Lung Cancer HighlightsASCO 2004

Heather Wakelee, MDStanford University

Adjuvant Therapy Abstracts: 7018, 7019

EGFR inhibitors

Abstracts: 7010, 7011, 7022

Adjuvant Therapy

Abstracts: 7018, 7019

Early Stage NSCLC Survival

Stage

II

IIII

IIIAIIIA

% Alive at 5 years

50-7050-70

30-5030-50

10-3010-30

National Cancer Institute: SEER Cancer Statistics Review; 1990-1999..Gloeckler Ries LA, The Oncologist 8:541-552, 2003

NSCLC Adjuvant Chemotherapy1995 Meta-Analysis

• Cisplatin-based regimens:• HR 0.87 (.74-1.02 95% CI) • 5% 5 year survival (p.08)

• Consensus: • Adjuvant Chemotherapy

Experimental

BMJ 31: 899-908, 1995

Post 1995 Meta-Analysis:NSCLC Randomized Adjuvant Trials

JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04

Trial Stage n Chemo Survival

ALPI I-III 1209 MVdP No

BLT I-III 381 Platin-based No

IALT I-III 1867 Vinca or EP Yes

NCIC IB-II 482 VbP YES

CALGB IB 344 PacCb YES

Adjuvant Lung Project: Italy (ALPI) ASCO 2002

• 1078 patients • Resected stage I-IIIA disease• Randomized to obs vs. post-op

chemo*• Radiation therapy optional (~45%)• HR=0.96 (0.81 - 1.13), p=0.585

Tonato Proc ASCO 2002, abstr 1157Scagliotti, JNCI 95:1453; 2003

*mitomycin / vindesine / cisplatin x 3

ALPI - Overall SurvivalScagliotti, JNCI 2003

ALPI - Overall SurvivalScagliotti, JNCI 2003

Events/Total

MVdP 278/548

Control 288/540

PROBABILITY

YEARS

HR 0.96 [0.81 - 1.13]p=0.589

International Adjuvant Lung Cancer Trial (IALT) ASCO

2003• 1867 patients• Resected stage IB - IIIA NSCLC• Randomized to obs vs. post-op chemo*• Radiation therapy optional (~30%)• 4.1% absolute benefit at 5 years,

p<0.03

LeChevalier Proc ASCO 2003, abstr 6NEJM 350:351, 2004

*cisplatin + etoposide or vinca alkaloid

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5

HR= 0.86 [0.76-0.98] p<0.03

IALT - Overall Survival

___ Control

___ Chemotherapy

Years

164286432602774935

181308450624775932At risk

JBR.10 - Study Design

RANDOM I

ZE

STRATIFIED Nodal * N0 * N1ras * Neg * Pos * UNK

No ChemotherapyELIGIBLE (N=482)

* T2N0, T1-2N1

* Lobectomy

* N2 samplingChemotherapyVbP* x 4 cycles

Winton, ASCO 23:7018, 2004

*Cisplatin 50 mg/m2 day 1,8 q 4 wVinorelbine 25 mg/m2 weekly x 16

JBR.10 - Overall Survival

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0164Wilcoxon test for equality of groups: p=0.0100Survival rate at 5 years for Observation: 54% - % C.I. ( 48%, 61%)Survival rate at 5 years for Vinorelbine: 69% - % C.I. ( 62%, 75%)

Observation Vinorelbine

Percentage

0

20

40

60

80

100

Time (years) # At Risk(Observation) # At Risk(Vinorelbine)

0.0239243

2.0182193

4.094

121

6.04751

8.01310

10.000

____ Vin/Cis, ____ Observation

*HR 0.7, p=0.012

Years

Winton, ASCO 23:7018, 2004

HR 0.696 [.524-.923]p=0.012 5 year survival

69%69% vs. 54%

%

A

L

I

V

E

QOL Results: After Completion of Treatment

• No differences in global or any of the QoL performance scales

• Clinically and statistically significant differences after completion of treatment in :– Parasthesias, numbness, hearing

Winton, ASCO 23:7018, 2004

JBR.10 - ConclusionsAdjuvant VbP in Stage IB/II NSCLC

• Adjuvant VbP safe (59% 3+ cycles)

• Limited impact on QoL - neurotoxicity

• Absolute benefit 15% at 5 years, p=0.0022

• 30% reduction risk of death, p=0.012

Winton, ASCO 23:7018, 2004

CALGB 9633 - Study Design

RANDOM I

ZE

STRATIFIED:

HistologyDifferentiationMediastinoscopy

No ChemotherapyELIGIBLE:(N=344)

T2N0

Lobectomy

N1/N2 sampling ChemotherapyPacCb* x 4 cycles

Strauss, ASCO 23:7019, 2004

*Paclitaxel 200 mg/m2 q 3 wCarboplatin AUC 6 q 3 w

CALGB 9633 - Overall Survival

----- Chemotherapy ----- Observation

HR 0.62 [0.41-0.95]p=0.028

0 20 40 60 80

Survival Time (Months)

0.0

0.2

0.4

0.6

0.8

1.0

Probability

5 year survival71% vs. 59%

4 yr

Strauss, ASCO 23:7019, 2004

CALGB 9633 - ConclusionsAdjuvant carboplatin/paclitaxel in

Stage IB NSCLC• Safe (85% 4 cycles)

• Overall Survival– Absolute benefit 12% at 4 years, p =.028– 38% reduction risk of death, p=0.028

• Lung Cancer Specific Mortality– Absolute reduction 11% at 4 years– 49% reduction risk of death, p=0.018

Strauss, ASCO 23:7019, 2004

NCIC & CALGB Adjuvant Chemotherapy

Why are the NCIC/CALGB results better? Patient Selection

Earlier stage disease No stage III vs. 39% IALT, 28% ALPI

Therapy 2 drug regimen Inclusion of 3rd generation agent Better compliance

CALGB 85% vs. 74% IALT, 60%ALPI Lack of radiation

No PORT vs. 27% IALT, 43% ALPI

Conclusions-NSCLC Adjuvant Chemotherapy• Adjuvant chemotherapy is the new standard of

care for completely resected stage IB-IIIA NSCLC– Cisplatin versus Carboplatin remains a ?– Which “new” agent to use also debatable

• Role of neoadjuvant therapy, especially for stage IIIA, needs further exploration– SWOG 9900 closed– Open NATCH, CHEST, MRC-Lu-22– Opening cis/docetaxel x 3 pre or post-op

• PORT remains of unclear benefit• How to customize therapy?

New directions in adjuvant therapy

• NCIC BR-19– Ongoing North American Intergroup trial

•Resected NSCLC post adjuvant chemotherapy•Randomized to Gefitinib vs. placebo

• New adjuvant trials of targeted agents should incorporate chemotherapy– Cooperative group trials in development

•bevacizumab plus chemotherapy - ECOG

EGFR Inhibition

Abstracts: 7010, 7011, 7022

R

K

R

K

ligand

Cell surface

Survival Proliferation Angiogenesis MetastasisCellular Responses

PI3K

Shc

Grb2 Ras Sos

Raf

MEK1/2

Akt

MAPK

PTEN

GSK-3mTOR FKHR BadIntra-CellularSignaling

NF-

[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]

p27

Gene Transcription/Cell Cycle Progression

ProliferationAnti-Apoptosis

HER2EGFR

Rationale for Study of EGFR Inhibitors Concurrent with

Combination Chemotherapy

• Synergistic or additive in preclinical models

• Safety demonstrated phase II trials

• Encouraging phase II efficacy data

0.00.10.20.30.40.50.60.70.80.91.0

Survival time (months)0 4 8 12 16 20 24

500 mg/day 250 mg/dayPlacebo

MST (months)1-year

500 mg8.7

37%

250 mg9.8

41%

Placebo9.9

42%

0.00.10.20.30.40.50.60.70.80.91.0

Survival time (months)0 4 8 12 16 20 24

500 mg/day 250 mg/dayPlacebo

MST (months)1-year

500 mg9.9

43%

250 mg9.9

41%

Placebo11.145%

INTACT 1INTACT 1Gemcitabine-

Cisplatin

INTACT 2INTACT 2Paclitaxel-

Carboplatin

INTACT Trials Show No Advantage to Gefitinib + Chemotherapy

JCO March 04

TALENT and TRIBUTE: Study Designs

Screening

Randomization

Daily oral erlotinib + chemotherapy

Placebo + chemotherapy

150mg/day p.o. after dose-selection phase TALENT: gemcitabine + cisplatinTRIBUTE: carboplatin: + paclitaxel

Daily oral erlotinib alone Placebo

Until disease progression Until disease progression

ASCO 2004 TRIBUTE (n=1,059) and TALENT (n=1,172) Phase III Trials

Endpoint Benefit to Chemo + Erlotinib?

Response rates No

Response duration No

Time to progression/death No

Time to symptom progression No

QOL parameters No

Overall survival No

TALENTGatzemeier, ASCO 23:7010, 2004 TRIBUTEHerbst, ASCO 23:7011, 2004

INTACT-1, INTACT-2, TALENT, TRIBUTE

• Lack of true predictive factor

• Chemotherapy and TKIs may kill same population of cells

• Despite their pro-cell death effects, the additional antiproliferative mechanism of TKIs may reduce chemotherapy benefit

“Negative” Results in >4300 PatientsRandomized…Why?

TRIBUTE: Overall Survival after 6 monthsS

urv

ival

rat

e

1.0

0.8

0.6

0.4

0.2

0

Months of study

0 5 10 15 20 25

ErlotinibPlacebo

Herbst, ASCO 23:7011, 2004

NCI Canada BR.21 Advanced NSCLC

RANDOM I ZE

Erlotinib* 150 mg

daily

Placebo “150 mg”daily

*2:1 Randomization

Stratified by:CenterPS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)Prior regimens, (1 vs 2)Prior platinum, (Yes vs no)

Shepherd, ASCO 23:7022, 2004

NCI Canada BR.21 ResultsEndpoint Erlotinib Placebo (n=427) (n=211)

CR+PR 9% <1%

Stable 35% 27%

PFS* (months) 2.2 1.8

OS* (months) 6.7 4.7

1 year survival 31% 22%

* p<0.001**p=0.04, 0.01, 0.02 for cough, dyspnea, pain respectively

Shepherd, ASCO 23:7022, 2004

NCI Canada BR.21 Overall Survival

*Adjusted for stratification factors

Erlotinib

Placebo

*HR 0.72,

p=0.001

Months

31%

22%

0

20

40

60

80

100

0.0 10.0 20.0

Per

cen

tag

e

Shepherd, ASCO 23:7022, 2004

BR.21 Factors Correlated w/ Response

Erlotinib

(N = 427)

P

Gender Male 6% 0.0065

Female 14%

Histology Adeno 14% <0.0001

Other 4%

Ever smoked Yes 4% <0.0001

No 25%

UNK 13%

Shepherd, ASCO 23:7022, 2004

BR.21 Factors NOT Correlated w/ Response

• EGFR status (3% RR if Neg)• Number of Prior Regimens (1 vs

2+)• Prior Platinum• Prior Response• ECOG Performance Status

Shepherd, ASCO 23:7022, 2004

BR.21 Survival by Smoking History

Months

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0000

Smoked/OSI-774 Smoked/PlaceboNever Smoked/OSI-774 Never Smoked/Placebo

Percentage

0

20

40

60

80

100

Time (months) # At Risk(Smoked/OSI-774) # At Risk(Smoked/Placebo)

# At Risk(Never Smoked/OSI-774) # At Risk(Never Smoked/Placebo)

0.035818710442

10.011646639

20.07340

30.00000

_____ Erlotinib Non-Smoker

_____ Erlotinib Smoker

_____ Placebo Non-Smoker

_____ Placebo Smoker

p=0.03*

* significant difference across the levels of the factor.

Shepherd, ASCO 23:7022, 2004

%

A

L

I

V

E

BR.21 Summary• First placebo controlled randomized trial

– oral EGFR-TKI can prolong survival

• Erlotinib Rx - Significant associations: – longer overall survival– longer progression free survival– improved lung cancer-related symptoms– improved QoL

Shepherd, ASCO 23:7022, 2004

Response and Sensitivity to EGFR Inhibition by Gefitinib Predicted by

Activating Mutations Clustered in Tyrosine Kinase Domain*

• Lynch TJ, Bell DW, Sordella R et al. NEJM 350:2124, 2004

• Paez JG, Janne PA, Lee JC et al. Science, 5/2004

*Reviewed/Discussed ASCO Special Session 6/07/2004

EGFR Mutations Cluster Within the ATP Binding Pocket of the Active Form of EGFR Kinase Domain

The EGFR Activating Mutations in NSCLC and Benefit from TKIs

Known So Far• Somatic mutation, gain-of-function• <10% unselected

patients• Majority selected responders, few non-responders• Adeno, female, Japanese (non-

smokers)• Lower dose needed than wild type

Not Yet Known• Frequency entire denominator and in all responders• Presence in stable disease• Will not fully explain OS benefit from TKIs• Mechanism for resistance if mutation but no response• Can subset be identified that benefits from chemo+TKI• When/who to test for mutation• Other mutations• Are all TKIs the same?

EGFR TKI Future Directions

• EGFR TKI proven benefit as single agent third (or second) line for advanced NSCLC

• New directions with TK inhibition:- Sequential approaches- Pulsed therapy- Inhibit cross-talk among signaling pathways- Populations enriched for mutation - early use

• Combine with other targeted agents– (gefitinib/bexarotene trial at Stanford)

• Tumor/blood specimens phase III trials

Conclusions

• Adjuvant Chemotherapy is new STANDARD of CARE for NSCLC– Stage IB-IIB– Which regimen is still open to debate

• EGFR-TKI can prolong survival– Should not be combined with

chemotherapy– Many predictive factors

•Mutation analysis, gender, smoking history…