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Advanced Non-Small Cell Lung Cancer: State of the Art. Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer Center. Frontline therapy of advanced NSCLC: “Back in the day” dogma (ie, 2009).

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advanced non small cell lung cancer state of the art

Advanced Non-Small Cell Lung Cancer: State of the Art

Primo N. Lara, Jr., MD

Professor of Medicine

University of California Davis Cancer Center

frontline therapy of advanced nsclc back in the day dogma ie 2009
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 pathwaysimprove outcomes in select patient subsets
slide3

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

bevacizumab in nsclc e4599

12 mo 24 mo Median

PC 44.4% 15.4% 10.3 mo

BV/PC 51.0% 22.0% 12.3 mo

Bevacizumab in NSCLC (E4599)

1.0

0.8

Median 12.3 mo

0.6

HR: 0.80, P = .013

Proportion surviving

Median 10.3 mo

0.4

0.2

0.0

12

24

36

0

6

18

30

42

48

Patients at risk

PC

190

36

5

444

318

104

9

1

0

BV/PC

216

54

8

434

340

127

25

3

0

Months

Non-squamous histology, no hemoptysis, no CNS mets, no anticoagulation

Sandler A, et al. N Engl J Med. 2006; 356:2542–2550

cisplatin vinorelbine cetuximab flex in egfr positive by ihc nsclc
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 OS47% vs 42%

Months

Pirker R, et al. (2008) ASCO

* One or more IHC positive cell(s)

metastatic nsclc the new issues i e october 2010
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?
maintenance therapy considerations
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
maintenance pemetrexed
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

slide10

Drug-related adverse events

* on-study or within 30 days post-study

Ciuleanu TE, et al. (2008) ASCO

slide11

JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy

Pemetrexed 4.0 mos

Placebo 10.6 mos

Placebo 2.0 mos

1.0

0.9

0.8

HR = 0.60 (95% CI: 0.49-0.73)P <0.00001

0.7

Progression-free

Survival

Progression-free Probability

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

3

6

9

12

15

18

21

24

Time (months)

1.0

0.9

HR = 0.79 (95% CI: 0.65-0.95) P = 0.012

0.8

0.7

Overall

Survival

Survival Probability

0.6

Pemetrexed 13.4 mos

0.5

0.4

0.3

0.2

0.1

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

Belani CP, et al. ASCO 2009. CRA8000.

Time (months)

slide12
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?

JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy

Belani CP, et al. ASCO 2009. CRA8000.

jmen maintenance pemetrexed vs placebo survival by histology
JMEN: “Maintenance” Pemetrexed vs Placebo: Survival by Histology

Pemetrexed 15.5 mos

Pemetrexed 9.9 mos

Placebo

10.3 mos

Placebo

10.8 mos

Non-squamous (n = 481)

Squamous (n = 182)

HR = 0.70 (95% CI: 0.56-0.88); 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

0.5

0.5

0.4

0.4

0.3

0.3

0.2

0.2

0.1

0.1

0.0

0.0

0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

0

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 2009. CRA8000.

maintenance chemotherapy points to ponder
Maintenance chemotherapy: Points to Ponder
  • Definition of “maintenance” varies
  • Benefit for pemetrexed confined to non-squamous histology
  • Many patients never received second-linetherapy!
    • 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
maintenance chemotherapy is it time for routine clinical use
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
maintenance biologics
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

saturn study design cappuzzo et al asco 2009 8001
SATURN study designCappuzzo et al, ASCO 2009, # 8001

Erlotinib

150mg/day

PD

Chemonaïve advanced NSCLC

n=1,949

4 cycles of first-line platinum doublet chemotherapy*

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

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

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

saturn trial efficacy summary
SATURN Trial: Efficacy Summary

Cappuzzo et al. J Thorac Oncol 2009; 4(suppl 1):S289 (abstract A2.1).

  • PFS benefit with erlotinib observed regardless of gender, race, histology or smoking history
pfs in egfr wild type tumors
PFS in EGFR wild-type tumors

PFS probability

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=199)

Placebo (n=189)

HR=0.78 (0.63–0.96)

Log-rank p=0.0185

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (weeks)

Capuzzo, ASCO 2009

pfs in egfr mutation tumors
PFS in EGFR mutation+ tumors*

PFS probability

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=22)

Placebo (n=27)

HR=0.10 (0.04–0.25)

Log-rank p<0.0001

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (weeks)

*60% censored

Capuzzo, ASCO 2009

saturn post study treatment
SATURN: Post-study Treatment

*% receiving ≥1 treatment

Cappuzzo F, et al. ASCO 2009. Abstract 8001.

atlas phase iii study design miller et al asco 2009 8002
ATLAS Phase III Study DesignMiller et al, ASCO 2009, #8002

Bevacizumab (15mg/kg)+

erlotinib (150mg) to PD

4 cycles of 1st-line

chemotherapy*

+ bevacizumab

Chemo-naïve

advanced NSCLC

N=1,160

Non-PD

n=768 (66%)

Post progressiontherapy

Unblind at PD

1:1

Bevacizumab+

placeboto 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)

*Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel.

**IIIB with pleural effusion

progression free survival
Progression-Free Survival

1.0

Proportion Without Event

Bev + Placebo (n=373)

0.8

Bev + Erlotinib (n=370)

0.6

HR=0.722 (0.592-0.881)

Log-rank P=0.0012

0.4

0.2

0.0

0

3

6

9

12

15

18

21

Progression-Free Survival (months)

Miller et al, ASCO 2009, #8002

atlas toxicity
ATLAS: Toxicity

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

take home points saturn and atlas trials
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
metastatic nsclc the new issues i e october 201026
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?

complexities of lung cancer pathogenesis result in diverse histologic subtypes
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

nsclc histology treatment considerations
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
slide29

R

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

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

slide30

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

pemetrexed influence of histology on efficacy
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

take home points histology based therapy
Take Home Points: Histology-based therapy
  • NSCLC histologyisnow 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
metastatic nsclc the new issues i e october 201033
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?

ipass study design
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 progressionWHO, World Health Organization; PS, performance status; AUC, area under the curve; EGFR, epidermal growth factor receptor

Mok et al 2008

progression free survival35
Progression-free survival

Gefitinib

Carboplatin /

paclitaxel

Probabilityof PFS

1.0

N

Events

609

453 (74.4%)

608

497 (81.7%)

0.8

HR (95% CI) = 0.74 (0.65, 0.85) p<0.0001

5.874%48%7%

0.6

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

0.4

Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS

0.2

0.0

0

4

8

12

16

20

24

Months

Patients at risk :

Gefitinib

609

363

76

24

5

0

212

C/P

608

412

118

22

3

1

0

Primary Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT populationPFS, progression-free survival; ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval; C/P, carboplatin/paclitaxel

Mok et al 2008

ipass egfr mutation positive status and clinical characteristics
IPASS: EGFR mutation positive status and clinical characteristics

Overall EGFR mutation positive rate = 59.7% (261 / 437)

% of samples EGFR mutation positive

68.5

63.0

60.7

60.2

56.7

60.0

57.1

57.8

49.0

46.9

Male

Female

PS 0/1

PS 0/2

Neversmoked

Light ex-smoker

Locallyadvanced

Metastatic

Age<65 yrs

Age>65 yrs

progression free survival in egfr mutation positive and negative patients
Progression-free survivalin EGFR mutation positive and negative patients

EGFR mutation positive

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 monthsMedian 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 monthsMedian 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

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Months

Months

Patients at risk :

Gefitinib

132

108

31

11

3

0

91

21

2

1

0

0

71

4

C/P

129

103

37

7

2

1

0

85

58

14

1

0

0

0

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

slide38

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 20-75 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

slide39

PFS

OS

Memondo, NEJM 2010

potential oncogenic drivers in non small cell lung cancer nsclc
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]

tumor responses to crizotinib for patients with alk positive nsclc n 82
Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC (N=82)

60

40

20

0

–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

77 of patients with alk positive nsclc remain on crizotinib treatment
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 9 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 13

0 3 69 12 15 18 21

Treatment duration (months)

N=82; red bars represent discontinued patients

clinical activity of crizotinib in patients with alk positive nsclc
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

* 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

median pfs has not been reached 70 of patients in follow up for pfs
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

0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

Progression-free survival (months)

treatment related adverse events in alk positive nsclc 10
Treatment-related Adverse Events in ALK-positive NSCLC (≥10%)

*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)

N=82

conclusions frontline nsclc therapy
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