1. CHEMO-IMMUNO-TARGET THERAPIES
Tre strategie di trattamento nel NSCLC in stadio avanzato
Camogli, Aprile 2016
Gli inibitori di EGFR in associazione alla chemioterapia nei pazienti wild-type
Erika Rijavec
UOS Tumori Polmonari
Azienda Ospedaliera Universitaria San Martino IST
Istituto Nazionale per la Ricerca sul Cancro
Genova

2. EGFR pathway

3. TALENT and TRIBUTE Trials
TALENT (N=1059): CDDP 80mg/mq gg1 + gemcitabine 1250 mg/mq gg1,8 q21
TRIBUTE (N=1172): CBDCA AUC 6 gg1 + paclitaxel 200 mg/mq gg1, q21
Gatzemeier U, JCO 2007; Herbst RS, JCO 2005

4. TALENT Results
TTP OS
Gatzemeier U, JCO 2007

5. TRIBUTE Results OS
TTP
Herbst RS, JCO 2005

6. INTACT 1 Trial Endpoints Patients (N=1093) + GEFITINIB 250 mg
CDDP + GEM 3 wkly
for 6 cycles
+ GEFITINIB 500 mg
until PD
+ GEFITINIB 250 mg
Patients (N=1093)
Age ≥18 years
PS 0-2
Stage IIIB/IV
No previous chemotherapy
Primary
Overall survival
Secondary
Response rate
Time to progression
Safety evaluation
CDDP + GEM 3 wkly
for 6 cycles
+ placebo
until PD
Giaccone G, JCO 2004 6 6

7. INTACT 1 Trial: Results
OS: G m G m Placebo 10.9 m (P=.460)
TTP: G m G m Placebo 6.0 m
(P=.76)
RR: G % G % Placebo 44.8 %

8. INTACT 2 Trial Endpoints Patients (N=1037) + GEFITINIB 250 mg Primary
CBDCA AUC 6 +
paclitaxel for 6 cycles
+ GEFITINIB 500 mg
until PD
+ GEFITINIB 250 mg
Patients (N=1037)
Age ≥18 years
PS 0-2
Stage IIIB/IV
No previous chemotherapy
Primary
Overall survival
Secondary
Response rate
Time to progression
Safety evaluation
CBDCA AUC 6 +
paclitaxel for 6 cycles
+ placebo
until PD
Herbst RS, JCO 2004 8 8

9. INTACT 2 Trial: Results OS: G250 9.8 m G500 8.7 m Placebo 9.9 m
TTP: G m G m Placebo 5.0 m
(P=.0562)
RR: G % G % Placebo 28.7 %

10. Potential antagonism CT + EGFR TKI
Tumor cells were driven to G0/G1 phase by EGFR TKI while CT usually works best in the mitotic phase

11. First-line Asian Sequential Erlotinib plus chemo trial (FAST-ACT)
Platinum (d1) Gemcitabine (d1, 8)
+ Erlotinib
D15-28 Q4weeks
x 6 cycles
Erlotinib
Untreated NSCLC IIIB/IV
No prior EGFR TKI
(N=154)
1:1
Platinum (d1) Gemcitabine (d1, 8)
+ Placebo
D15-28 Q4weeks
x 6 cycles
Placebo
Primary endpoint: NPR at 8 w
Secondary endpoints: NPR at 16 w, RR,
PFS, OS, duration of response, safety
Mok T, JCO 2009

12. FAST-ACT Results PFS NPR no difference (80.3% vs 76.9%)
Mok T, JCO 2009

13. Previously untreated stage IIIB/IV NSCLC, PS 0/1
FAST-ACT 2 Study Design
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles
GC-erlotinib (n=226)
Erlotinib 150mg/day PD
Previously untreated stage IIIB/IV NSCLC, PS 0/1
(n=451)
1:1; stratified by stage, histology, smoking status and chemo regimen
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + placebo (d15–28);
q4wks x 6 cycles
GC-placebo (n=225)
Placebo PD
Primary endpoint: PFS
Wu YL, Lancet 2013

14. FAST-ACT 2 Results HR=0.57 (95% CI 0.47–0.69) p<0.0001
Wu YL, Lancet 2013

15. PFS and OS in EGFR WT subgroup
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
12.2
14.9
GC-erlotinib (n=69)
GC-erlotinib (n=69)
GC-placebo (n=67)
GC-placebo (n=67)
HR=0.97 (0.69–1.36)
p=0.8467
RR: 26.1% vs 19.4%
HR=0.77 (0.53–1.11)
p=0.1612
PFS probability
OS probability
5.9
6.7 4 8 12 16 20 24 28 32 36 40 4 8 12 16 20 24 28 32 36 40
Time (months)
Time (months)

16. PFS and OS in EGFR mut subgroup
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
GC-erlotinib (n=49)
GC-erlotinib (n=49)
GC-placebo (n=48)
GC-placebo (n=48)
HR=0.25 (0.16–0.39)
p<0.0001
RR: 83.7% vs 14.6%
HR=0.48 (0.27–0.84)
p=0.0092
PFS probability
OS probability
6.9
16.8
20.6
31.4 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 36
Time (months)
Time (months)

17. Cetuximab Recombinant human/mouse IgG1 monoclonal antibody
Specifically binds to the EGFR with higher affinity than its natural ligands (TGFa, EGF)
Induce apoptosis and ADCC1
Preclinical synergistic activity in combination with chemotherapy and radiotherapy

18. FLEX Study Design Pirker R, Lancet 2009 Primary endpoint: OS
Secondary endpoints: PFS, ORR, quality of life, safety
Pirker R, Lancet 2009

19. FLEX Study Results OS: 11.3 m vs 10.1 m (P= 0.044)
Pirker R, Lancet 2009

20. FLEX Adverse Events
Pirker R, Lancet 2009

21. Survival according EGFR expression
Low EGFR expression
P=0.88
Hight EGFR expression
P=0.011
Pirker R, Lancet 2012

22. BMS099 Study Lynch TJ, JCO 2010 1:1 N=676 Primary endpoint: PFS-IRRC
Secondary endpoints: OS, ORR, quality of life, safety
Lynch TJ, JCO 2010

23. BMS099 Study Results: PFS IRRC
Lynch TJ, JCO 2010

24. Meta-analysis
OS: 10.3 m vs 9.4 m (P=0.009) PFS: 4.7 m vs 4.5 m (P=0.045)
Pujol JL, Lung Cancer 2014

25. Necitumumab

26. INSPIRE: Study Design Paz-Ares L, Lancet 2015 Primary endpoint: OS
Secondary endpoints: PFS, ORR, TTF, safety, immunogenicity of necitumumab, EGFR protein expression
Paz-Ares L, Lancet 2015

27. INSPIRE: Results
OS: 11.3 m vs 11.5 m (P= 0.96) PFS: 5.6 m vs 5.6 (P= 0.96)
High EGFR expression was associated to better outcomes in both treatment arms
Paz-Ares L, Lancet 2015

28. INSPIRE: Toxicity
Paz-Ares L, Lancet 2015

29. Squire: Study Design Thatcher N, Lancet 2015 N=1093
Primary endpoint: OS
Secondary endpoints: PFS, ORR, TTF, health status, immunogenicity of necitumumab, safety, pharmacokinetics
Thatcher N, Lancet 2015

30. Squire: Results OS: 11.5 m vs 9.9 m (P= 0.01)
PFS: 5.7 m vs 5.5 m (P= 0.02)
Thatcher N, Lancet 2015

31. Squire: Subgroup Analysis
Thatcher N, Lancet 2015

32. Squire: Adverse Events
Thatcher N, Lancet 2015

33. EGFR expression
Thatcher N, Lancet 2015

36. Grazie per l’attenzione!