1. Therapeutic Algorithm for Lung Adenocarcinoma
Suresh S. Ramalingam, MD Professor
Director of Medical Oncology
Emory University
Atlanta, USA

2. Disclosures Advisory board
Amgen, Aveo, Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Clovis, Genentech, Lilly, Novartis

3. Outline Role of systemic chemotherapy Integration of targeted agents
Targeted agents with salvage chemotherapy

4. Treatment Algorithm For Advanced NSCLC
Lung Adenocarcinoma
Known Oncogenic Driver
Targetable
(EGFR, ALK, ROS)
Targeted Therapy
First-line, Maintenance or Salvage
No Proven Targeted Therapy
(KRAS, HER2, RAF, MET, PIK3CA)
Clinical Trial or Chemotherapy
Absence of Driver Mutations / Unknown Molecular Status
Chemotherapy

5. First- Line TKI Therapy in EGFR Mutated NSCLC—Randomized Phase III Trials
Study N
Treatment
Arm
Control
Stage
Median
PFS OS
Indication
IPASS
(Mok TS, et al.
N Engl J Med.
2009;361: )
1217
Gefitinib
Carboplatin/ Placitaxel
IIIB/IV
5.7 vs 5.8 months (HR for EGFR mutated pts 0.48; HR for nonmutated pts 2.84)
18.6 vs 17.3 months
(P = NS)
First-line
WJTOG3405
(Mitsudomi T, et al. Lancet Oncol. 2010;
11: )
177 (M+)
Cisplatin, Docetaxel
9.2 vs 6.3 months
(P < 0.001)
Maemondo M, et al. N Engl J Med. 2010;
362:
230 (M+)
Carboplatin, Paclitaxel
10.8 vs 5.4 months (HR 0.3, P < )
30.5 vs 23.6 months
OPTIMAL
(Zhou C, et al.
Lancet Oncol. 2011;12: )
165 (M+)
Erlotinib
Carboplatin/
Gemcitabine
13.6 vs 4.6 months (HR 0.16, P < )
EURTAC
(Rosell R, et al.
Lancet Oncol. Jan 25, 2012 [Epub ahead of print].)
153 (M+)
Platinum-based chemotherapy
9.4 vs 5.2 months (HR, 0.42, P < )
22.9 vs 18.8 months
(P = 0.42)
PFS is superior, no survival advantage for first line TKI- effect of cross-over

6. Afatinib Vs. Chemotherapy
Exon 19
Exon 21
Yang et al, Lancet Oncol, 2015

7. Phase III Study in Chemotherapy Naïve Patients with NSCLC: Study Design
Pemetrexed 500 mg/m2 +
Cisplatin 75 mg/m2 day 1
Stage IIIB/IV NSCLC
PS 0-1
No prior chemo
Randomization: gender, PS, stage, histo vs cyto dx, brain mets
Primary objective: OS
15% non-inferiority margin (HR 1.17)
N = 1700, Power 80% R
Gemcitabine 1250 mg/m2 +
Cisplatin 75 mg/m2 day 1;
Gemcitabine 1250 mg/m2 day 8
B12, folate, and dexamethasone given in both arms
Scagliotti GV et al. J Clin Oncol. 2008;26:

8. Overall Survival: Entire Patient Population and Patients With Non Squamous Histology
Median; 95% CI CP
10.3; 9.8, 11.2 CG
10.3; 9.6, 10.9
CP vs CG
Adjusted HR; 95% CI
0.94; 0.84, 1.05
Median; 95% CI CP
11.8; 10.4, 13.2 CG
10.4; 9.6, 11.2
CP vs CG
Adjusted HR; 95% CI
0.81; 0.70, 0.94
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1 6 12 18 24 30
Survival Time (months) in All Patients
Survival Probability
Survival Time (months) in Patients
With Nonsquamous Histology
Scagliotti GV et al. J Clin Oncol. 2008;26: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

9. Docetaxel + Cisplatin versus Pemetrexed + Cisplatin in 1st Line non-squamous NSCLC
Study objective
To prove the non-inferiority of docetaxel + cisplatin compared with pemetrexed + cisplatin in patients with non-squamous NSCLC
Docetaxel 60 mg/m2 + cisplatin 70 mg/m2 q3w, up to 4 cycles (n=76)
Key patient inclusion criteria
Stage IV non-squamous NSCLC
Chemotherapy naïve
ECOG PS 0–2
(n=156)
Pemetrexed or EGFR-TKI or docetaxel
Stratification
ECOG PS (0–1 vs. 2) and sex R
1:1
Pemetrexed 500 mg/m2 + cisplatin 70 mg/m2 q3w, up to 4 cycles (n=80)
Primary endpoint
PFS
Secondary endpoints
Response rate, ORR and safety
Note: the trial was closed early due to slow accrual and, therefore, the results should be interpreted with caution
Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

10. PFS & OS
Partial remission was observed in 33.3% of patients who received docetaxel + cisplatin, compared with 31.2% who received pemetrexed + cisplatin OS
PFS
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Docetaxel + cisplatin: 28.0 months (95% CI 7.5, 48.5)
Pemetrexed + cisplatin: 19.7 months (95% CI 10.8, 28.6)
Docetaxel + cisplatin: 4.6 months (95% CI 3.7, 5.6)
Pemetrexed + cisplatin: 4.7 months (95% CI 4.4, 5.1)
HR (95% CI 0.74, 1.40)
Days
Days
Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

11. Pemetrexed + cisplatin
Toxicity
Compared with pemetrexed + cisplatin, significantly higher rates of grade 3/4 neutropenia and febrile neutropenia, as well as a greater number of SAEs were observed with docetaxel + cisplatin
Conclusion
In patients with non-squamous NSCLC, treatment with docetaxel + cisplatin produced similar PFS and response rate as pemetrexed + cisplatin, but was associated with more SAEs and toxicity
Docetaxel + cisplatin
(n=72)
Pemetrexed + cisplatin
(n=77)
Neutropenia grade 3/4
10 (13.9%)**
1 (1.3%)
Febrile neutropenia
8 (11.1%)*
Total number of SAE 42 24
Number of cases with SAE
29 (40.3%)*
17 (22.1%)
*p<0.05, **p<0.01
Kim et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA41_PR

12. No Premedication for hypersensitivity Dexamethasone + Antihistamines
Nab-Paclitaxel
Albumin-bound paclitaxel
100 mg/m2 d1, 8, 15
Carboplatin AUC 6 d1
21 Day Cycles
No Premedication for hypersensitivity
Chemo-naive
PS 0-1
Stage IIIb/IV NSCLC
N = 1,050
1:1
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
21 Day Cycles
With Premedication of
Dexamethasone + Antihistamines
Dr Socinski
Stratification factors:
Stage (IIIb vs IV)
Age (<70 vs ≥70)
Sex
Histology (squamous vs nonsquamous)
Geographic region
Socinski, MA et al. J Clin Oncol., 2012.

13. Objective Responses by Histology*
ab-P/C showed 67% improvement in response rate over P/C in squamous patients
Response ratio = P = 0.808
Response ratio = P < 0.001
Percent Responses
Ab-P/C (n=228) P/C (n=221)
Dr Socinski
Yellow font: Increased RR in SCCA
*Subgroup analyses exploratory in nature; by independent radiologic review

14. Summary of Efficacy By Histology
Population
Ab-P/Carbo (ORR, PFS, OS)
Paclitaxel/Carbo (ORR, PFS, OS)
RR/HR (PFS, OS)
P-Value (ORR, PFS, OS)
ITT
(n=1052)
33%
6.3 mos
12.1 mos
25%
5.8 mos
11.2 mos
1.313
0.902
0.922
0.005
0.214
0.271
Squamous (n=450)
41%
5.6 mos
10.7 mos
24%
5.7 mos
9.5 mos
1.680
0.865
0.890
<0.001
0.245
0.284
Non-Squamous (n=602)
26%
6.9 mos
13.1 mos
6.5 mos
13.0 mos
1.030
0.933
0.950
0.808
0.532
0.611
Dr Socinski

15. Phase III Trial of Bevacizumab in Non-Squamous NSCLC: ECOG 4599
CbP
Paclitaxel 200 mg/m2
Carboplatin AUC = 6
(q3wks) x 6 cycles
N = 855 (eligible)
Eligibility
– Non-squamous NSCLC
– No history of hemoptysis
– No CNS metastases
No crossover to bevacizumab permitted
CbP + Bevacizumab
CbP x 6 cycles +
Bevacizumab (15mg/kg q3wks) to PD
Stratification Variables
– RT vs. no RT
– Stage IIIB or IV vs. recurrent
– Weight loss < 5% vs. ≥ 5%
– Measurable vs. non-measurable
AUC=area under the curve; CbP=carboplatin, bevacizumab, paclitaxel; CNS=central nervous system; PD=progressive disease; RT=radiotherapy.
Sandler A, et al. N Engl J Med. 2006;355:

16. Carboplatin/Paclitaxel +/- Bevacizumab
RR: 15% for CbP vs. 35% for CbP + Bevacizumab
PFS OS
100
CbP
100
CbP
CbP + Bevacizumab
CbP + Bevacizumab 80 80
p < 0.001; HR = 0.66
Median PFS: 6.2 mos vs mos
6-Mos PFS: 55% vs. 33%
1-Yr PFS: 15% vs. 6%
p = 0.003; HR = 0.79
Median OS: 12.3 mos vs mos
1-Yr OS: 51% vs. 44%
2-Yr OS: 23% vs. 15%
Patients Surviving (%) 60 60
Patients With PFS (%) 40 40 20 20 6 12 18 24 30 36 6 12 18 24 30 36
Time (mos)
Time (mos)
CbP=carboplatin, bevacizumab, paclitaxel; PFS=progression-free survival; RR=response rate.
Sandler A, et al. N Engl J Med. 2006;355:

17. Are 4–6 Cycles of Chemotherapy Enough?
Diagnosis
CR/PR/SD
First-Line Treatment Platinum Doublet Chemotherapy
(4–6 cycles)
‘Watch-and-Wait’ PD
Second and Further Lines of Treatment
As a result of cumulative toxicity, patients receive a limited number of cycles of chemotherapy
‘Watch-and-Wait’ approach
According to ASCO guidelines, those with SD will be observed, with regular follow-up to check for PD
Pfister DG, et al. J Clin Oncol 2004;22:330–53
CR = complete response; PR = partial response; SD = stable disease; ASCO = American Society of Clinical Oncology.
Pfister DG et al. J Clin Oncol 2004;22:330–353. Azzoli CG et al. J Clin Oncol. 2009;27(36): 17 17

18. JMEN : Double-blind, Placebo-controlled, Multicenter, Phase III Trial of Maintenance Pemetrexed vs Placebo
Patients
- Stage IIIB/IV NSCLC
- PS 0-1
- 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD
Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*
2:1
Randomization
Primary Endpoint = PFS
Randomization factors:
gender PS
stage
best tumor response to induction
non-platinum induction drug
brain mets
Placebo (d1, q21d) + BSC (N=222)*
*B12, folate, and dexamethasone given in both arms
Ciuleanu T et al. Lancet. 2009;374: 18

19. Pemetrexed: Switch Maintenance
Improved overall survival over placebo
Pem
Placebo
PFS
OS (ITT Population)
Post study therapy: 51% in pem arm and 67% in placebo arm;
18% of placebo patients received post-study pemetrexed
Ciuleanu T et al. Lancet. 2009;374:

20. PARAMOUNT: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
Maintenance Therapy (Until PD)
21 to 42 Days
500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d
CR, PR, SD PD
Placebo + BSC, d1, q21d
500 mg/m2 Pemetrexed + BSC, d1, q21d
2:1 Randomization
Patients enrolled if:
Nonsquamous NSCLC
No prior systemic treatment for lung cancer
ECOG PS 0/1
Stratified for:
PS (0 vs 1)
Disease stage (IIIB vs IV) prior to induction
Response to induction (CR/PR vs SD)
Randomized, placebo-controlled, double-blind, phase III study
Folic acid and vitamin B12 administered to both arms
Paz-Ares LG et al. J Clin Oncol. 2013;31(23):

21. PFS
Paz-Ares LG et al. J Clin Oncol. 2013;31(23):

22. Outcomes for Subsets
Paz-Ares LG et al. J Clin Oncol. 2013;31(23):

23. SATURN Co-primary endpoints Secondary endpoints Placebo
Erlotinib
150mg/day PD
Chemonaïve advanced NSCLC
n=1,949
4 cycles of 1st-line platinum-based doublet*
Non-PD
n=889
1:1
Placebo PD
Mandatory tumor sampling
Co-primary endpoints
PFS in all patients
PFS in patients with EGFR IHC+ tumors
Secondary endpoints
Overall survival (OS) in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC– tumors; biomarker analyses; safety; time to symptom progression; quality of life (QoL)
Stratification factors:
EGFR IHC (positive vs negative vs indeterminate)
Stage (IIIB vs IV)
ECOG PS (0 vs 1)
CT regimen (cis/gem vs carbo/doc vs others)
Smoking history (current vs former vs never)
Region
889 is the intention to treat population (ITT)
Cappuzzo F et al. Lancet Oncol. 2010;11(6): 23

24. Erlotinib as Maintenance Therapy
All patients
EGFR mt
Cappuzzo F et al. Lancet Oncol. 2010;11(6):

25. AVAPERL: Bevacizumab ± Pemetrexed Continuation Maintenance
Edited JA 8/18/11
1:1
RANDOM I Z E
Bevacizumab
(7.5mg/kg) q3w
(7.5mg/kg) + pemetrexed q3w PD
Previously untreated stage IIIB/IV nonsquamous NSCLC
Bevacizumab
pemetrexed
cisplatin q3w
4 cycles of induction therapy (n=373)
Maintenance therapy (n=244)
Criteria: CR/PR/SD (RECIST)
Open-label, randomized, multicenter, phase III study
Stratified by: gender, smoking status (never smoker vs past/current smoker), and disease control after 4 cycles
Primary endpoint: PFS
Secondary endpoint: OS, safety
Barlesi F et al. J Clin Oncol. 2013;31(24):

26. Double Maintenance: PFS
From Induction
From Randomization
Barlesi et al,
Ann Oncol
2014

27. Overall Survival From Induction From Randomization Barlesi et al,
Ann Oncol
2014

28. Primary endpoint Overall Survival
ECOG 5508: Schema R A N D O MI Z E
Bevacizumab
IIIB/IV NSCLC
PS0/1
No Prior Tx
N=1495 CR PR SD
N=897
Carboplatin
Paclitaxel
Bevacizumab
X 4 cycles
Pemetrexed
Bevacizumab
Pemetrexed
Stratification Factors:
Smoking status, Gender
Histology, Best response, Stage
Primary endpoint Overall Survival

29. Salvage Therapy

30. TKI Vs. Chemotherapy in EGFR-WT
Lee et al, JAMA, 2014

31. Presented By Maurice Perol at 2014 ASCO Annual Meeting
REVEL: Study Design
Presented By Maurice Perol at 2014 ASCO Annual Meeting

32. Presented By Maurice Perol at 2014 ASCO Annual Meeting
Progression-Free Survival<br />ITT Population, Investigator Assessment
Presented By Maurice Perol at 2014 ASCO Annual Meeting

33. Overall Survival<br />ITT Population
Presented By Maurice Perol at 2014 ASCO Annual Meeting

34. Presented By Maurice Perol at 2014 ASCO Annual Meeting
Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm
Presented By Maurice Perol at 2014 ASCO Annual Meeting

35. Characteristics of Nintedanib
Oral angiokinase inhibitor targeting VEGFR 1–3, FGFR 1–3, and PDGFR α/β as well as RET1,2
No drug–drug interaction liability via CYP4503
Single-agent nintedanib was active in a phase II trial in recurrent NSCLC8
1. Hilberg F, et al. Cancer Res 2008;68:4774–8; 2. Data on File; 3. Stopfer P, et al. Xenobiotica 2011;41:297–311; 4. Bousquet G, et al. Br J Cancer 2011;105:1640–5; 5. Ellis PM, et al. Clin Cancer Res 2010;16:2881–9; 6. Doebele RC, et al. Ann Oncol 2012;23:2094–102; Data on File (clinicaltrials.gov NCT ); 7. Soria J-C, et al. Ann Oncol 2012;23(Suppl.9): abs 979; 8.Reck M, et al. Ann Oncol 2011;22:1374–81.

36. LUME-Lung 1 Study Design
RANDOMIZE
Nintedanib 200mg BID p.o., D2–21, + Docetaxel 75mg/m2 IV, D1, 21-day cycles (n=655) PD
Stage IIIB/IV or recurrent NSCLC patients after 1st line chemotherapy
(all histologies)
1:1
Placebo BID p.o., D2–21, + Docetaxel 75mg/m2 IV, D1, 21-day cycles (n=659) PD
N=1314
Number of docetaxel cycles not restricted
Monotherapy allowed after ≥4 cycles of combination therapy
Stratification: ECOG PS (0 vs 1)
Prior bevacizumab (yes vs no)
Histology (squamous vs non-squamous)
Brain metastases (yes vs no)
Regions: Europe / Asia / South Africa
Accrual: Dec 23, to Feb 9, 2011

37. Overall Survival Patients with Adenocarcinoma Histology
100
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
12.6
10.3
HR (95% CI)
0.83 (0.70 to 0.99)
p-value
0.0359 80 60
52.7%
Probability of survival (%) 40
44.7%
25.7% 20
Analysis of OS in the adenocarcinoma patient subpopulation showed a statistically significant improvement favoring treatment with nintedanib + docetaxel over placebo + docetaxel. Second-line treatment with the nintedanib/docetaxel combination increased median OS to 12.6 months, i.e. more than 1 year, compared with 10.3 months in the placebo + docetaxel arm; a median improvement of 2.3 months. The hazard ratio for the difference was 0.83 and the associated p-value was
19.1%
Time (months)
No. at risk
Nintedanib
Placebo

38. Adenocarcinoma histology
GALAXY-1 Study Schema
Ganetespib + Docetaxel
G: 150 mg/m2 days 1,15 q3w
D: 75 mg/m2 day 1 q3w
Advanced NSCLC
1 prior regimen
Adenocarcinoma histology
RANDOMIZE 1:1
Docetaxel
D: 75 mg/m2 day 1 q3w
Stratification Factors
ECOG PS (0 vs. 1)
Time since diagnosis of advanced disease (≤6 mo vs. >6 mo)
Baseline serum LDH (< or > ULN)
Smoking status
Endpoints
Co-primary: PFS in elevated LDH, mKRAS groups
Key secondary: PFS and OS in all adenocarcinoma patients
Ramalingam SS et al. WCLC

39. Population selected for Phase 3
Summary: PFS, OS
Hazard Ratio
G+D vs. D
(90% CI)
Elevated LDH
N=76
mKRAS
N=63
Chemosensitive
(Dx >6m)
N=178
ITT
N=252
PFS
Unadjusted
0.94 (0.57, 1.36)
p=0.409
0.83 (0.52, 1.33)
p=0.256
0.73 (0.55, 0.96)
p=0.031
0.84 (0.67, 1.06)
p=0.114
Adjusted
0.69 (0.43, 1.08)
p=0.088
0.95 (0.58, 1.54)
p=0.427
0.72 (0.53, 0.96)
p=0.030
0.84 (0.66, 1.06)
p=0.110 OS
0.69 (0.45, 1.05)
p=0.073
1.12 (0.67, 1.88)
p=0.641
0.75 (0.56, 1.03)
p=0.065
0.90 (0.70, 1.17)
p=0.217
0.52 (0.33, 0.81)
p=0.009
1.22 (0.71, 2.07)
p=0.727
0.72 (0.52, 0.98)
p=0.040
0.86 (0.66, 1.12)
p=0.175
Database lock: Oct 2013
Population selected for Phase 3
All p-values 1-sided. Adjusted: prespecified analysis for hazard ratio after adjusting for other variables in study with Cox Proportional Hazards model (gender, smoking status, LDH, ECOG performance status, interval since diagnosis advanced disease, age, total baseline target lesion size, and geographic region).

40. PFS: Dx >6 months Population
HR, unadjusted (0.55,0.96), P = 0.031
HR, adjusted (0.53,0.96), P = 0.030
Median G+D vs. D: 5.3 vs. 3.4 months
Events: 138 (78%)
Docetaxel
Ganetespib Docetaxel
Progression-Free Probability
Months
Ramalingam SS et al. WCLC

41. Conclusions
Individualized therapy is a reality for lung adenocarcinoma patients
Molecular testing is recommended for newly diagnosed patients regardless of clinical characteristics
Systemic chemotherapy continues as the main stay of treatment for majority of lung adenocarcinoma patients