1. Personalized Therapeutic Approaches for NSCLC Case Discussions
Roman Perez-Soler, MD
Montefiore Medical Center
Albert Einstein College of Medicine

2. Disclosure Slide Consultant and Speakers Bureau
Genentech BioOncology, Lilly USA LLC, Roche Laboratories Inc

3. Case 1: Adenocarcinoma, wt EGFR, Cavitated Primary Tumor
59-year-old female, smoker 20 pack x year
Chest pain, weight loss, PS 1, no hemoptysis
Bronchoscopy: Adenocarcinoma, wt EGFR
Stage IV: T2 N2 (R mediastinum) M1 (bone, adrenals)
No brain metastases

5. Possible Options Paclitaxel/carboplatin/bevacizumab (Phase III, E4599)
Pemetrexed/cisplatin (Phase III, Scagliotti et al)
Vinorelbine/cisplatin/cetuximab (Phase III, FLEX)
Docetaxel/cisplatin (Phase III, TAX 326)
Pemetrexed/carboplatin/bevacizumab (Phase II, Patel et al)

6. Case 1: Follow-Up
Patient was treated with carboplatin, paclitaxel and bevacizumab and achieved a partial response after 2 cycles

8. Case 1: Follow-Up
Patient completed 4 cycles of therapy and was put on bevacizumab maintenance
Patient progressed after 4 cycles of bevacizumab maintenance, started erlotinib, had stable disease for 5 months, progressed and was treated with pemetrexed

9. Discussion Points
What is the best chemotherapy in combination with bevacizumab in NSCLC?
What are the current contraindications for the use of bevacizumab in NSCLC?
Is the type of non-squamous histology important for the use of bevacizumab?
Why not treat this patient with pemetrexed + cisplatin given the 2-month median survival superiority over gemcitabine + cisplatin in Scagliotti’s study?
Would switch maintenance therapy with pemetrexed or erlotinib be a reasonable option for this patient?
Are there any biomarkers to predict bevacizumab antitumor efficacy?
Should this tumor be tested for the ALK translocation nowadays?

10. Comments (1)
Carboplatin/paclitaxel is the only chemotherapy regimen with which bevacizumab has shown to have an impact on survival.
Main current contraindications for the use of bevacizumab are squamous histology, hemoptysis and history of severe cardiovascular disease.
Tumor cavitation, brain metastases and use of anticoagulation are not contraindications.
Best survival results in E4599 were observed in patients with adenocarcinoma (14 vs 10 months).

11. Comments (2)
The use of cisplatin + pemetrexed as front-line therapy has emerged more recently as an excellent option but precludes the use of bevacizumab for the treatment of this patient as bevacizumab is only approved and has only shown clinical benefit as front-line therapy.
Switch maintenance is a form of early second-line therapy and appears to benefit more patients with stable disease with front-line therapy than patients with a response to front-line therapy.
There are no biomarkers predictive of bevacizumab efficacy in NSCLC. In other tumors, VEGF levels have been found to be predictive of efficacy.
The ALK translocation should be analyzed in oligosmokers who have wt EGFR tumors.

12. Case 2: Adenocarcinoma, Brain Mets, wt EGFR
61-year-old female, 80 pack x year tobacco use, quit 1 year ago, well-controlled hypertension, no hemoptysis
Dizziness, ataxia
MRI brain: Large cerebellar tumor, numerous bilateral brain metastases
PET/CT: RUL mass, bilateral pulmonary nodules, liver metastases
Resection of cerebellar tumor
Histology: Adenocarcinoma, wt EGFR, ALK translocation not tested

14. Case 2: Adenocarcinoma, Brain Metastases, EGFR wt — Follow-Up
Whole brain XRT: Asymptomatic off dexamethasone
Started on pemetrexed/carboplatin/bevacizumab
Good tolerance to treatment, except significant nausea
Remarkable response after 4 cycles

16. Discussion Points
Is pemetrexed + carboplatin + bevacizumab a reasonable option for this patient?

17. Pemetrexed/Carboplatin/Bevacizumab
Bevacizumab 15 mg/kg
x 6 cycles
Efficacy outcomes
n = 49
Overall response rate
55%
Best response, n Complete response Partial response Stable disease Progressive disease
Median PFS, months (95% CI)
9.3 (5.5–15.0)
Median OS, months (95% CI)
13.5 (10.8–19.6)
PD/ toxicity
Off study
CR/PR/SD
Pemetrexed*
Bevacizumab 15 mg/kg
until PD or unacceptable toxicity
Primary endpoint: PFS
* Vitamin B12, folate and dexamethasone given
Patel et al. ASCO 2008

18. Comment
The combination of pemetrexed + cisplatin is superior to gemcitabine + cisplatin in patients with adenocarcinoma histology (Scagliotti study).
The best survival results in E4599 were observed in patients with adenocarcinoma, with little impact observed in other non-squamous histologies.
Although there is only Phase II data supporting the use of bevacizumab with pemetrexed combinations, these two observations have led to the widespread use of pemetrexed + bevacizumab combinations for the treatment of patients with adenocarcinoma.

19. Discussion Points
Is pemetrexed + carboplatin + bevacizumab a reasonable option for this patient?
Is continuation maintenance pemetrexed a reasonable option for this patient?

20. Comments
Continuation maintenance with pemetrexed has been recently reported to prolong PFS in patients with non-small cell lung cancer (PARAMOUNT study).
In contrast with switch maintenance therapy, continuation maintenance is a form of therapy intensification and as such appears to benefit mostly those patients who achieve a response with front-line therapy.
Therefore, this patient would be a good candidate for continuation pemetrexed maintenance therapy.

21. Paramount: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
21 to 42 Days
Maintenance Therapy (Until PD)
500 mg/m2 Pemetrexed + BSC, d1, q21d
Patients enrolled if:
Nonsquamous NSCLC
No prior systemic treatment for lung cancer
ECOG PS 0/1
CR, PR, SD
2:1 Randomization
Placebo + BSC, d1, q21d
Stratified for:
PS (0 vs 1)
Disease stage (IIIB vs IV) prior to induction
Response to induction (CR/PR vs SD)
500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d PD
Randomized, placebo-controlled, double-blind, Phase III study
Folic acid and vitamin B12 administered to improve pemetrexed tolerability
PD: progressive disease, BSC: best supportive care, CR: complete response, PR: partial response, SD: stable disease, NSCLC: non-small cell lung cancer, ECOG: Eastern Cooperative Oncology Group, PS: performance status 21 21

22. Investigator-Assessed Progression-Free Survival (Induction Phase)
Placebo + BSC (n = 180)
Pemetrexed + BSC (n = 359)
p-value
Hazard ratio*
Median PFS (months)
5.59
6.90
<
0.59
* Unadjusted BSC = best supportive care 22 22

23. Case 2: Adenocarcinoma, Brain Metastases, wt EGFR — Follow-Up
Continued on pemetrexed/bevacizumab maintenance
Developed thrombocytopenia that required pemetrexed dose reduction
PD after 6 cycles of pemetrexed/bevacizumab maintenance, started on erlotinib, no response
ALK translocation not tested

24. Case 3: Second-Line Treatment Squamous Cell Carcinoma
68-year-old white male, smoker since age 21, current smoker of 1 pack/day
Presents with 2.5 cm-spiculated peripheral mass in RUL, no clear hilar adenopathy
PET/CT: Bilateral adrenal metastases
CT brain negative
Bronchoscopy: Squamous cell carcinoma
PS 2: Cough, SOB on exertion, weight loss
Started on carboplatin + paclitaxel: PD in lung and adrenal glands after 2 cycles

25. Case 3: Squamous Cell Carcinoma — Options
Docetaxel
Erlotinib
Docetaxel + cetuximab

26. Case 3: Squamous Cell Carcinoma — Follow-Up
Started on erlotinib
Symptom improvement
No skin or GI toxicity
Stable disease at 8 weeks
Continues to smoke

27. Case 3: Squamous Cell Carcinoma — Options
Docetaxel
Increase erlotinib to 200 mg
Continue erlotinib at 150 mg
Supportive care

28. Discussion Points
Is vinorelbine + cisplatin + cetuximab a better option than carboplatin + paclitaxel in a patient with squamous carcinoma?
Is erlotinib inferior to docetaxel in this setting?
Is there a rationale for erlotinib dose adjustment?
Are there any new agents with a preferential activity against squamous carcinoma?

29. Comments
Cetuximab is the only targeted agent that has shown to add to chemotherapy in patients with squamous carcinoma (FLEX study).
EGFR expression by IHC staining has been recently shown to be a predictor of benefit with chemotherapy + cetuximab (IHC score >200).
Erlotinib has similar activity to docetaxel in non-selected patients in the second-line setting and is less toxic.
Current smokers must quit smoking before starting erlotinib or must have the erlotinib dose adjusted.
Several new agents have shown preliminarily a preferential activity against squamous carcinoma.

30. FLEX: OS — Caucasians (N = 946) Prespecified Analysis
Median OS
1-year survival
CV + cetuximab (N = 466)
10.5 mos
45%
CV (N = 480)
9.1 mos
37%
HR = 0.803; p = 0.003
p-value: stratified log-rank test (2-sided)
Median OS
CV + cetuximab CV HR
Caucasians (N = 946)
10.5 mos
9.1 mos
0.803
Adenocarcinoma (N = 413)
12.0 mos
10.3 mos
0.815
Squamous cell (N = 347)
10.2 mos
8.9 mos
0.794
Other (N = 185)
9.0 mos
8.2 mos
0.807
CV = cisplatin/vinorelbine
Pirker. ASCO 2008 (abstr 3). 30 30

31. Survival in the High EGFR Expression Group (N = 345)
Median OS
1-year
2-year
CT + cetuximab
12.0 mo
50%
24% CT
9.6 mo
37%
15%
Hazard ratio = 0.73 (95% CI ); p = 0.011
Pirker R, Paz-Ares L. Proc IASLC 2011;Abstract 1557. 31 31

32. Erlotinib Is Effective in Both Squamous and Non-Squamous Tumours
Adenocarcinoma: HR = 0.7; p = 0.008*
Squamous: HR = 0.67; p = *
* Log-rank test
Shepherd FA et al. N Engl J Med 2005;353(2): 32 32

33. Comparison of Phase III Trials in Relapsed NSCLC: Efficacy*
Outcome
Erlotinib1,2 150 mg/day
Docetaxel3,4 75 mg/m2
Pemetrexed5 500 mg/m2
Response rate (%)
8.9
7.1–8.8
9.1
Median duration of response (months)
7.9
5.3–9.1
4.6
1-year survival rate (%) 31
30–37 30
Median survival in PS 0/1 patients with 1 prior regimen (months)
9.42
9.15
9.45
Median survival (months)
6.7
5.7–7.9
8.3
Erlotinib and chemotherapy have similar efficacy in the second-line setting
* Results cannot be compared directly because of different patient populations
1 Shepherd F et al. N Engl J Med 2005;353:123–32; 2 OSI and Roche data on file; 3 Shepherd F et al. J Clin Oncol
2000;18:2095–103; 4 Fossella F et al. J Clin Oncol 2000;18:2354–62; 5 Hanna N et al. J Clin Oncol 2004;22:1589–97. 33 33

34. Phase III TITAN-SLS (BO18602): Erlotinib in Treatment of Advanced NSCLC — Second-Line Setting
Tumour samples
Erlotinib
150 mg/day PD
Off study
4 cycles of first-line standard platinum-based doublet
Chemotherapy naïve Stage IIIb/IV NSCLC PD
Pemetrexed or docetaxel PD
Off study
Non-PD
SATURN
Primary endpoint = OS
Secondary endpoints = PFS, RR, QoL (FACT-L), correlation of biomarkers with clinical outcome
Ciuleanu T et al. Chicago Multidisciplinary Symposium in Thoracic Oncology, Dec 2010 (Abs. LBOA5)

35. Similar OS with Second-Line Erlotinib and Chemotherapy in EGFR wt NSCLC: TITAN
Erlotinib (n = 75), median OS = 6.6 months
Chemotherapy (n = 74), median OS = 4.4 months
Hazard ratio = 0.85
Ciuleanu T et al. Chicago Multidisciplinary Symposium in Thoracic Oncology, Dec 2010 (Abs. LBOA5)

36. PKs of Erlotinib in Smokers versus Non-Smokers (Healthy Volunteers)
Single dose of erlotinib 150 mg
AUC0–∞ non-smoker (18,726 ng•h/mL)
AUC0–∞ smoker (6,718 ng•h/mL) p < Exposure in smokers versus non-smokers = 35.9%
Cmax non-smoker (1,056 ng/mL)
Cmax smoker (689 ng/mL) p = 0.310
Maximum exposure in smokers versus non-smokers = 65.2%
Likely explanation: Cigarette smoke induces CYP enzymes responsible for metabolism of erlotinib
Hamilton et al. Proc Am Assoc Cancer Res 2005.
Hamilton et al. Clin Cancer Res 2006.

37. Agents with Claimed Preferential Activity in Squamous Cell Carcinoma
Anti IGF-1R antibody: Figitumumab
Nab paclitaxel
Anti CTLA-4 antibody: Ipilimumab

38. Case 3: Squamous Cell Carcinoma — Follow-Up
Patient was convinced to quit smoking
Erlotinib dose was increased to 200 mg and rash Grade 1 was noted
Patient had SD for 6 months and then progressed

39. Case 4: Adenocarcinoma, EGFR Mutant
76-year-old female, Chinese, never smoker
Presents with shortness of breath
PET/CT shows large R pleural effusion, RLL mass and R mediastinal adenopathy
PS 1, no hemoptysis, no brain metastases
Pleural fluid: Adenocarcinoma, EGFR mutation analysis pending
Stage IVa adenocarcinoma

40. Case 4: Adenocarcinoma, Never Smoker, EGFR Pending — Options
Paclitaxel/carboplatin/bevacizumab
Pemetrexed/cisplatin
Wait for EGFR mutation analysis
Erlotinib

41. Case 4: Adenocarcinoma, Never Smoker, EGFR Pending/Mutant
Started with paclitaxel/carboplatin/bevacizumab
Good tolerance to first cycle of treatment
EGFR mutation test reported before cycle #2: Exon 19 deletion
Patient continued on paclitaxel + carboplatin + bevacizumab: SD after 2 cycles, PD in lung lesion after 4 cycles

43. Case 4: Adenocarcinoma, EGFR Mutant
Started on erlotinib 150 mg
Symptom improvement at one week; skin rash Grade 2 at 2 weeks
Tumor response on PET/CT at 6 weeks Continues with minimal residual disease on erlotinib 150 mg at 36 months

45. Case 5: Adenocarcinoma, EGFR Mutant
62-year-old male from Dominican Republic; 5 pack x year smoking history, quit 38 years ago
Presents with headache at another hospital
MRI shows multiple brain metastases
PET/CT shows spiculated LUL mass: FNA shows adenocarcinoma
Tumor sent for EGFR testing
Whole brain radiotherapy
Pemetrexed + cisplatin x 2: No response

46. Case 5: Adenocarcinoma, EGFR Mutant
Referred to our Institution
EGFR mutations analysis results received after starting first cycle of chemotherapy show exon 19 deletion
Started on erlotinib 150 mg
Develops Grade 2 rash and Grade 3 paronychia: Dose adjusted to 100 mg
Complete remission at 6 weeks
Last follow-up at 18 months shows no evidence of disease in brain and lungs
Continues with erlotinib 100 mg with Grade 1 rash

49. Discussion Points
Unless patients are highly symptomatic, physicians should wait for results of EGFR mutation analysis before starting therapy with chemotherapy
Both patients did not respond to front-line chemotherapy
Caucasian patients with EGFR-mutated tumors have a very low response to chemotherapy (15%, EURTAC study, ASCO 2011)
What are the options for tumors that develop resistance to erlotinib?

50. Platinum-based doublet chemotherapy q3w x 4 cycles*
EURTAC Study Design
EURTAC; NCT
Erlotinib 150 mg/day PD
Chemonaїve
Stage IIIB/IV NSCLC
EGFR exon 19 deletion or exon 21 L858R mutation
ECOG PS 0–2
(n = 174)
Stratification
Mutation type
ECOG PS (0 vs 1 vs 2) R
Platinum-based doublet chemotherapy q3w x 4 cycles* PD
Phase III, randomised, open-label, active-controlled
Primary endpoint
Progression-free survival (PFS)
Interim analysis planned at 88 events
Secondary endpoints
Objective response rate (ORR)
Overall survival (OS)
Location of progression
Safety
EGFR mutation analysis in serum
Quality of life (QoL)
* Cisplatin 75 mg/m2 d1/docetaxel 75 mg/m2 d1; cisplatin 75 mg/m2 d1/gemcitabine 1,250 mg/m2 d1,8; carboplatin AUC6 d1/docetaxel 75 mg/m2 d1; carboplatin AUC5 d1/gemcitabine 1,000 mg/m2 d1,8.
With permission from Rosell R et al. Proc ASCO 2011;Abstract 7503. 50 50

51. EURTAC Best Overall Response in ITT Population
Interim analysis (Aug 2, 2010)
Updated analysis (Jan 26, 2011)
Erlotinib (n = 77)
Chemotherapy (n = 76)
Erlotinib (n = 86)
Chemotherapy (n = 87)
Complete response 3 2
Partial response 52 11 56 15
ORR 55 58
Stable disease 23 21 51
Disease control rate 78 66 79
Progressive disease 8 13 7
No response assessment 14 22
Rosell R et al. Proc ASCO 2011;Abstract 7503. 51 51

52. EURTAC PFS in ITT Population (Updated Analysis 26 Jan 2011)
1.0
0.8
0.6
0.4
0.2
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR = 0.37 (0.25–0.54)
Log-rank p <
PFS probability
5.2
9.7
Time (months)
Patients at risk
Erlotinib Chemo
With permission from Rosell R et al. Proc ASCO 2011;Abstract 7503. 52 52

53. Resistance to Erlotinib
EGFR mutant tumors: Irreversible EGFR inhibitors have shown activity against tumors carrying the T790M EGFR resistance mutation: Afatinib
EGFR wild-type and mutant tumors: MET pathway activation has been identified as a mechanism of resistance to erlotinib: MetMAb
Pemetrexed and erlotinib are synergistic in second- line therapy

54. MetMAb + Erlotinib as Second-Line Therapy in Met+ Patients
The addition of MetMAb to erlotinib in this population resulted in a 2-fold reduction in the risk of progression and a near 3-fold reduction in the risk of death
Erlotinib + placebo
Erlotinib + MetMAb
Median (months)
1.5
2.9
95% CI
0.28–0.99
Erlotinib + placebo
Erlotinib + MetMAb
Median (months)
3.8
12.6
95% CI
0.19–0.72
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
PFS: HR = 0.53
OS: HR = 0.37
Probability of progression free
Probability of overall survival 3 6 9 12 15 18 3 6 9 12 15 18 21
Time (months)
Time (months)
With permission from Spigel D et al. Proc ASCO 2011;Abstract 7505. 54 54

55. Pemetrexed vs Pemetrexed + Erlotinib in Second-Line TherapyHR RR
10.8%
17.1%
0.181
PFS
2.9 mo
3.2 mo
0.62 OS
7.8 mo
11.8 mo
0.68
Von Pawel J et al. Proc ASCO 2011;Abstract 7526.