1. Advanced Non-Small Cell Lung Cancer: State of the Art
Primo N. Lara, Jr., MD
Professor of Medicine
University of California Davis Cancer Center

2. Frontline therapy of advanced NSCLC: “Back in the day” dogma (ie, 2009)
Prognostic factors for survival (PS, Weight Loss, Gender) are known and clinically apparent
Platinum-based chemotherapy results in prolongation of life, symptom control, & superior QOL compared with supportive care alone
Four to six cycles are sufficient
Inhibitors of epidermal growth factor and angiogenesis pathways improve outcomes in select patient subsets
Small cell lung cancer, which proportionally accounts for 15% of all new lung cancer diagnoses in the US, causes up to 40K deaths annually.
Over the past 2 decades the std systemic therapy for extensive stage SCLC has been platinum/etoposide.
Over that same time period, the median survival time for pts with E-SCLC has remained the same – approx 8-10 mos.
It is clear that new treatments are needed.

3. ECOG 1594: Platinum-based doublets have similar survival outcomes
Cis/Gem
Cis/Docetaxel
Carbo/Paclitaxel
Control arm: Cisplatin/paclitaxel
Schiller JH, et al. N Engl J Med. 2002; 346:92–98

4. Duration of chemotherapy: 4-6 cycles are sufficient
Author
Study design
Patients
Median survival (months)
P value
Smith
JCO 2001
MVP x 3
155 6 .2
MVP x 6
153 7
Socinski
JCO 2002
Carbo/Pac x 4
114
6.6
.63
Carbo/Pac till PD
116
8.5
Eberhardt W, et al. (2007) ASCO

5. Bevacizumab in NSCLC (E4599)
1.0
BV/PC 51.0% 22.0% mo
PC 44.4% 15.4% mo
12 mo 24 mo Median
0.8
Median mo
0.6
HR: 0.80, P = .013
Proportion surviving
Median mo
0.4
0.2
KEY POINT: Overall survival was significantly prolonged by the addition of bevacizumab to paclitaxel and carboplatin.
0.0 6 12 18 24 30 36 42 48
Patients at risk
ADDITIONAL INFORMATION
A significantly higher percentage of patients in the bevacizumab group were alive at 12 months (51% vs 44.4%) and 24 months (22% vs 15.4%)
The median overall survival was 12.3 months vs 10.3 months for the bevacizumab plus PC group vs PC alone
The hazard ratio was 0.80, with a 20% relative reduction in the risk of death; P = .013
REFERENCES
Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006. PC
444
318
190
104 36 9 5 1
BV/PC
434
340
216
127 54 25 8 3
Months
Non-squamous histology, no hemoptysis, no CNS mets, no anticoagulation
Sandler A, et al. N Engl J Med. 2006; 356:2542–2550

6. Cisplatin/vinorelbine + cetuximab (FLEX) in EGFR-positive
Cisplatin/vinorelbine + cetuximab (FLEX) in EGFR-positive* (by IHC) NSCLC
Cetuximab +CT CT
HR = 0.871, 0.762–0.996
Log-rank P =.044
11.3
Patients surviving, %
10.1
1-year OS 47% vs 42%
Months
Pirker R, et al. (2008) ASCO
* One or more IHC positive cell(s)

7. Metastatic NSCLC: The New Issues (i.e., October 2010)
Maintenance therapy
After completing platinum-based chemo, should all patients receive maintenance therapy?
Tumor histology
Should we routinely use histology to select therapy?
Frontline biologics
Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

8. Maintenance therapy: Considerations
Continuing same chemotherapy past 4–6 cycles yields no clear benefit
E4599 and FLEX trials included maintenance therapy of bevacizumab and cetuximab, respectively
Maintenance therapy with non-cross resistant agents may be more efficacious

9. Maintenance pemetrexed
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
Stage IIIB/IV NSCLC
PS 0-1
4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD
Randomization factors:
gender PS
stage
best tumor response to induction
non-platinum induction drug
brain mets
Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N = 441)*
2:1
Randomization
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC (N = 222)*
*B12, folate, and dexamethasone given in both arms
Ciuleanu TE, et al. (2008) ASCO; Belani CP, et al. (2009) ASCO 9

10. Drug-related adverse events
Pemetrexed
n = 441
Placebo n = 222
P value
Drug-related deaths*
0.0%
1.000
≥ 1 serious AE (SAE)
4.3%
.001
≥ 1 grade 3/4 AE
14.3%
3.6%
< .001
Drug-related CTCAE grade 3/4 toxicity (≥ 2% of pts)
Anemia
2.7%
0.5%
.070
Neutropenia
.011
Fatigue
.004
* on-study or within 30 days post-study
Ciuleanu TE, et al. (2008) ASCO 10

11. Progression-free Probability
JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy
1.0
0.9
0.8
HR = 0.60 (95% CI: ) P <
Progression-free
Survival
0.7
Progression-free Probability
0.6
0.5
Pemetrexed 4.0 mos
0.4
0.3
0.2
Placebo 2.0 mos
0.1
0.0 3 6 9 12 15 18 21 24
Time (months)
1.0
0.9
HR = 0.79 (95% CI: ) P = 0.012
0.8
0.7
Overall
Survival
Survival Probability
0.6
Pemetrexed 13.4 mos
0.5
0.4
0.3
Placebo 10.6 mos
0.2
0.1
0.0
Belani CP, et al. ASCO CRA8000. 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months) 11

12. JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy
Any systemic therapy
51%
67%
Docetaxel
22%
29%
Erlotinib
21%
Gefitinib
13%
10% 1%
19%
Post-study therapy was not balanced between the arms
51% of patients on the pemetrexed arm received further therapy (equates to third-line therapy)
Only 19% of placebo-arm patients received pemetrexed
Would survival benefits have been preserved if more patients on the placebo arm received pemetrexed?
Belani CP, et al. ASCO CRA8000. 12

13. JMEN: “Maintenance” Pemetrexed vs Placebo: Survival by Histology
Non-squamous (n = 481)
Squamous (n = 182)
HR = 0.70 (95% CI: ); P = 0.002
HR = 1.07 (95% CI: 0.49–0.73); P = 0.678
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Survival Probability
Pemetrexed 15.5 mos
Pemetrexed 9.9 mos
0.5
0.5
0.4
0.4
0.3
0.3
Placebo
10.3 mos
Placebo
10.8 mos
0.2
0.2
0.1
0.1
0.0
0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Time (months)
Belani CP, et al. ASCO CRA8000. 13

14. Maintenance chemotherapy: Points to Ponder
Definition of “maintenance” varies
Benefit for pemetrexed confined to non-squamous histology
Many patients never received second-line therapy!
Survival in control arms may have diminished due to lack of life-prolonging second line therapy
Difficult to reconcile with maintenance bevacizumab, cetuximab, and erlotinib

15. Maintenance chemotherapy: Is it time for routine clinical use?
Issues of cost, convenience, toxicity, and QOL need to be weighed against (modest) PFS benefit in the palliative care setting
Many patients desire a “drug holiday”
Maintenance chemotherapy can be considered only for selected, highly motivated patients
Bottom line: It’s not for everyone

16. Maintenance biologics
SATURN trial (N = 889)
Phase III erlotinib vs. placebo following initial treatment with platinum-based chemotherapy
ATLAS trial (N = 1157)
Phase III bevacizumab ± erlotinib following initial treatment with chemo + bevacizumab
Brain mets, non-centrally located squamous, anticoagulation allowed
1. Cappuzzo F, et al. (2009) ASCO; 2. Miller VA, et al. (2009) ASCO

17. SATURN study design Cappuzzo et al, ASCO 2009, # 8001
Erlotinib
150mg/day PD
Chemonaïve advanced NSCLC
n=1,949
4 cycles of first-line platinum doublet chemotherapy*
Non-PD
n=889
1:1
Placebo PD
Mandatory tumour sampling
Co-primary endpoints:
PFS in all patients
PFS in patients with EGFR IHC+ tumours
Secondary endpoints:
OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; 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)
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel 17

18. SATURN Trial: Efficacy Summary
Erlotinib
(n = 438)
Placebo
(n = 451) HR
P Value
PFS
(n = 437)
(n = 447)
0.71
< .0001
PFS at 12 weeks
53%
40%
PFS at 24 weeks
31%
17%
Median PFS
12.3 weeks
11.1 weeks
Median OS
12 months
11 months
0.81
.0088
(n = 436)
(n = 445)
ORR
12% 5% NA
.0006
DCR
61%
51%
.0035
PFS benefit with erlotinib observed regardless of gender, race, histology or smoking history
Cappuzzo et al. J Thorac Oncol 2009; 4(suppl 1):S289 (abstract A2.1).

19. PFS in EGFR wild-type tumors
PFS probability
1.0
0.8
0.6
0.4
0.2
Erlotinib (n=199)
Placebo (n=189)
HR=0.78 (0.63–0.96)
Log-rank p=0.0185
Eratepfsb3_g_2000
Time (weeks)
Capuzzo, ASCO 2009 19

20. PFS in EGFR mutation+ tumors*
PFS probability
1.0
0.8
0.6
0.4
0.2
Erlotinib (n=22)
Placebo (n=27)
HR=0.10 (0.04–0.25)
Log-rank p<0.0001
Eratepfsb3_g_2000
Time (weeks)
*60% censored
Capuzzo, ASCO 2009 20

21. SATURN: Post-study Treatment
Erlotinib*
(n = 438)
Placebo*
(n = 451)
All classes
55%
64%
Taxanes (including docetaxel)
26%
27%
Antimetabolites (including pemetrexed)
18%
20%
Antineoplastic agents
11%
15%
Tyrosine-kinase inhibitors 5%
16%
Platinum compounds 8%
Note: not all post-study treatments are detailed here, and some patients may have received more than one further line of therapy, so percentages do not add up.
*% receiving ≥1 treatment
Cappuzzo F, et al. ASCO Abstract 8001. 21

22. ATLAS Phase III Study Design Miller et al, ASCO 2009, #8002
Bevacizumab (15mg/kg) +
erlotinib (150mg) to PD
Chemo-naïve
advanced NSCLC
N=1,160
4 cycles of 1st-line
chemotherapy*
+ bevacizumab
Non-PD
n=768 (66%)
Post progression therapy
1:1
Unblind at PD
Bevacizumab +
placebo to PD
Eligibility
Stage IIIB**/IV NSCLC
ECOG performance status 0-1
Stratification factors
Gender
Smoking history (never vs former/current)
ECOG performance status (0 v >1)
Chemotherapy regimen
Primary endpoint
PFS in all randomized pts
Secondary endpoints
Overall survival
Safety
Exploratory endpoints
Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation)
Note <6 % of patients on both arms received adjuvant therapy.
78.5% power to detect a 26% improvement in PFS
3 Interim analyses; FPI May 2005 LPI May 2008
Stratification factors will consist of sex, smoking history (never vs. prior/current), ECOG performance status from pre-randomization assessment (0 vs.  1), and initial chemotherapy regimen (carboplatin/paclitaxel vs. carboplatin/gemcitabine vs. carboplatin/docetaxel vs. cisplatin/gemcitabine vs. other chemotherapy regimens).
PFS Definition: PFS was defined as time from randomization until disease progression or death at any time (i.e., no censoring for NPT)
*Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel.
**IIIB with pleural effusion 22 22

23. Progression-Free Survival
Proportion Without Event
1.0
Bev + Placebo (n=373)
0.8
Bev + Erlotinib (n=370)
0.6
HR=0.722 ( )
Log-rank P=0.0012
0.4
0.2
CR rate at randomization 41. and 4.0%, respectively
0.0 3 6 9 12 15 18 21
Progression-Free Survival (months)
Miller et al, ASCO 2009, #8002 23

24. The most common adverse events were rash and diarrhea
ATLAS: Toxicity
Bev + Placebo, n (%)
(n=368)
Bev + Erlotinib, n (%)
(n=367)
Any Grade AE
313 (85.1%)
349 (95.1%)
Grade 3–4 AE
112 (30.4%)
162 (44.1%)
Grade 5 AE
4 (1.1%)
8 (2.2%)
SAE
60 (16.3%)
84 (22.9%)
The most common adverse events were rash and diarrhea
Formal statistical comparison testing between treatment arms was not done.
Miller et al, ASCO 2009, #8002 24 24

25. Take Home Points: SATURN and ATLAS trials
Trials confirm that erlotinib is an active agent in NSCLC (duh!)
Patients on maintenance erlotinib had more toxicities than those on placebo
Only a minority (16% in SATURN, 40% in ATLAS) of placebo patients ever received subsequent EGFR TKI therapy!!!
As expected, PFS benefit was best in patients with EGFR-mutated tumors
Need to balance consequences of increased toxicity and cost in the context of modest PFS benefit

26. Metastatic NSCLC: The New Issues (i.e., October 2010)
Maintenance therapy
After completing platinum-based chemo, should all patients receive maintenance therapy?
Tumor histology
Should we routinely use histology to select therapy?
Frontline biologics
Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

27. (Not Otherwise Specified
Complexities of lung cancer pathogenesis result in diverse histologic subtypes
SCLC
(~15%)
Squamous Cell Ca (~25%)
Adenocarcinoma
(~45%)
BAC
(~5-10%)
Large Cell
(~5-10%)
NOS
(Not Otherwise Specified
(~10-30%)
Sun S, et al. Nat Rev Cancer. 2007; 7:778–790

28. NSCLC histology: Treatment Considerations
Bevacizumab is FDA-approved for non-squamous histology due to SAFETY issues
Severe hemoptysis
Pemetrexed is FDA-approved for non-squamous histology due to EFFICACY issues
PFS and OS benefit confined to non-squamous
EGFR TKIs traditionally viewed as more efficacious in adenocarcinoma
Likely due to higher rate of EGFR mutants in adeno

29. Vitamin B12, folate, and dexamethasone given in both arms
JMDB trial: Cisplatin/pemextexed (CP) vs cisplatin/gemcitabine (CG) in Adv NSCLC
Randomization Factors
Stage PS
Gender
Histo vs cyto dx
Brain mets hx
Cisplatin 75 mg/m2 day 1 plus
Pemetrexed 500 mg/m2 day 1 R
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
Vitamin B12, folate, and dexamethasone given in both arms
Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

30. Cisplatin/pemetrexed (CP) vs cisplatin/gemcitabine (CG) in NSCLC
No difference in
PFS or OS
CP improves survival over CG
in non-SCCA (HR 0.81, P = .005)
CG improves survival over CP
in SCCA (HR 1.23, P = .05)
Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

31. Pemetrexed: Influence of histology on efficacy
In two other phase III trials (docetaxel vs. pemetrexed; maintenance pemetrexed vs. placebo), benefit was confined to patients with non-squamous histology
Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

32. Take Home Points: Histology-based therapy
NSCLC histology is now a consideration in therapeutic selection for chemotherapy
This is but one (primitive) step in the direction of “personalized therapy”
Still unclear how “NSCLC NOS” or cytologic diagnoses (by FNA) should be treated
True personalized therapy will rely on molecular profiling rather than histology

33. Metastatic NSCLC: The New Issues (i.e., October 2010)
Maintenance therapy
After completing platinum-based chemo, should all patients receive maintenance therapy?
Tumor histology
Should we routinely use histology to select therapy?
Frontline biologics
Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

34. IPASS Study design
Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong and Singapore
Randomization period: March 2006 – October 2007
End points
Patients
Chemo-naïve
Age ≥18 years
Adenocarcinoma histology
Never or ex-light smokers*
Life expectancy ≥12 weeks
WHO PS 0-2
Measurable stage IIIB / IV disease
Gefitinib (250 mg / day)
Primary
Progression-free survival (non-inferiority)
Secondary
Objective response rate
Overall survival
Quality of life
Disease-related symptoms
Safety and tolerability
Exploratory
Biomarkers
EGFR mutation
EGFR-gene-copy number
EGFR protein expression
1:1 randomization
Carboplatin
(AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly#
*Never smokers, <100 cigarettes in lifetime; ex-light smokers, stopped 15 years ago and smoked 10 pack years; #limited to a maximum of 6 cycles. Carboplatin/paclitaxel was offered to gefitinib patients upon progression WHO, World Health Organization; PS, performance status; AUC, area under the curve; EGFR, epidermal growth factor receptor
Mok et al 2008 34 34 34

35. Progression-free survival
Probability of PFS
1.0
Gefitinib
Carboplatin /
paclitaxel N
Events
609
453 (74.4%)
608
497 (81.7%)
0.8
HR (95% CI) = 0.74 (0.65, 0.85) p<0.0001
0.6
Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free
5.7 61% 48% 25%
5.8 74% 48% 7%
0.4
Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS
0.2
0.0
Patients at risk : 4 8 12 16 20 24
Months
Gefitinib
609
363
212 76 24 5
C/P
608
412
118 22 3 1
Primary Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population PFS, progression-free survival; ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval; C/P, carboplatin/paclitaxel
Mok et al 2008 35 35 35

36. IPASS: EGFR mutation positive status and clinical characteristics
% of samples EGFR mutation positive
Overall EGFR mutation positive rate = 59.7% (261 / 437)
68.5
63.0
60.0
57.1
60.7
57.8
60.2
56.7
49.0
46.9
Male
Female
PS 0/1
PS 0/2
Never smoked
Light ex- smoker
Locally advanced
Metastatic
Age <65 yrs
Age >65 yrs 36

37. Progression-free survival in EGFR mutation positive and negative patients
EGFR mutation negative
Gefitinib (n=132) Carboplatin/paclitaxel (n=129)
Gefitinib (n=91) Carboplatin/paclitaxel (n=85)
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Median PFS G, 9.5 months Median PFS C/P, 6.3 months
HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001
No. events gefitinib , 88 (96.7%) No. events C/P, 70 (82.4%) Median PFS G, 1.5 months Median PFS C/P, 5.5 months
1.0
1.0
0.8
0.8
0.6
0.6
Probability of progression-free survival
Probability of progression-free survival
0.4
0.4
0.2
0.2
0.0
0.0 4 8 12 16 20 24 4 8 12 16 20 24
Months
Months
Patients at risk :
Gefitinib
132
108 71 31 11 3 91 21 4 2 1
C/P
129
103 37 7 2 1 85 58 14 1
Treatment by EGFR mutation status interaction test, p<0.0001
Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population
Mok et al 2008 37 37

38. First line gefinitib vs. chemotherapy in EGFR mutated NSCLC
Primary endpoint
PFS
2ndary endpoints OS
Response
Side-effects
QOL
NSCLC with sensitive EGFR mutations
Stage IIIb/ IV
No prior chemo.
PS 0-1
age of y.o
Gefitinib　
n=160　　 R
balanced :
Institution
sex
stage
CBDCA+TXL　n=160
The sample size was calculated to be 320 in total (alpha=5%, power=80%) to confirm the superiority of Arm A (hazard ratio = 0.69).
An interim analysis to investigate PFS was planned 4 months after 200 pts were entered .
North East Japan (NEJ) Gefitinib Study Group

39. PFS OS
Memondo, NEJM 2010

40. Memondo, NEJM 2010

41. Potential Oncogenic “Drivers” in Non-small Cell Lung Cancer (NSCLC)
Adenocarcinoma
Other
ALK (~5%)
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; Her2 = human epidermal growth factor receptor 2; PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide
Massachusetts General Hospital, data on file. [AT Shaw, personal communication] 41

44. Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC (N=82)60 40 20
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Maximum change in tumor size (%)
–30% *
*Partial response patients with 100% change have non-target disease present

45. 77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment
Duration of treatment (median: 5.7 months)
0–3 mo 13 pts
>3–6 mo 29 pts
>6–9 mo 24 pts
>9–12 mo pts
>12–18 mo  4 pts
>18 mo 3 pts
Individual patients
Reasons for discontinuation
Related AEs 1
Non-related AEs 1
Unrelated death 2
Other 2
Progression
Treatment duration (months)
N=82; red bars represent discontinued patients 45

46. Clinical Activity of Crizotinib in Patients with ALK-positive NSCLC
Objective response rate (ORR): 57% (95% CI: 46, 68%)
63% including 5 as yet unconfirmed PRs
57% (8/14) for patients with performance status 2 or 3
No. prior regimens*
ORR % (n/N)
80 (4/5) 1
52 (14/27) 2
67 (10/15) ≥3
56 (19/34)
* Unknown for 1 patient
Response duration: 1 to 15 months
DCR† (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%)
†Disease control rate 46 46

47. Median PFS has Not been Reached 70% of Patients in Follow-up for PFS
1.00
0.75
0.50
0.25
0.00
PFS probability at 6 months: 72% (95% CI: 61, 83%) 
Progression-free survival probability
Median follow-up for PFS: 6.4 months
(25–75% percentile: 3.5–10 months)
95% Hall–Wellner confidence bands
Progression-free survival (months)

48. Treatment-related Adverse Events in ALK-positive NSCLC (≥10%)
Grade 1 n (%)
Grade 2 n (%)
Grade 3 n (%)
Grade 4 n (%)
Total n (%)
Nausea
43 (52)
1 (1)
44 (54)
Diarrhea
38 (46)
39 (48)
Vomiting
35 (43)
36 (44)
Visual disturbance*
34 (42)
Constipation
18 (22)
2 (2)
20 (24)
Peripheral edema
13 (16)
Dizziness
12 (15)
Decreased appetite
11 (13)
Fatigue
8 (10)
*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)
N=82 48

49. Conclusions: Frontline NSCLC therapy
Optimal therapy is rapidly evolving
Maintenance therapy is an option for highly motivated patients
Clinical, histologic, and molecular biomarkers are now important considerations for therapy selection
Future advances in NSCLC outcomes will likely be due to molecular selection
Support for clinical trials testing this paradigm is essential