2 years follow-up 3D conformal RT: Total dose 66 Gy 33 fractions of 2 Gy All patients received folic acid, vitamin B12 and dexamethasone as per PEM label 1American Joint Committee on Cancer TNM Staging System for Lung Cancer, 6 th edition, 2002 2Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.0; Therasse et al., J Natl Cancer Inst 2000;92:205-16.
  37. 37. Summary of CT and RT Exposure Cycles received, n (%) All patients (N = 90) Completed 2 cycles of induction CT 85 (94.4) Started concurrent CT+RT 75 (83.3) Completed 4 cycles of CT 72 (80.0)a a 64/72 patients also received ≥60 Gy of RT („completed treatment“) RT dose received, n (%) Started concurrent CT+RT Received full dose (66 Gy) All patients (N = 90) 75 (83.3) 65 (72.2) Received 60 to <66 Gy Received <60 Gyb b 4 (4.4) 6 (6.7) Range 18 – 52 Gy/9 – 26 fractions
  38. 38. Progression free survival PFS Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 Time (months) 24 30
  39. 39. Proximity of Disease Progression to Radiation Field All patients (N = 90) n (%) With documented disease progression 53 (58.9) With PD and not eligible to receive RT 12 (13.3) Documented PD and started CT+RT 41 (45.6) Local disease progression 19 (21.1) Within radiation field 14 (15.6) Outside of radiation field, within thorax Distant metastases 5 (5.6) 22 (24.4)
  40. 40. Tumor Response (RECIST 1.0) All patients (N = 90) Best overall response n (%) Complete response (CR) Partial response (PR) Response rate (CR+PR) Stable disease (SD) Disease control rate (CR+PR+SD) 7 (7.8)a 46 (51.1) 53 (58.9) 95% CI: 48.0, 69.2 17 (18.9) 70 (77.8) 95% CI: 67.8, 85.9 Progressive disease (PD) 12 (13.3) Not evaluableb/not done 7b/1 (7.8/1.1) a b 3 patients after CT+RT, 4 patients after CT+RT + surgery 7 patients who discontinued study treatment before starting the concurrent CT+RT phase due to reasons other than PD were considered as not evaluable for best overall response. RECIST 1.0: Therasse et al., J Natl Cancer Inst 2000;92:205-16
  41. 41. Safety Data – Overview All patients (N = 90) n (%) with event Any treatment-emergent adverse event (TEAE) Grade 3/4 TEAEs Related to study treatment Serious TEAEs Related to study treatment 85 (94.4) 38 (42.2) 33 (36.7) 23 (25.6) 17 (18.9) Death due to toxicity 1 (1.1)a Adverse events leading to discontinuation 6 (6.7) Related to study treatment a b 4 (4.4)b Death due to enteritis, during concurrent CT+RT, Cycle 4 1 patient had renal failure, 1 patient had hypoacusis, 2 patients had radiation esophagitis Analysis of adverse events according to NCI-CTCAE, Version 3.0 . Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
  42. 42. Grade 3/4 Toxicities (CTCAE) Number (%) of patients with G3/4 CTCAEs During Induction CT N = 90 During conc. CT+RT N = 75 During complete treatment period N = 90 Neutropenia 2 (2.2) 8 (10.7) 8 (8.9) Leukopenia 0 7 (9.3) 7 (7.8) Thrombocytopenia 0 2 (2.7) 2 (2.2) Anemia 0 1 (1.3) 1 (1.1) Esophagitis/dysphagia 0 9 (12.0) 9 (10.0) Mucositis 0 1 (1.3) 1 (1.1) 1 (1.1) 1 (1.3) 2 (2.2) Hematologic Non-hematologic toxicities a,b Acute pneumonitis a b Selected based on clinical relevance for combined CT+RT Only 1 G4 esophagitis, all other events reported in Table were G3
  43. 43. Conclusions In this study of PEM+CIS induction, followed by concurrent full-dose PEM+CIS plus RT in patients with locally advanced NS-NSCLC: • PFS (1-year rate 51.3%) was in the same range as previously observed with other CIS-based induction CT followed by concurrent CT+RT1,2 • The overall response rate was 58.9% (disease control rate 77.8%) • Delivery of full dose PEM+CIS CT+RT was feasible, with 71% of patients completing treatment • Grade 3/4 toxicities ≥10% during concurrent CT+RT included esophagitis (12%) and neutropenia (11%), which are considered acceptable for locally advanced NSCLC 1 Descourt et al., J Thorac Oncol 2011;6:351-57 2Fournel et al., J Clin Oncol 2006; 24(June 20 Suppl):7048
  44. 44. Comentarios a futuro: ¿Denver 2015? • Es necesario realizar estudios en subgrupos específicos de los estadios IIIA-IIIB • Son necesarios factores predictivos de individualización terapéutica • Son necesarios estudios en las poblaciones mayoritarias (comorbilidad, edad) • Es necesario incluir en objetivos de los estudios toxicidad y valoración subjetiva
  45. 45. Albert Camus (1913-1960) • Adquirimos la costumbre de vivir antes que la de pensar". (El mito de Sísifo). • “Lo que más distingue al hombre del animal es la imaginación”. (Carnets 2) A. Camus Obras Completas Alianza Editorial. Madrid 1996
  46. 46. bmassutis@seom.org

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