1. Non-Small Cell Lung Cancer
Corey J. Langer, MD, FACP
Medical Director, Thoracic Oncology
Fox Chase Cancer Center
Philadelphia, PA

2. Case 2 Early Stage NSCLC
53-year-old AA woman with 30 pack-year smoking history presents with vague DOE and cough after quitting smoking
CXR demonstrates a 3 cm spiculated mass in the RML
FNA shows a moderately differentiated adenocarcinoma with papillary and mucinous features
IHC stains are positive for TTF-1
CT and PET are otherwise entirely negative with no other sites of involvement
The mediastinum appears normal

3. Case 2 Early Stage NSCLC
She undergoes RMLobectomy and mediastinal node dissection
Final pathology confirms a 3.2 x 3.0 cm RML adenocarcinoma with microscopic involvement in 3/5 peri-bronchial nodes, 2/5 hilar nodes and 2 of 6 subcarinal nodes.
Remaining mediastinal nodes are negative

4. Case 2 Early Stage NSCLC
Is there a role for adjuvant therapy for this patient?
Yes No

5. Case 2 Early Stage NSCLC
Is there a role for adjuvant therapy for this patient?
Yes No
Answer:
Yes, adjuvant therapy would be appropriate for this patient.

6. Case 2 Early Stage NSCLC
Which regimen has been shown in phase III studies to yield a survival advantage in this situation?
Cisplatin + paclitaxel
Cisplatin + docetaxel
Cisplatin + vinorelbine
Cisplatin + gemcitabine
Carboplatin + paclitaxel

7. Case 2 Early Stage NSCLC
Which regimen has been shown in phase III studies to yield a survival advantage in this situation?
Cisplatin + paclitaxel
Cisplatin + docetaxel
Cisplatin + vinorelbine
Cisplatin + gemcitabine
Carboplatin + paclitaxel
Answer:
Cisplatin/vinorelbine has been shown to yield a survival advantage in phase III studies.

8. Randomized International Adjuvant Lung Cancer Trial (IALT): Design
*Each center selected chemotherapy regimen
†Optional, but predefined by N stage at each center
Select eligibility criteria:
Stage I-III
Complete surgical resection within 60 days
Age ≤ 75
(N = 1,867) R A N D O M I Z E*
Cisplatin 80 mg/m2 q 3 wk  4 OR Cisplatin 100 mg/m2 q 4 wk  3-4 OR Cisplatin 120 mg/m2 q 4 wk  3
PLUS
Etoposide 100 mg/m2  3 days/cycle OR Vinorelbine 30 mg/m2 weekly OR Vinblastine 4 mg/m2 weekly OR Vindesine 3 mg/m2 weekly
(N = 935)
Observation ± Thoracic RT ≤ 60 Gy†
(N = 932)
Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation.
Arriagada et al. N Engl J Med. 2004;350:351.

9. IALT: Overall Survival
Median yr
OS (mos) OS (%)
Chemotherapy
Observation ± RT
Observation ± RT
Chemotherapy
Months
164
286
432
602
774
935
181
308
450
624
775
932
At risk: 20 40 60 80
100 12 24 36 48
HR = 0.86 [ ]
P < 0.03
Overall Survival (%)
Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation.
Arriagada et al. N Engl J Med. 2004;350:351.

10. IALT Trial: Results ARM Adjuvant chemo Control Number of enrollees 935
932
Dead from disease progression
361
405
Tx-related deaths (N) 14 2
Compliance with RT (%) 71 85
Median DFS (mos.)
39.4
34.3
2-yr DFS (%) 61 55
5-yr DFS (%) 39 34
Median Survival Time (mos.)
50.8
44.4
2-yr OS (%) 70 67
5-yr OS (%)
44.5
40.4

11. Additional Perspectives from IALT
Benefit seen across most demographic variables: gender, type of surgery, use of RT, geographical location
Decreased Benefit
PS 2; ≥ 65; Stage I/II; T1 vs. T2,3
Stage-Specific LTS
Adjuvant Control Abs %↑
Stage I
Stage II
Stage III

12. Criticisms of IALT
Heterogenous staging, chemo and application of RT (HR favored stage III, not stage I or II)
Study actually closed earlier than planned because of emerging interest in neoadjuvant Tx
Bio-correlatives still pending (could there have been molecular imbalances?)
Elderly (> 75) excluded; how do we address this expanding cohort?
Why was this trial positive when so many similar trials proved negative?

13. Other Recent Negative Trials of Adjuvant CT in Completely Resected NSCLC
Study
Country CT
Regimen
# of Patients
Outcome
on OS
INT 0115
ALPI/EORTC
BLT
USA
Italy/Europe
International
VP16-P x 4
MVP x 3
V-P x 4
462
1197
481
Negative

14. : Paradigm Shift
Recently Completed Positive Randomized Adjuvant Trials in Early Stage NSCLC
Stage No. Intervention
CALGB IB Carboplatin/paclitaxel
NCI-C IB-II Cisplatin/vinorelbine
ANITA I-IIIA Cisplatin/vinorelbine
IALT I-IIIA , Cisplatin/vincalkaloids or
Cisplatin/etoposide

15. BR 10: NCI-Canada Trial of Adjuvant Vinorelbine and Cisplatin in Resected NSCLC Schema
Resected stage IB and II NSCLC
Stratified by:
Nodal status
RAS mutation status
(N = 482)
Arm A q 4w  4 cycles
Cisplatin 50 mg/m2 days 1, 8
Vinorelbine 25 mg/m2 day 1, 8, 15, 21
Arm B
Observation
RANDOMIZE
Started July 1994
Completed April 2001
Winton et al. NEJM. 2005;352:

16. BR 10: NCI-Canada Trial of Adjuvant Vinorelbine and Cisplatin in Resected NSCLC Survival24 48 72 96
Months 20 40 60 80
100
Vinorelbine/cisplatin
Observation
HR = 0.7; P = 0.012
% Survival
5-year survival: 69% vs. 54%
Winton et al. NEJM. 2005;352:

17. Complete Surgical Resection
Paclitaxel and Carboplatin Following Resection in Stage IB NSCLC CALGB 9633
T2 N0 M0
Stage IB
NSCLC
Paclitaxel 200 mg/m2 +
Carboplatin AUC 6
q 3w x 4 cycles
N = 173
Observation
N = 171
Randomized within 4-8 weeks of resection
Stratified by:
Squamous vs. adenocarcinoma
Poorly differentiated vs. other
Mediastinoscopy: yes or no
Complete Surgical Resection
Started July 1994
Completed April 2001
Strauss et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s Abstract 7019

18. Paclitaxel and Carboplatin Following Resection in Stage IB NSCLC CALGB 963320 40 60 80
100
Months
% Survival
Paclitaxel/carboplatin
Observation
HR = 0.62; P = 0.028
4-year survival:
71% vs. 59%
Strauss et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s Abstract 7019

19. Adjuvant Navelbine International Trialist Association (ANITA Study)
Open, Multicentric (101 centers), Phase III Study
(840 patients enrolled)
Surgery
Observation
Chemotherapy
(Vinorelbine/CDDP)*
*Vinorelbine (30 mg/m2) q wk x 16 + Cisplatin 100 mg/m2 q 4 wks x 4
Douillard J-Y et al. Lancet Oncol 7:719, 2006

20. ANITA Trial Overall Survival (ITT Population)
1.00
0.75
0.50
0.25
OBS.
NVB + CDDP
Median (mos.)
43.8
65.8
P-value
0.013
Hazard Ratio
0.79 [ ]
Survival Distribution Function
Obs
NVB + CDDP 20 40 60 80
100
120
Months
Douillard J-Y et al. Lancet Oncol 7:719, 2006

21. ANITA Trial Results Arm Observation Adjuvant No 433 407 RFS (mo) 21 36
Median Surv (mos.)* 44 66
2-yr OS 63 68
5-yr OS 43 51
7-yr OS 37 48
5-yr OS by Stage
Stage I 62
Stage II 39 52
Stage III 26 42
* P = 0.002; HR 0.79 ( )
Douillard J-Y et al. Lancet Oncol 7:719, 2006

22. ANITA Trial Adjuvant Toxicities
Neutropenia Gr 3+4
86%
Febrile Neutropenia
12.5%
Nausea/Vomiting Gr 3+4
27%
Aesthenia
28%
Constipation 5%
Peripheral Neuropathy 3%
Drug-Related Fatality 1%
Douillard J-Y et al. Lancet Oncol 7:719, 2006

23. Scorecard for Adjuvant CT Subset Analyses as of 2005
Stage IA IB II
IIIA
ALPI
IALT
NCI-C
CALGB
ANITA
Not tested
Positive
Negative

24. Positive Adjuvant Trials: NSCLC
Stage
Control
Adj
P-value
Rel Surv 
IALT
I-III
40.5%
44.5%
< 0.03
10%
BR10
IB-II
54%
69%
0.012
28%
CALGB IB
59%
71%
0.028
20%
ANITA
43%
51%
0.013
19%

25. CALGB 9633: Overall Survival Then and Now
ASCO: 2006 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Probability
Observation
Chemo 1 3 5 7 9
HR = 0.80; 90% CI:
P = 0.10
ASCO: 2004
HR = 0.62; 90% CI: P = 0.028

26. CALGB 9633 (ASCO 2006) Arm CbP Obs P-value MS 95m 78m 0.10 DFS 89m 52m
0.03
Recurred or Dead
43%
52%
5-yr DFS
48%
0.21
3-yr OS*
79%
70%
5-yr OS^
59%
57%
0.375
Median F/U still short: < 5 yrs;
150 deaths required for final analysis; yet only 131 have died
^5-yr OS still significantly better for tumors ≥ 4 cm (HR = 0.62; P = 0.04)
Strauss et al. Proc Am Soc Clin Oncol. 2006; Abstract 7007.

27. CALGB 9633 Survival: Patients with Tumors ≥ 4.0 cm
HR = 0.66; 90% CI:
P = 0.04
N = 99

28. NSCLC 2006 Positive Adjuvant Trials
Stage
Control
Adj
P-value
Rel Surv 
IALT
I-III
40.5%
44.5%
<0.03
10%
BR10
IB-II
54%
69%
0.012
28%
CALGB IB
57%
60%
0.10 5%
ANITA
43%
51%
0.013
19%

29. Scorecard for Adjuvant CT Subset Analyses: Updated (ASCO 2006)
Stage IA IB II
IIIA
ALPI
IALT
NCI-C
CALGB
ANITA
Not tested
Positive
Negative
Indeterminate

30. Stage-Specific Hazard Ratios Recent Adjuvant TrialsIB II
IIIA
IALT
0.95
0.93
0.79
BR-10
0.94
0.59
N/A
ANITA
1.10
0.71
0.69
CALGB
0.80
JCOG (UFT)
0.48
LACE
0.92
0.83
Negative
Positive
Indeterminate
Not tested

31. ECOG 1505: Adjuvant Bevacizumab
RANDOM I Z E
Chemotherapy
x 4 cycles
Elibility:
Resected IB^ -IIIA
Lobectomy
No prior chemo
No planned XRT
No h/o CVA/TIA
No ATE w/in 1-yr
Stratified:
Stage
Histology
Gender
Chemotherapy regimen +
Bevacizumab
x 1-year
Investigator Choice of 3 chemo regimens
^ Allows ≥ 4cm

32. Chemotherapy Regimens
Therapy to start 6-12 weeks post-operatively
Investigator Choice of Chemo x 4 cycles (12 wks)
Carboplatin/Paclitaxel
Carboplatin AUC 6, Paclitaxel 200 mg/m2 both d 1 q21 d
Cisplatin/Vinorelbine
Cisplatin 75 mg/m2 d 1, Vinorelbine 25 mg/m2 d1,8 q21 d
Cisplatin/Docetaxel
Cisplatin 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d
Cisplatin/Gemcitabine
Cisplatin 75 mg/m2 d 1, Gemcitabine 1,250 mg/m2 d1,8 q 21 d
Bevacizumab 15 mg/kg q 21 days x 12 months

33. Chemotherapy Regimens
Therapy to start 6-12 weeks post-operatively
Investigator Choice of Chemo x 4 cycles (12 wks)
Carboplatin/Paclitaxel
Carboplatin AUC 6, Paclitaxel 200 mg/m2 both d 1 q21 d
Cisplatin/Vinorelbine
Cisplatin 75 mg/m2 d 1, Vinorelbine 25 mg/m2 d1,8 q21 d
Cisplatin/Docetaxel
Cisplatin 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d
Cisplatin/Gemcitabine
Cisplatin 75 mg/m2 d 1, Gemcitabine 1,250 mg/m2 d1,8 q 21 d
Bevacizumab 15 mg/kg q 21 days x 12 months

34. Case 2 Early Stage NSCLC
Which marker has been shown to be predictive of benefit in this situation?
EGFR
RAS
TTF-1
ERCC-1
HER-2

35. Case 2 Early Stage NSCLC
Which marker has been shown to be predictive of benefit in this situation?
EGFR
RAS
TTF-1
ERCC-1
HER-2
Answer:
ERCC-1 has been shown to be predictive of benefit.

36. Soria et al., ASCO 2006 Abstract 7010
Immunohistochemical Staining of the Excision Repair Cross-Complementing 1 (ERCC-1) Protein as Predictor for Benefit of Adjuvant Chemotherapy (CT) in the International Lung Cancer Trial (IALT)
Soria et al., ASCO 2006 Abstract 7010

37. IALT Trial
761 pts. (28 centers,14 countries) evaluable for ERCC-1 expression
ERCC-1 repairs cisplatin-DNA adducts, so expression indicates platinum resistance
ERCC-1 a “double-edged sword”; worse prognosis of NSCLC if low expression, but more responsive to platinum

38. ERCC-1-Negative Tumors Overall Survival
Adjusted HR = 0.65, 95% PI [ ]
P = 0.002
Soria et al. Proc Am Soc Clin Oncol. 2006; Abstract 7010.

39. ERCC-1-Positive Tumors Overall Survival
Adjusted HR = 1.14, 95% CI [ ]
P = 0.40
Soria et al. Proc Am Soc Clin Oncol. 2006; Abstract 7010.

40. Results of ERCC-1 Analysis 5-Year Survival
Overall positivity = 44% (H-score > 1.0)
Significant correlation of ERCC-1 expression seen with age (lower in younger pts.), histological subtype (lower in adenocarcinoma), and pleural invasion (lower if no pleural invasion)
Predictive Adjusted Analysis (5-year survival)
Chemo
(N = 389)
Control
(N = 372) HR
P-value
ERCC-1 negative
(N = 426)
47%
56 mos.
39%
42 mos.
0.65
.002
ERCC-1 positive
(N = 335)
40%
50 mos.
46%
55 mos.
1.14
.40
Soria et al. Proc Am Soc Clin Oncol. 2006; Abstract 7010.

41. Case 2 Early Stage NSCLC
Is there a role for adjuvant XRT in patients with N2 involvement?
Yes No
Controversial

42. Case 2 Early Stage NSCLC
Is there a role for adjuvant XRT in patients with N2 involvement?
Yes No
Controversial
Answer:
The use of adjuvant XRT in patients with N2 involvement is controversial.

43. Adjuvant Radiotherapy
LCSG 773
T2N1, T3, chest wall, N2
completely resected (R0)
squamous cell carcinoma only
Observation
N = 108
Adjuvant RTx 50 Gy/6 wks
N = 102
Local recurrence went from 41% to 3% with RTx
Weisenburger et al, NEJM 1986.

44. Adjuvant Radiotherapy
MRC Lung Cancer Working Party
T1-2 N1-2 NSCLC
completely resected (R0)
N = 306
Observation
Adjuvant RTx
40 Gy/15 fractions
N2 appeared to gain 1 month in survival...
Stephens et al, Br J Cancer 1996.

45. Adjuvant Radiotherapy Meta-Analysis 1998
Individual data from 9 randomized trials including 2,128 patients
Treatment details (staging, surgery, RT) highly variable among series
PORT: better local control: 29% fewer local recurrences LR vs. 276 LR for no RT
Overall HR = 1.21 ( ) ~ survival decrement of 7% at two years (55% vs. 48%)
Increase risk greater for early stage patients (Stage I/II vs. III)
Lancet 25 July 1998.

46. PORT Meta-Analysis Survival Curves
Stewart et al, Lancet 1998.

47. PORT Heterogeneity of Hazard
No increased risk for patients with N2 disease
Patients with the least to gain have the most to lose
Stewart et al, Lancet 1998.

48. PORT Meta-Analysis Methodologic Flaws
Variable and unspecified staging
Variable and unspecified interval between resection and PORT
Inadequate RT
Suboptimal doses
Poor treatment planning
Outmoded techniques (e.g: use of low-energy photons or 60Co for a substantial proportion of patients)
Inclusion of N0 patients
Unpublished data (2 of 9 studies)
Relatively short F/U (< 4 yrs)

49. Risks of PORT with Modern Technology
Retrospective review
202 patients treated with surgery and PORT for Stage II and III disease
Median dose 55 Gy
Actuarial rate of death from intercurrent disease was 13.5% compared to expected rate of 10%
Machtay et al JCO 2001.

50. Overall Survival in Patients Receiving PORT ANITA Trial
OBS
(N = 144)
NVB + CDDP
(N = 88)
Median (mos.)
33.3
47.4
5-Yr survival (%) 33
44.6
5-Yr overall survival 43 51
OBS
NVB + CDDP
Douillard J-Y et al. Lancet Oncol 7:719, 2006 50

51. Overall Survival in N1 Patients ANITA Trial
0.00
0.25
0.50
0.75
1.00
Median Overall Survival:
65.7 mos. CT
31.2 mos. OBS
46.6 mos.
93.6 mos.
50.2 mos.
25.9 mos.
CT + PORT CT
PORT
OBS
Survival Distribution Function 20 40 60 80
100
120
Duration of Survival (Months)
Douillard J-Y et al. Lancet Oncol 7:719, 2006 51

52. Overall Survival in N2 Patients ANITA Trial
Median Overall Survival:
32.6 mos. CT
20 mos. OBS
47.4 mos.
23.8 mos.
22.7 mos.
12.7 mos.
CT + PORT CT
PORT
OBS
0.00
0.25
0.50
0.75
1.00 20 40 60 80
100
120
Survival Distribution Function
Duration of Survival (Months)
Douillard J-Y et al. Lancet Oncol 7:719, 2006 52

53. Overall Survival in N2 Patients ANITA Trial
Median Overall Survival:
32.6 mos. CT
20 mos. OBS
47.4 mos.
23.8 mos.
22.7 mos.
12.7 mos.
CT + PORT CT
PORT
OBS
0.00
0.25
0.50
0.75
1.00 20 40 60 80
100
120
RT Effect? Or Serendipity?
Survival Distribution Function
Duration of Survival (Months)
Douillard J-Y et al. Lancet Oncol 7:719, 2006 53

54. ANITA 5-Year Survival According to Treatment
Observation
62.3%
31.4%
16.6%
PORT
43.8%
42.6%
21.3%
Chemotherapy
59.7%
56.3%
34.0%
Chemotherapy + PORT
44.4%
40.0%
47.4%
Douillard J-Y et al. Lancet Oncol 7:719, 2006

55. PORT Stage II-III SEER Data
7,465 pts, lobectomy or pneumonectomy ( )
> 4 mos. survival post-op
Median F/U: 3.5-years
Lally et al., JCO 2006.

56. Conclusions No role for PORT in N0 (N1?) patients
Role of PORT in N2 patients remains controversial
Modern RT techniques essential
Recent randomized trials with chemo do not show increased toxicity with RT
Randomized trials are necessary

57. “Lung ART” P.I. Dr. Cécile Le Pechoux
Completely resected N2 NSCLC
Primary end-point: DFS
Sample size: 700 pts S U R G E Y
Conformal RT
54 Gy/27-30 fxs
No post-op RT
Pre- or post-op chemotherapy allowed
Concomitant chemo not allowed
Sponsors: FNCLCC, IFCT, LARS-G, EORTC

58. Case 3 Advanced NSCLC
49-year-old WM with 25 pack-year smoking history presents with 5 lb weight loss, rib pain and dyspnea
PE shows a 2 cm (L) mid-cervical node with decreased breath sounds at the (L) base
CXR demonstrates a (L) pleural effusion, with a mass abutting the lateral chest wall
CT of the neck, chest and abdomen reveals a 3.8 cm spiculated mass invading the chest wall in the (L) mid-lung, a moderate (L) pleural effusion, mediastinal and (L) hilar adenopathy, and (L) mid-cervical and supraclavicular nodes. The (R) adrenal appears nodular and enlarged (~3 cm). The liver appears normal.
Pleural tap confirms adenocarcinoma, as does FNA of the (L) mid-cervical node
MRI of the brain is negative

59. Case 3 Advanced NSCLC
Phase III data suggest a benefit for which of the following regimens?
Carboplatin + paclitaxel + bevacizumab
Carboplatin + paclitaxel + erlotinib
Cisplatin + gemcitabine + bevacizumab
Cisplatin + gemcitabine + erlotinib
1 and 3

60. Case 3 Advanced NSCLC
Phase III data suggest a benefit for which of the following regimens?
Carboplatin + paclitaxel + bevacizumab
Carboplatin + paclitaxel + erlotinib
Cisplatin + gemcitabine + bevacizumab
Cisplatin + gemcitabine + erlotinib
1 and 3
Answer:
Phase III data suggest a benefit for regimens 1 and 3.

61. Case 3 Advanced NSCLC
The patient receives 6-cycles of gemcitabine + carboplatin + bevacizumab
He gains weight, with complete resolution of rib pain and dyspnea and enters a PR radiographically

62. Case 3 Advanced NSCLC What is indicated at this point?
Maintenance bevacizumab
Maintenance erlotinib + bevacizumab
Maintenance docetaxel
Observation (active surveillance)

63. Case 3 Advanced NSCLC What is indicated at this point?
Maintenance bevacizumab
Maintenance erlotinib + bevacizumab
Maintenance docetaxel
Observation (active surveillance)
Recommended Approach:
At this point, maintenance bevacizumab should be considered for this patient.

64. Cisplatin-Based Therapy in Advanced NSCLC
Improves survival
Median: 2 mos.
1-yr: 10% survival increase
Hazard rate reduction of 26%
Relieves symptoms: 66%-78% in Stage III/IV
Improves QoL
Cost-effective

65. NSCLC: Standard Agents
OLD (pre-1990) NEWER (post-1990)
Cisplatin • Paclitaxel
• Etoposide • Docetaxel
• Vinblastine • Gemcitabine
• Ifosfamide • Vinorelbine
• Mitomycin-C • Irinotecan
• Carboplatin
LATEST (post-2000)
Pemetrexed
Gefitinib
Erlotinib
Bevacizumab

66. Metastatic NSCLC Survival Advances

67. Are We Making Progress in NSCLC?
Modest, but real increase in survival
Potential explanations
New agents

68. Are We Making Progress in NSCLC?
Modest, but real increase in survival
Potential explanations
New agents
Stage migration
Selection bias
Second-line Tx
Improved BSC

69. Current Treatment Options for NSCLC NCCN Guidelines
Chemotherapy and targeted therapy (inoperable or unresectable, locally advanced or metastatic disease)
First-line
Gemcitabine plus platinum-based chemotherapy
Taxanes (docetaxel or paclitaxel) plus platinum-based chemotherapy
Vinorelbine, single-agent or in combination with platinum-based chemotherapy
Addition of bevacizumab in selected pts
Second-line
Docetaxel (after failure of prior platinum-based chemotherapy)
Pemetrexed (after prior chemotherapy)
Erlotinib (approved 11/04)
Third-line
Erlotinib or gefitinib* (after failure of both platinum-based and docetaxel chemotherapies)
*now only approved for those who have already demonstrated a benefit to gefitinib
Pfister et al. J Clin Oncol. 2004;22:330.
Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925.

70. 2003 ASCO Guidelines for Stage IV NSCLC
2-drug combination regimen recommended as first-line chemotherapy
Non-platinum-based chemotherapy potential alternative in first-line therapy
Consider single-agent therapy for elderly or patients with PS 2
3 agents: no advantage over 2
4 to 6 cycles of chemo for non-progressors
No proven role for maintenance or consolidation with cytotoxics

71. ECOG 1594 Treatment Schema RANDOM I ZE Stage IIIB or IV NSCLC
Arm A*
q 3 wk
Stage IIIB or IV
NSCLC
Stratified by:
Extent of disease PS
Weight loss
Brain metastases
(N = 1,207)
Cisplatin: 100 mg/m2, day 1
Gemcitabine: 1,000 mg/m2, days 1,8,15
(N = 301)
Docetaxel: 75 mg/m2, day 1
Cisplatin: 75 mg/m2, day 1
(N = 304)
Arm C
Paclitaxel: 225 mg/m2, day 1
Carboplatin: AUC=6, day 1
(N = 299)
Arm D
Arm B
q 4 wk
Paclitaxel: 135 mg/m2, day 1
Cisplatin: 75 mg/m2, day 2
(N = 303)
RANDOM I ZE
*Control arm
Schiller JH et al. N Engl J Med. 2002;346:92-98.

72. ECOG 1594 Survival % Survival Months
NS = not significant.
% Survival
Months
Cisplatin + paclitaxel 7.8; P = NS
Cisplatin + gemcitabine 8.1; P = NS
Cisplatin + docetaxel 7.4; P = NS
Carboplatin + paclitaxel 8.1; P = NS
Median survival (mo)
100 80 60 40 20 5 10 15 25 30
Schiller JH et al. N Engl J Med. 2002;346:92-98.

73. ECOG 1594 Efficacy Paclitaxel- Cisplatin (N = 288)
Gemcitabine- Cisplatin (N = 288)
Docetaxel- Cisplatin (N = 289)
Paclitaxel- Carboplatin (N = 290)
ORR (%) 21 22 17 16
TTP (mos.)
3.4
4.2
3.7
3.1
Median survival (mos.)
7.8
8.1
7.4
1-year survival (%) 31 36 34
2-year survival (%) 10 13 11
ORR = overall response rate; TTP = time to tumor progression.
Schiller JH et al. N Engl J Med. 2002;346:92-98.

74. E4599: Phase III Trial of Bevacizumab/Paclitaxel/Carboplatin in First-Line Advanced NSCLC
Paclitaxel 200 mg/m2
carboplatin AUC 6 (PC) q 3wk × 6 (no crossover permitted)
First-line treatment of patients with stage IIIB with malignant pleural effusion, or IV, or recurrent NSCLC
(N = 878)
Progression of disease or unacceptable toxicity
Bevacizumab 15 mg/kg q 3wk until progression of disease or unacceptable toxicity
Bevacizumab (BV) 15 mg/kg q 3wk + PC × 6 (BV/PC)
KEY POINT: On the basis of the results of the phase II study, a placebo-controlled phase III trial was designed and conducted in the first-line setting for patients with histology other than squamous cell NSCLC.
Stratified by
Disease stage
Degree of weight loss
Prior radiotherapy
Measurable disease
End points
Primary
Overall survival
Secondary
Response rates
Progression-free survival
Toxicity
Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.

75. E4599: Patient Characteristics
Patients, %
(N = 878)
Stage IIIB disease 12
Previous weight loss ≥ 5% 28
Age ≥ 65 years 43
Male sex 55
KEY POINT: The arms of the trial were balanced regarding patient characteristics.
Sandler et al. NEJM 2006.

76. E4599: Overall Survival 12 mos. 24 mos. Median
HR = 0.80; P = .013
BV/PC 51.0% 22.0% mos.
PC 44.4% 15.4% mos.
0.0
0.2
0.4
0.6
0.8
1.0
Proportion surviving 6 42 48 18 30
12 mos mos. Median 12 24 36
444
318 1
104 9
190 5
434
340 3
127 25
216 54 8 PC
BV/PC
Months
Patients at risk
Median 12.3 mos.
Median 10.3 mos.
KEY POINT: Overall survival was significantly prolonged by the addition of bevacizumab to paclitaxel and carboplatin.
Sandler et al. NEJM 2006.

77. E4599: Investigator Assessed* Progression-Free Survival
HR: 0.65, P < .0001
BV/PC 56.0% 21.0% mos.
PC 39.0% 9.0% mos.
0.0
0.2
0.4
0.6
0.8
1.0
Proportion with PFS 6 42 48 18 30
6 mos mos. Median 12 24 36
444
126 13 1 27 2
434
201 21 3 70 PC
BV/PC
Months
Patients at risk
Median 6.4 mos.
Median 4.8 mos.
*Based on investigator assessment which was not independently verified.
KEY POINT: Progression-free survival was prolonged by the addition of bevacizumab to paclitaxel and carboplatin.
Genentech, data on file.

78. * All Differences were statistically significant P < 0.05
E4599: Outcome*
Arm
CbP
CbPB
RR (%) 15 35
PFS (mos.)
4.8
6.4
MS (mos.)
10.2
12.5
1-yr OS (%)
43.7
51.9
2-yr OS (%)
16.9
22.1
* All Differences were statistically significant P < 0.05
Sandler et al. NEJM 2006.

79. Randomized Trials with CT ± Targeted Therapies in Treatment-Naïve NSCLC
TRIAL TARGET CT GROUP COMMENT
ZD EGFR GC AstraZeneca Closed, no benefit
ZD EGFR PC AstraZeneca Closed, no benefit
OSI EGFR PC Genentech/OSI Closed, no benefit
OSI EGFR GC Genentech/OSI Closed, no benefit
AG MMP PC Agouron Closed, no benefit
AG MMP GC Agouron Closed, no benefit
BMS MMP PC BMSO Closed, no benefit
Lonafarnib FT (ras) PC Schering Closed, no benefit
ISIS PKC PC ISIS Closed, no benefit
Targretin RXR PC Ligand Closed, no benefit
E VEGF PC ECOG Closed, positive

80. E4599: Key Entry Criteria Key inclusion criteria
First-line locally advanced, metastatic, or recurrent NSCLC
ECOG PS 0 or 1
Measurable or non-measurable disease
Key exclusion criteria*
Patients with predominant squamous histology
Central nervous system metastases
Gross hemoptysis (≥ 0.5 tsp of red blood) added with Protocol Amendment 1
Unstable angina
Patients receiving therapeutic anticoagulation
KEY POINT: The key inclusion criteria were first-line locally advanced, metastatic, or recurrent NSCLC. The key exclusion criteria were squamous cell histology, CNS metastases, cardiovascular disease, uncontrolled hypertension, history of thrombotic or hemorrhagic disorders, or history of (or) current gross hemoptysis.
*Patients were not excluded from study E4599 due to tumor location or unclassified histology (not otherwise specified, NOS).
Sandler et al. NEJM 2006.

81. Phase III Study of Bevacizumab + Cisplatin + Gemcitabine in Chemo-Naïve Patients with Advanced or Recurrent NSCLC (B017704) PD
Bevacizumab 2 1
Placebo CG
15mg/kg + CG
7.5mg/kg + CG
Placebo 15 + CG
Previously untreated,
IIIb, IV or recurrent
non-squamous NSCLC
No tumor invasion of major blood vessels
No ≥ Gr 2 hemoptysis
No brain mets
RANDOMI ZE
Primary Objective: PFS
Statistical Analysis: median PFS 4.5 months placebo versus 6.4 months bevacizumab (corresponding to a hazard ratio of 0.7)
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

82. Phase III: Bevacizumab/Cisplatin/Gemcitabine PFS: Primary Analysis
Arm
CGP
CGBv
(7.5 mg/kg)
(15 mg/kg)
No. Patients
347
345
351
Med. PFS (mos.)
6.1
6.7
6.5 HR --
0.75
0.82
95% CI
0.62, 0.91
0.68, 0.98
P-value
0.0026
0.0301
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

83. Phase III: Bevacizumab/Cisplatin/Gemcitabine PFS: Primary Analysis (ITT)
1.0
1.0
Placebo CG
(N = 347)
Bv 7.5 mg/kg
(N = 345)
Bv 15 mg/kg
(N = 351)
Median PFS (mos)
6.1
6.7
6.5 HR
[95% CI]
- - -
0.75
[0.62, 0.91]
0.82
[0.68, 0.98]
P-value
0.0026
0.0301
0.8
0.8
0.6
0.6
Possibility of PFS
0.4
0.4
Placebo +CG
Bv 7.5mg/kg + CG
0.2
0.2
Bv 15mg/kg + CG
0.0
0.0 3 6 9 12 15 18
No. at risk
Placebo + CG
347
228
122 36 12 3
Bv CG
345
251
150 52 18
Bv 15 + CG
351
238
148 46 16 5
Time (months)
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

84. Phase III: Bevacizumab/Cisplatin/Gemcitabine PFS: Primary Analysis (NPT Censored*)
Arm
CGP
CGBv
(7.5 mg/kg)
(15 mg/kg)
No. Patients
347
345
351
Med. PFS (mos.)
6.1
6.7
6.6 HR --
0.68
0.74
95% CI
0.56 ,0.83
0.60, 0.90
P-value
0.0001
0.0021
*7% of pateints receive non-protocol antineoplastic therapy (NPT) prior
to disease progression
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

85. Phase III: Bevacizumab/Cisplatin/Gemcitabine Overall Response
Arm
CGP
CGBv
(7.5 mg/kg)
(15 mg/kg)
No. Patients
324
323
332
OR (%) 20 34 30
P-value --
<
0.0017
Dur. of Resp. (mos.)
4.7
6.1
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

86. Phase III: Bevacizumab/Cisplatin/Gemcitabine Conclusions
Statistically significant progression-free survival advantage for either low- or high-dose bevacizumab in combination with GC compared to GC alone
Significant increase in response rate
Survival data immature
No new safety signals; no untoward toxicity
Manegold et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7514.

87. Erlotinib: First-Line Lung Cancer TRIBUTE
NSCLC
IIIB/IV
PS 0/1
No prior chemotherapy
Stratification:
IIIB vs IV
Weight loss
Measurable vs. evaluable R A N D O M I Z E
Carbo/Paclitaxel x 6
+ Placebo
+ Erlotinib
Primary Endpoint: Survival
Secondary Endpoints: Symptomatic progression/QOL, response rate
*Genentech Sponsored (US)

88. Erlotinib: First-Line Lung Cancer TRIBUTE
NSCLC
IIIB/IV
PS 0/1
No prior chemotherapy
Stratification:
IIIB vs IV
Weight loss
Measurable vs. evaluable R A N D O M I Z E
Carbo/Paclitaxel x 6
+ Placebo
+ Erlotinib
NEGATIVE
Primary Endpoint: Survival
Secondary Endpoints: Symptomatic progression/QOL, response rate
*Genentech Sponsored (US)

89. Erlotinib: First-Line Lung Cancer TALENT
NSCLC
IIIB/IV
PS 0/1
No prior chemotherapy
Stratification:
IIIB vs IV
Weight loss
Measurable vs. evaluable R A N D O M I Z E
Gemcitabine/Cisplatin x 6
+ Placebo
+ Erlotinib
Primary Endpoint: Survival
Secondary Endpoints: Symptomatic progression/QOL, response rate
*Roche Sponsored (EU)

90. Erlotinib: First-Line Lung Cancer TALENT
NSCLC
IIIB/IV
PS 0/1
No prior chemotherapy
Stratification:
IIIB vs IV
Weight loss
Measurable vs. evaluable R A N D O M I Z E
Gemcitabine/Cisplatin x 6
+ Placebo
+ Erlotinib
NEGATIVE
Primary Endpoint: Survival
Secondary Endpoints: Symptomatic progression/QOL, response rate
*Roche Sponsored (EU)

91. TRIBUTE & TALENT Trials
Arm
CPE CP
No. Pts.
526
533
OR (%)
21.5
19.3
TTP (mos.)
5.1
4.9
MS (mos.)
10.8
10.6
Arm
GPE GP
No. Pts.
586
TTP (mos.)
5.4
5.6
MS (mos.)
9.9
10.1
1-yr OS (%) 41 42
Gatezemeier et al. Proc Am Soc Clin Oncol. 2004; Abstract 7010.
Herbst et al. Proc Am Soc Clin Oncol. 2004; Abstract 7011.

92. Maintenance or Consolidation Therapy
Is There a Role?

93. Immediate vs. Delayed Second-Line Docetaxel in Advanced NSCLC
Eligibility
NSCLC Stage IIIB/IV
Chemo-naïve
ECOG PS 0-2
CNS Mets allowed
GC Phase
Gemcitabine,
1000 mg/m2,
d1, 8
Carboplatin
AUC 5, d1
q 21 days x 4 R A N D O MI Z E
Immediate Docetaxel
75mg/m2 d1 q 21 days
until PD or
maximum of 6 cycles
Delayed Docetaxel
BSC → start therapy at PD
75mg/m2 on d1 q 21 days, until PD or
CR, PR SD
Primary endpoint:
Overall survival
HR = 1.43
Fidias et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7516.

94. Immediate vs. Delayed Docetaxel Patient Disposition
Chemo-naϊve
Stage IIIB/IV NSCLC
N = 562
GC Phase
N = 552
(388 received 4 cycles)
Off Study
N = 245
Randomized
SD, PR, CR
N = 307
Immediate
N = 153
Delayed
N = 154
Treated
N = 142
N = 91
ORR 29%
Fidias et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7516.

95. Immediate vs. Delayed Docetaxel PFS: Total Randomized Population
Immediate (N = 153)
Delayed (N = 154) LR
P-Value
Median PFS (mos.)
(95% CI)
6.5
(4.4, 7.2)
2.8
(2.6, 3.4)
<
12-month PFS
20% (13, 26)
9% (5, 14)
Please note: the PFS curves only showed up to 24 months since very few patients left without PD/survival 24 months after randomization.
Patients at Risk I:
153 72 27 11 5 D
154 28 10 4 2
Fidias et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7516.

96. Overall Survival Time (months)
Immediate vs. Delayed Docetaxel Overall Survival: Total Randomized Population
Immediate (N = 153)
Delayed (N = 154) LR
P-Value
Median OS, (mos.)
(95% CI)
11.9
(10.0, 13.7)
9.1
(8.0, 11.2)
0.071
12-mo survival
48.5% (39.9, 57.1)
38.3%
(30.0, 46.5)
Survival Probability
Overall Survival Time (months)
Patients at Risk I: D:
Fidias et al. Proc Am Soc Clin Oncol. 2007; Abstract LBA7516.

97. Immediate vs. Delayed Docetaxel Conclusions
Significant improvement in PFS
Trend toward improved OS (underpowered)
Thought-provoking, hypothesis-generating, but….
Not yet ready for prime time

98. Case 3 Advanced NSCLC
Patient receives bevacizumab alone for 10 months with excellent quality of life
Unfortunately, 15 months after diagnosis, he develops H/A and subtle (R) arm weakness
MRI of the brain demonstrates multiple space-occupying lesions with vasogenic edema
CT confirms new pulmonary nodules and regrowth of the (R) adrenal lesion
He receives WBRT with complete resolution of his neurologic symptoms
He is offered salvage therapy

99. Case 3 Advanced NSCLC Which would be an inappropriate salvage therapy?
Docetaxel
Erlotinib
Pemetrexed
Double-dose pemetrexed

100. Case 3 Advanced NSCLC Which would be an inappropriate salvage therapy?
Docetaxel
Erlotinib
Pemetrexed
Double-dose pemetrexed
Correct answer:
Double-dose pemetrexed would be inappropriate salvage therapy.

101. Approved Second-Line Therapies for Advanced and Metastatic Disease
Clinical Efficacy

102. TAX 317B: Second-Line NSCLC Schema
Stage IIIB or IV NSCLC
Stratified by: PS
Best response to cisplatin
N = 204
Arm A
Docetaxel
N = 104
Arm B q 3w
Control
Best supportive care
N = 100
RANDOMIZE
75 mg/m2 q 3w
N = 55
100 mg/m2 q 3w
N = 49
Premed: Dexamethasone 8 mg PO bid  5 days (first dose 24 hr prior to each docetaxel infusion) for the docetaxel groups.
Shepherd et al. J Clin Oncol. 2000;18:2095.

103. TAX 317B: Second-Line NSCLC Survival
Median survival 7.5 vs. 4.6 mos.; P = 0.01
1-year survival 37% vs. 12%; P = 0.003
100 80 60 40 20 9 3 6 12 15 18 21
Months
% Survival
Docetaxel 75 mg/m2
Best supportive care
Shepherd et al. J Clin Oncol. 2000;18:2095.

104. TAX 320B: Second-Line NSCLC Schema
Stage III/IV locally advanced or metastatic NSCLC
Stratified by:
Response to previous platinum-based therapy PS
N = 373
Arm A q 3w Docetaxel 75 mg/m2 N = 125
Arm B q 3w
Docetaxel 100 mg/m2 N = 125
Arm C q 3w Control
Vinorelbine 30 mg/m2 days 1, 8, 15
or ifosfamide 2 mg/m2 days 1-3
N = 123
RANDOMIZE
Fossella et al. J Clin Oncol. 2000;18:2354.

105. TAX 320B: Second-Line NSCLC Survival
100
Docetaxel vs. Vinorelbine or Ifosfamide
Docetaxel 75 mg/m2 vs. vinorelbine/ifosfamide
1-year survival 30% vs. 20%; P=0.05, 2
Median 5.7 vs. 5.6 mos. (NS) 80 60
Docetaxel 100 mg/m2 vs. vinorelbine/ifosfamide
1-year survival 23% vs. 20%
Median 5.5 vs. 5.6 mos. (NS)
% Survival 40 20
Docetaxel 100 mg/m2
Docetaxel 75 mg/m2
Vinorelbine/ifosfamide 3 6 9 12 15 18 21
Months
NS = not significant.
Fossella et al. J Clin Oncol. 2000;18:2354.

106. Pemetrexed vs. Docetaxel for Second-Line NSCLC Schema
Stage IIIB or IV NSCLC
Stratified by: PS
Prior platinum or paclitaxel therapy
Number of prior therapies
Best response to chemotherapy
Time since last chemotherapy
Geographic region
N = 571
RANDOMIZE
Arm A q 3w
Pemetrexed 500 mg/m2 day 1
N = 283
Arm B q 3w
Docetaxel 75 mg/m2 day 1
N = 288
Hanna et al. J Clin Oncol. 2004;22:1589.

107. Pemetrexed vs. Docetaxel for Second-Line NSCLC Overall Survival (ITT)
Survival Distribution
Months
0.00
0.25
0.50
0.75
1.00
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
MST 8.3 mos.
1-yr OS: 29.7%
HR = 0.99
95% CI of HR (0.82, 1.20)
MST 7.9 mos.
Pemetrexed (N = 283)
Docetaxel (N = 288)
ITT = intent to treat
HR = hazard ratio
CI = confidence interval
MST = median survival time
Hanna et al. J Clin Oncol. 2004;22:1589.

108. Pemetrexed vs. Docetaxel for Second-Line NSCLC Progression-Free Survival (ITT)
0.00
0.25
0.50
0.75
1.00
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Months
% Progression
MPFS = 2.9 mos.
HR = 0.97
95% CI of HR (0.82, 1.16)
Pemetrexed (N = 283)
Docetaxel (N = 288)
ITT = intent to treat
HR = hazard ratio
CI = confidence interval
MPFS = median progression-free survival
Hanna et al. J Clin Oncol. 2004;22:1589.

109. Pemetrexed vs. Docetaxel for Second-Line NSCLC Response Rates
Percent (%)
[CI=5.9,13.2]
[CI=5.7,12.8]
Hanna et al. J Clin Oncol. 2004;22:1589.

110. Pemetrexed vs. Docetaxel for Second-Line NSCLC Hematological Toxicities
Pemetrexed Docetaxel
Grade 3/4 (% patients) (N = 265) (N = 276) P-value
Neutropenia < .001
Febrile Neutropenia < .001
Infect w/ Gr 3/4 Neutropenia
Anemia
Thrombocytopenia 2 <
Hanna et al. J Clin Oncol. 2004;22:1589.

111. Pemetrexed vs. Docetaxel for Second-Line NSCLC Hospitalizations, Transfusions & Growth Factors
Pemetrexed Docetaxel
(N = 265) (N = 276) P-value
Patients with ≥ 1 hosp % 40.6% .032
due to an adverse event
Total hospitalizations % 13.4% < .001
due to febrile neutropenia
G-CSF/GM-CSF 2.6% 19.2% < .001
Erythropoietin 6.8% 10.1% .169
Red blood cell 16.6% 11.6% .085
transfusions
Hanna et al. J Clin Oncol. 2004;22:1589.

112. Phase III Trial of Erlotinib in Advanced NSCLC (BR.21): Schema
Erlotinib 150 mg/d
+ best supportive care
N = 488
Placebo
N = 243 R A N D O M I Z E
2:1 randomization to the experimental arm.
Stage IIIB/IV locally advanced or metastatic NSCLC
PS 0-3
≥1 failed prior chemotherapy regimen
≥18 years
No prior HER1/EGFR inhibitors
No prior malignancies or uncontrolled CNS metastases
Stratified by
Center
PS (0/1 vs 2/3)
Response to prior therapy (CR/PR:SD:PD)
Prior regimens (1 vs 2)
Prior platinum (Yes vs No)
N=731
Primary End Point: Overall survival
Secondary: Time to deterioration, PFS, ORR, duration of response , QOL, safety
Shepard et al. J Clin Oncol. 2004; 22(suppl)622. Abstract 7022 and oral presentation.

113. Phase III Trial of Erlotinib in Advanced NSCLC (BR.21): Schema
Erlotinib 150 mg/d
+ best supportive care
N = 488
Placebo
N = 243 R A N D O M I Z E
2:1 randomization to the experimental arm.
Stage IIIB/IV locally advanced or metastatic NSCLC
PS 0-3
≥1 failed prior chemotherapy regimen
≥18 years
No prior HER1/EGFR inhibitors
No prior malignancies or uncontrolled* CNS metastases
Stratified by
Center
PS (0/1 vs 2/3)
Response to prior therapy (CR/PR:SD:PD)
Prior regimens (1 vs 2)
Prior platinum (Yes vs No)
N=731
POSITIVE
Primary End Point: Overall survival
Secondary: Time to deterioration, PFS, ORR, duration of response , QOL, safety
Shepard et al. J Clin Oncol. 2004; 22(suppl)622. Abstract 7022 and oral presentation.

114. BR.21: Overall Survival 42.5% improvement in median survival
HR = 0.73; P < 0.001*
Erlotinib
(N = 488)
Placebo
(N = 243)
Median survival (mos.)
6.7
4.7
1-year survival (%) 31 21
Months
% Survival
100 80 40 20 60
*Adjusted for stratification factors at randomization, and HER1/EGFR status.
Adapted from Shepherd et al. J Clin Oncol. 2004;22(suppl):622. Abstract 7022 and oral presentation; Data on file, Genentech, Inc.

115. BR.21: Survival Across Subgroups
Subset n
All patients
731
PS 0-1
486
PS 2-3
245
Male
475
Female
256
<65 y
452
65 y
279
Adenocarcinoma
365
Squamous cell carcinoma
222
Other histology
144
Prior wt loss <5%
Prior wt loss 5%-10%
132
Prior wt loss >10% 81
Never smoked
146
Current/ex-smoker
545
1 prior regimen
364
2 prior regimens
367 1 2 3
Decreased risk of death
Increased risk of death
Circle size proportional to subset size.
Data on file, Genentech, Inc.

116. BR.21: Survival by Gender Female Male
HR = 0.80 (95% CI, ) RR = 14.4%
Months
% Survival
Placebo
(N = 83)
Erlotinib
(N = 173)
100 80 60 40 20
Male
HR = 0.76 (95% CI, ) RR = 6.0%
MS: 5.7 vs. 4.5 mos.
Months
% Survival
Placebo
(N = 160)
Erlotinib
(N = 315)
100 80 60 40 20
Adapted from Shepherd et al. J Clin Oncol. 2004;22(suppl)622. Abstract 7022 and oral presentation; Data on file, Genentech, Inc.

117. BR.21: Survival by Histology
Squamous Cell Carcinoma
HR = 0.72 (95% CI, ) RR = 13.9%
MS: 7.8 vs. 5.4 mos.
Adenocarcinoma
Months
Survival distribution function
Placebo
(N = 119)
Erlotinib
(N = 246)
1.00
0.75
0.50
0.25
HR = 0.67 (95% CI, ) RR = 3.8%
MS: 5.6 vs. 3.6 mos.
1.00
Months
0.75
0.50
0.25
Survival distribution function
Placebo
(N = 78)
Erlotinib
(N = 144)
Adapted from Shepherd et al. J Clin Oncol. 2004;22(suppl)622. Abstract 7022 and oral presentation; Data on file, Genentech, Inc.

118. BR.21: Survival by Smoking History
Never Smoked
HR = 0.42 (95% CI, ) RR = 24.7%
Months
% Survival
100 80 60 40 20
Placebo
(N = 42)
Erlotinib
(N = 104)
Current and Ex-smokers
HR = 0.87 (95% CI, ) RR = 3.9%
Months
100 80 60 40 20
Placebo
(N = 187)
Erlotinib
(N = 358)
% Survival
Adapted from Shepherd et al. J Clin Oncol. 2004;22(suppl)622. Abstract 7022 and oral presentation; Data on file, Genentech, Inc.

119. ASCO 2007 – NSCLC
Commentary