1. Post - ASCO 2007 Unresectable Stage IIIA/B NSCLC
CONTENT
Take Home Message
Key Issues
Chemotherapy and RT
Navelbine and RT
Targeted agents and RT
ASCO ‘08 NSCLC IIIA/IIIB

2. ASCO 08 NSCLC unresectable Stage IIIA/B Take Home Message
Many data on CT-RT without major results
Phases II with Taxanes, Pemetrexed
Integration of targeted agents (Cetuximab, Bevacizumab, Erlotinib) in concurrent CT-RT
Docetaxel as consolidation not recommended
Low MS with paclitaxel-CBDCA (known data…)
New data on NVB Oral and concurrent CT-RT
Focus on RT & CT-RT-induced toxicities (lung) (#7555p, #7573p, #7602p)
ASCO ‘08 NSCLC IIIA/IIIB

3. ASCO 08 NSCLC unresectable Stage IIIA/B RT ant then… Induction, Sequential or Consolidation CT?
Induction CT before concurrent CT-RT:
GEM-platin alone(#7599p)+ Taxane(#7589p) (#7592p) before D-platin-RT “limited impact on OS and PFS” or “GPG concurrently with GEM 225 mg/m2/w too toxic” but GEM-CDDP before CDDP-RT more favourable(#7558p)
Consolidation CT after concurrent CT-RT:
HOG LUN 01 update: docetaxel not recommended
GEM vs GEM-CBDCA(#7559p): no benefit from the combination (46 vs 42% 2y-OS)
GEM vs GEM-D after EP-RT(#7597p): better PFS for the doublet (24 vs 8 mo) but at the price of higher toxicity
Sequential CT:
Meta-analysis on 13 rando trials, 2776 pts (Bozcuk #7575p):
The shorter is the time to RT after the onset of induction CT, the greater is the benefit
ASCO ‘08 NSCLC IIIA/IIIB

4. 3rd generation CT with CDDP–RT likely superior to 2nd generation
ASCO 08 NSCLC unresectable Stage IIIA/B Key Issues: Chemotherapy (1/2)
Docetaxel (D):
Ph III DP vs MVP with concur. RT(#7515p): benefit of 3rd generation CT
HOG-LUN 01 update (#7519p): refer to consolidation section
Weekly D in CT-RT schemes:
D-CDDP induction  wkly D-RT (#7561p): MS 21 mo & 2y OS 34%
D-CDDP induction  D-CDDP+concur. RT (#P 7585): 65% RR
Concurrent wkly D-CBDCA-RT (20 mg/m2, AUC 2, 60Gy)  consol. D-CBDCA (#7565p): 2y OS of 20%!, 21% G3 esophagitis & pneumonitis  scheme not recommended
Concurrent D-RT (20 mg/m2, #7581p): significant G3-4 tox. (20% esophagitis & 9% pneumonitis) + 5.5% related-death, MS 12.2mo
Paclitaxel-CDDP: sequential vs induction + RT (#7520p):
- Low median survival in both arms: 13.2 and 15.4 m
3rd generation CT with CDDP–RT likely superior to 2nd generation
Unimproved outcome from taxanes as concurrent or consolidation CT in CT-RT
ASCO ‘08 NSCLC IIIA/IIIB

5. ASCO 08 NSCLC unresectable Stage IIIA/B Key Issues: Chemotherapy (2/2)
Pemetrexed (PEM) :
Concurrent Pem-CDDP-RT  consol. D (#7569p): 53% RR
Pilot study of CBDCA + dose-dense Pem (#7571p)
Ph I concur. Pem-CDDP-RT(#7550p)
Other CT agents & concurrent RT:
S1 (Oral Fluoropyrim.) (Japan) + P + RT Ph II (#7556p):
87% RR (46% IIIA), PFS 13.4 mo, 6% FN, 24% G3 neutropenia, 12% G3 esophagitis and 4% pneumonitis,
- Oral platinum (#7560p): MTD to be confirmed 30 mg /m2/d
ASCO ‘08 NSCLC IIIA/IIIB

6.  Effective and safe concurrently with RT, even in elderly pts
ASCO 08 NSCLC unresectable Stage IIIA/B Key Issues : Navelbine Oral/i.v.
Navelbine Oral is effective in elderly pts
70 % ORR and 40% 2y-OS in “curative” intent (60 Gy RT) concurrent CT-RT setting (Silvano #20698p)
Navelbine iv or Oral:
A retrospective experience (Portalone #18507p)
 Effective and safe concurrently with RT, even in elderly pts
ASCO ‘08 NSCLC IIIA/IIIB

7. ASCO 08 NSCLC unresectable Stage IIIA/B Key Issues : Targeted Therapies
Cetuximab
Appears safe and promising when grafted onto various chemoradiation regimens (#7516p) (#7607p)
Bevacizumab and Erlotinib
Addition seems to be feasible but squamous histology requires major caution (pulmonary hemorrage G3-5) (#7517p)
Erlotinib added to RT, no convincing early results (#7563p)
ASCO ‘08 NSCLC IIIA/IIIB

8. ASCO 2008 Chemotherapy and RT
ASCO ‘08 NSCLC IIIA/IIIB

9. Concomitant Docetaxel-CDDP vs MVP: A Japanese Phase III Experience (Kiura, #7515p*)
Schedule
Eval.
pts OR
CT-RT
(%)
Median
Survival
(mo)
PFS
2YS
5YS
Arm A: DP-RT
- Docetaxel: 40 mg/m² D1, 8, 29, 36
- Cisplatin 40 mg/m²
- RT 60Gy (2 Gy/d for 5 d/w , no split) 99
St IIIA/B 33/66
78.8%
26.8
6.7
60.3*
23.5
Arm B: MVP-RT
- Mitomycine: 8 mg/m² D1, 29
Cisplatin 40 mg/m² D1, 29
Vindesine: 3 mg/m² D1, 8, 29, 36
101
St IIIA/B 33/68
70.3%
23.7
8.4
48.1*
16.6
*p= 0,00183 for 2y OS
# = N Abstract; O = Oral presentation; P = Poster;
3rd generation CDDP based CT seems superior to 2nd generation cytotoxic
The MS and RR are related to the characteristics of Japanese population
ASCO ‘08 NSCLC IIIA/IIIB

10. More esophagitis and treatment-related deaths in the DP-RT arm
Concomitant Docetaxel-CDDP vs MVP: A Japanese Phase III Experience (Kiura, #7515p*)
Toxicity G3-4 (% pts)
Study Arms
pts
Neutro
Thrombo
Esophagitis
TTT -deaths FN
Arm A: DP-RT 99 61 2 14
6 (pneumonitis, sepsis 22
Arm B: MVP-RT
101 94 25 6
1 (pneumonia) 39
# = N Abstract; O = Oral presentation; P = Poster;
More esophagitis and treatment-related deaths in the DP-RT arm
ASCO ‘08 NSCLC IIIA/IIIB

11. Consolidation CT by TXT cannot be recommended
Consolidation Docetaxel: Survival update of HOG LUN – 01 (#Mina 7519p)
Schedule
Eval pts
Median
Survival
(mo)
3YS
(%)
Consolidation with TXT
vs observation CT after concurrent EP-RT:
E 50 mg/m2
D1,8,29,36
CDDP 50 mg/m2
D1-5,29-33
RT 60 Gy 
3 C TXT 75mg/m2 q3w
Or Obs
Entered: 243
(DSMB: 203)
Randomized:
166; 84/82
(DSMB:
147; 73/74)
IIIA 41,2%
IIIB 58,8%
DSMB*:
TXT 24.2 vs
Obs 25.9 p=
29.6
33.6
Entire:
24.2
26.1
# = N Abstract; O = Oral presentation; P = Poster;
*DSMB = Data safety monitoring board
Consolidation CT by TXT cannot be recommended
ASCO ‘08 NSCLC IIIA/IIIB

12. Paclitaxel-platinum compound: Induction & concurrent scheme (Ardizzoni #7520p)
Schedule
Eval.
pts OR
CT-RT
(%)
Median
Survival
(mo)
PFS
3YS
Arm A:
- Paclitaxel: 200 mg/m²
- Carboplatin AUC 6 or Cisplatin 80 mg/m²
Followed by RT Gy (1.8-2 Gy/d for 5 d/w for 6-7 weeks) 82
St IIIA/B 69.5/30.5%
54%
13.2
6.7
22.2
Arm B:
Followed by C-RT for 6-7 w
- RT :60-63Gy (1.8-2 Gy/d for 5 d/w)
+ concurrent Paclitaxel: 60 mg/m²/w 69
St IIIA/B 67/33%
52%
15.4
8.4
21.9
# = N Abstract; O = Oral presentation; P = Poster;
Poor survival results in both groups, in line with previous data with paclitaxel
ASCO ‘08 NSCLC IIIA/IIIB

13. Arm B Induction plus concurrent CT/RT
Paclitaxel-platinum compound: Induction & concurrent scheme (Ardizzoni #7520p)
Toxicity G3-4 (% pts)
Arm A
Sequential CT-RT
Arm B Induction plus concurrent CT/RT
Evaluable pts 82 69
G3-4 AE (pts)
13.8%
29.5%
Neutropenia
1.5%
Fever
3.1%
Thrombocytopenia
Esophagitis
3.5%
7.8%
Mucositis
# = N Abstract; O = Oral presentation; P = Poster;
Fewer additional toxicity in the concurrent scheme than the sequential one
ASCO ‘08 NSCLC IIIA/IIIB

14. And … Pneumonitis and eosophagitis are not reported !
Gemcitabine CBDCA Induction: before CDDP + concurrent RT (Germonpré, #7558p)
Schedule
Eval.
pts OR
(%)
1/2/3YS
Median
OS (mo)
PFS
(mo)
Induction: q3w x3
-Carboplatin: AUC5 d1
Gemcitabin: 1200 mg/m² d1,d8
Followed by concurrent:
RT: 2.0 Gy/fr x5/w (total 60Gy)
Cisplatin: 30mg/m²/Week
Total: 45
Males: 34
St:
IIIA 14
IIIB 31
58%
(2% CR, 56% PR)
62%/
38%/
17%
20.4
11.1
TOXICITY G3-4:
Neutropenia 36% and FN 1%
Thrombocytopenia 18%
# = N Abstract; O = Oral presentation; P = Poster;
Pre-Treatment FEV1 impacts on results: MS 21.6/9 mo if FEV1 70% /<70%
And … Pneumonitis and eosophagitis are not reported !
ASCO ‘08 NSCLC IIIA/IIIB

15. ASCO 2008: Navelbine and RT
ASCO ‘08 NSCLC IIIA/IIIB

16. NBVo concurrently with 60 Gy RT effective in elderly population
Navelbine Oral concurrently with RT in Elderly Stage IIIA/B NSCLC (Silvano, #20698p)
Oral VRB : 20mg/m2 twice weekly concurrently with RT
25 pts > 65 y, ECOG < 2, Stage IIIA/B 30/70%
> 1 poor risk inclusion criteria: 60%
10 pts received 60Gy as “curative” intent RT
15 pts received 45Gy as palliative RT
Palliative RT: improvement of PS ECOG in 65% pts
ORR
2y OS
Toxicity
60 Gy RT(10 pts)
70% (40% CR)
40%
No G3/4 hematologic
1 G4 esophagitis
# = N Abstract; O = Oral presentation; P = Poster;
NBVo concurrently with 60 Gy RT effective in elderly population
ASCO ‘08 NSCLC IIIA/IIIB

17. Navelbine concurrently with RT A retrospective analysis in Stage IIIA/B (Portalone P#18507)
31 pts, 16 males, median age 60y, Stage IIIA/B 80.7/19.3%
Induction: CDDP 80 mg/ m2 or CBDCA AUC 5 plus either GEM 1200 mg/ m2 or NVBiv 25 mg/ m2 D1, 8, 21
CT-RT: NVB iv 5 mg/ m2 or NVBo 12 mg/ m2 x 3 / week 2 hours before RT(2 Gy /d for 6 w)
Induction RR
CT-RT
TTP
(mo) MS OS 1y 2y
Toxicity
38.7%
43.3%
5 underwent surgery (2 IIIB) 10
15.3
(21.6 IIIA, 14.6 IIIB)
65 %
35 %
8% G3 & 1.3% G4 hemato
Esophagitis: 1 G3 + 1 G4
No toxic death
# = N Abstract; O = Oral presentation; P = Poster;
NVB concurrently with RT effective and safe
ASCO ‘08 NSCLC IIIA/IIIB

18. ASCO 2008: Targeted Therapies and RT
ASCO ‘08 NSCLC IIIA/IIIB

19. Data updated since published abstract
Erlotinib & concurrent 3D-RT vs 3D-RT Randomized Phase II-Efficacy (Martinez, #7563p*)
Data updated since published abstract
Schedule
Eval.
pts OR
(%)
Median
Survival
(mo)
PFS
A: 3DRT(66Gy, 33 fr for 6,5 w).
B: 3DRT(66Gy 33 fr for 6,5 w). Erlotinib: 150 mg/day p.o. continued up to 6 months
36 enrolled (13 arm A, 23 arm B),
34 for safety (12 &22),
20 for efficacy (10 &10)
St I/II: 36%
St III: 64%
A:70
B:70
A:15.3
B:NR NA
Arm B : moderate skin rash (54.5%) and diarrhea (22.7%) G3-4 toxicities: 4.5% radiodermitis and skin rash; 9.1% renal failure
# = N Abstract; O = Oral presentation; P = Poster;
Erlotinib is safe & reported similar OR added to RT with OS not yet mature
ASCO ‘08 NSCLC IIIA/IIIB

20. Cetuximab plus CT-RT (Paclitaxel-CBDCA): Ph
Cetuximab plus CT-RT (Paclitaxel-CBDCA): Ph. II RTOG (Blumenschein #7516p*)
Efficacy
Schedule
Eval.
pts
- Sex (%male)
- PS=O
IIIA
IIIB % 0R
CT-RT %
Median OS (mo)
2yS
(%)
Cetuximab:
400 mg/m² loading
→250mp/m² wk2-17
CT-RT: Wk 2-11
- Paclitaxel 45 mg/m²
- CBDCA AUC 2
RT 63Gy
Consolidation: wk 12-17
Paclitaxel 200 mp/m²
CBDCA AUC6
Enrolled 93 →
Eval 87
- 57%
- 67% 46 54 62
22.7
49.3
Toxicity G3-4 (% pts)
Evaluable pts 93
Haematology G4 20
Pneumonitis 7
Esophagitis 8
G5 events 5
# = N Abstract; O = Oral presentation; P = Poster;
*Median FU: 21,6 mo
Paclitaxel-CBDCA scheme & Cetuximab: MS not far from the doublet NVB-CDDP
ASCO ‘08 NSCLC IIIA/IIIB

21. Cetuximab plus CT-RT (Paclitaxel-CBDCA): Randomized Phase II trial GALGB 30407– (Govindan, #7518p)
Toxicity G3-4 (% pts)
Schedule
Pem-CBDCA + RT 70Gy
Arm A: q3w, 4cycles
-Pemetrexed 500 mg/m² D1
CBDCA AUC 5 D1
Pem-CBDCA + RT 70Gy + Cetuximab
Arm B
Same scheme with Cetuximab
400 mg/m² D1 wk1
→250mp/m² D1/w –6wks
Evaluable pts 54 52
Anemia 14 16
Neutropenia/ FN
38/5
37/7
Thrombocytopenia 30 34
Nausea/vomiting 10 12
Esophagitis 35 22
Skin rash 3 23
# = N Abstract; O = Oral presentation; P = Poster;
Acceptable toxicities from the addition of Cetuximab
ASCO ‘08 NSCLC IIIA/IIIB

22. Caution to lung hemorrage risks
Bevacizumab (B) + Erlotinib (E) plus CT-RT: Phase II trial – Toxicity G3-4(%pts) and ORR (Socinski, #7517p)
Induction: D1 &22
-Paclitaxel 225 mg/m² + CBDCA AUC 6 D1
-Bv 15 mg/m²
Consolidation:
B 15 mg/m² q 3wX6 + E 150mg/m²/d X 6
CT-RT:
RT 74Gy (2Gy/d)
CT: q3w, 4cycles Paclitaxel 45 mg/m² + CBDCA AUC 2
3 cohorts:
- 1: B 10 mg/m² q 2wX4
- 2: B 10 mg/m² q 2wX4 + E 100mg/m² Tues-fri (CT-RT)
- B: 3 10 mg/m² q 2wX4 + E 150mg/m² Tues-fri (CT-RT
Evaluable pts 20
Pulmonary hemorrage 5
Anemia
Pneumonitis 10
Neutropenia 30
Esophagitis 25
Thrombocytopenia
G5 events
ORR after CT-RT: 70%
# = N Abstract; O = Oral presentation; P = Poster;
The cohort II chosen for futher investigations (3 grade 3 lung toxicities)
Caution to lung hemorrage risks
ASCO ‘08 NSCLC IIIA/IIIB