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Systemic therapy in early stage NSCLC

Christian Manegold MDChristian Manegold MDChristian Manegold, MDChristian Manegold, MDProfessor of Medicine, Heidelberg University

Interdisciplinary Thoracic OncologyDepartment of Surgery

University Medical Center Mannheim, Germany

Disclosures

• Consultancy: Hoffmann-La Roche, Pfizer, Eli Lilly, Merck-Serono, Novartis, Amgen, Boehringer Ingelheim AstraZenecaBoehringer Ingelheim, AstraZeneca

• Speaking: Hoffmann-La Roche, Eli Lilly, Merck-Serono, AstraZeneca

• Grant support: Merck-Serono, Sanofi-Aventis, Eli Lilly

• Travel Support: Hoffmann-La Roche, Merck-Serono, Eli Lilly, AstraZeneca

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Chemotherapy in early stage NSCLC

Stage I Stage I –– III III

operableoperable

Stage IStage I--III III

inoperableinoperableChemotherapy

adjuvant / postoperativeChemoRadiotherapy

sequential

C CChemotherapy neoadjuvant/ preoperative

ChemoRadiotherapy concomitant

Expected outcome following surgical resection in operable NSCLC

Pisters and Le Chevallier, J Clin Oncol 23, 3270-3278, 2005

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Neo-adjuvant chemotherapy

Adjuvant chemotherapy

ESMO - clinical practice guidelines

Neo-adjuvant cisplatin-based chemotherapy is recommended in stage IIIA/N2 - radically

resected NSCLC

Crino et al. Ann Oncol 21 (Suppl 5), 103-115, 2010

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Early NSCLC: advantages of neoadjuvant chemotherapy

E l t t t f di t t i t t t• Early treatment of distant micrometatstases

• Local-regional cytoreduction preoperatively

• Better patient acceptance

• Better tolerability and dose delivery

Pisters et al. J Thor Cardiovasc Surg 119, 429,2000

EORTC 089551

EORTC 089582

EORTC089843

SAKK 4 Tampa 5

Early NSCLC – neoadjuvant chemotherapy (phase II)

Cis /Gemcitabine

Carbo /

Paclitaxel

Cis /

Docetaxel

Cis /

Docetaxel

Pemetrexed/

Gemcitabine

Pts 47 40 40 90 45

CR 6.3% - 2.5% 8% 2%

PR 63.8% 59% 42.5% 58% 31%

SD 6.3% 18% 35% 25% 56%

PD 4.2% 23% 2.5% 9% 7%

1van Zandwijk et al J Clin Oncol 18,2658-2664, 2000; 2O‘Brien et al Proc ASCO 18 (Abstr. 1898), 1999; 3 Betticher et al J Clin Oncol 21, 1752-59, 2003; 4 Bisma et al EJC 42, 1399-1406,2006; 5 Bepler et al J Clin Oncol 24, (18S), 396 (Abstr. 7129), 2006

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NSCLC - neoadjuvant chemotherapy: metaanalysis surgery/CT vs. surgery alone

Gilligan et al. Lancet 369: 1929-1937, 2007Burdett et al. J Thorac Oncol 1: 611-621, 2006

Chemotherapy benefit in early NSCLC

N dj t h thNeoadjuvant chemotherapy:

HR 0.88 (95%CI: 0.76-1.01)

corresponding with an absolute

survival benefit of 5.4 % at 5 years

Gilligan et al. Lancet 369: 1929-1937, 2007

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Neo-adjuvant chemotherapy

Adjuvant chemotherapy

ESMO - clinical practice guidelines

Adjuvant chemotherapy is recommended in stage II - III radically resected NSCLC

Crino et al. Ann Oncol 21 (Suppl 5), 103-115, 2010

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NSCLC- adjuvant chemotherapy: summary of recent trials

N HR (95%CI) Stage Year

BMJ meta 1394 0.87 (0.74-1.02) I-III 1995

IALT 1867 0.86 (0.76-0.98) I-III 2004

ALPI 1209 0.94 (0.79-1.12) I-IIIA 2003

ECOG3590 488 0.93 (0.74-1.18) II-IIIA 2000

BLT 381 1.02 (0.77-1.35) I-III 2004

BR.10 482 0.70 (0.62-0.92) II 2005

ANITA 840 0.79 (0.66-0.95) IB-IIIA 2006

BMJ meta update 8147 0.86 (0.81-0.93) I-III 2007

French meta 2660 0.89 (0.81-0.97) I-IIIA 2007CALGB9633 344 0.83 (0.64-1.08) IB 2008LACE meta 4584 0.89 (0.82-0.96) IA-IIIB 2008

Early NSCLC – adjuvant chemotherapy (LACE- metaanalysis): effect on OS and DFS

HR: 0.89; 95% CI: 0.82-0.96; p=.005

HR: 0.84; 95% CI: 0.78-0.91; p<.0010.82 0.96; p .005 0.78 0.91; p .001

Pignon et al J Clin Oncol 26: 3552-3559, 2008

11% reduction in risk of death; absolute benefit of 5.4% at 5 years

16% reduction in risk of disease progression;absolute benefit of 5.8% at 5 years

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NSCLC – adjuvant chemotherapy: metaanalyses

Adding CT to surgery: absolute survival increase of 4% at 5 years

Adding CT to surgery/RT:

NSCLC-metaanalysis collaborative group: Lancet 375, 1267-1277, 2010

absolute survival increase of 4% at 5 years

Early NSCLC - adjuvant chemotherapy: LACE-metaanalysis

Efficacy by stage

OS Pts. HR [95% CI]

Stage IA 347 1.40 [0.95;2.06]

Stage IB 1371 0.92 [0.78;1.10]

Stage II 1616 0.83 [0.73;0.95]

Stage III 1247 0.83 [0.73;0.95]

Pignon et al J Clin Oncol 26, 3552-3559, 2008

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Elderly patients and

adjuvant chemotherapy

• Platinum-based chemotherapy improves s r i al ( ith or itho t RT)

NSCLC – adjuvant chemotherapy in the elderly: SEER database/ Ontario cancer registry

survival (with or without RT)• Chemotherapy did not improve survival in

pts. ≥ 80 years• Tolerability appeared similar between pts.

<70 years versus ≥ 70 years• Chemotherapy was associated with

Wisnivesky et al, BMJ 14; 343: d4013. doi: 10.1136/bmj.d4013, 2011Cuffe et al. J Clin Oncol 30, 1813-1821, 2012

Chemotherapy was associated with increased SAE

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Type / duration of adjuvant chemotherapy

NSCLC - adjuvant chemotherapy: type / duration in randomized clinical trials

Study Pts. Type of CT AuthorStudy Pts. Type of CT (no. of cycles)

Author

ALPI 474 Cisplatin-based (3) Scagliotti (2003)BLT 192 Cisplatin-based (3) Waller (2003)IALT 932 Cisplatin-based (3/4) Olaussen (2004)CALGB 9623 124 Carboplatin/Tax (4) Strauss (2008)p / ( ) ( )ANITA 367 Cisplatin/Vin (4) Douillard (2006)BR10 233 Cisplatin/Vin (4) Winton (2005)

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Chemotherapy benefit in early NSCLC

Adjuvant chemotherapy:Adjuvant chemotherapy:

HR 0.89 (95%CI: 0.82-0.96)corresponding with an absolute

survival benefit of 5% at 5 yearsy

Pignon et al J Clin Oncol 26: 3552-3559, 2008

Compliance and adjuvant chemotherapy

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NSCLC - adjuvant chemotherapy : compliance in randomized clinical trials

Study Pts. Compliance AuthorStudy Pts. Compliance AuthorALPI 474 69% Scagliotti (2003)BLT 192 64% Waller (2003)IALT 932 74% Olaussen (2004)CALGB 9623 124 84% Strauss (2008)ANITA 367 50% Douillard (2006)ANITA 367 50% Douillard (2006)BR10 233 50% Winton (2005)

Adjuvant chemotherapy followed by adjuvant radiotherapy

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Early NSCLC – adjuvant CT / RT (ANITA): survival according to lymph node status

Best survival in stage III/N2 for adjuvant CT followed by RT

Douillard et al. Lancet Oncol 7: 719-727, 2006

NSCLC - adjuvant radiotherapy:Cancer Care Ontario/ASCO - Guidelines

Pisters et al. J Clin Oncol 25:5506-5518, 2007

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Pemetrexed and adjuvant chemotherapy

NSCLC - adjuvant chemotherapy (TREAT - phase II): Cis/Pemetrexed vs. Cis/Vinorelbine

• Cis/Pemetrexed is similar effective

• Cis/Pemetrexed less toxic

• Cis/Pemetrexed with superior dose delivery

• Cis/Pemetrexed with higher dose density

Kreuter et al. J Clin Oncol 29 (suppl 15), 453, (abstr 7002), 2011

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NSCLC: adjuvant chemotherapy- Pemetrexed containing regimens/trials -

Japan UMIN000006737 Phase III

Carbo-Gem/Pac/Pem

+/- Killer cellsDentritic cells

N=800 Stage II-IV

resected

China NCT01533727 PhaseII

Platin-Pem/Vin

+/- Killer cells(CIK)

N=222 Stage IB-IIIA

USA ECOG1505-NCT00324805

Phase III

Cis-Vin/Doc/Gem/Pem

+/- Bevacizumab N=1500 StageIB-IIIA

Pharmocogenomics and adjuvant chemotherapy

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NSCLC (ITACA – phase III): International Tailored (ERCC1/TS) adjuvant chemotherapy

High Profile 4

Control*

Taxane

ERCC1

High TS

Low Profile 3

Profile 2

Pemetrexed

Cis/Gem

Control

Control*

High

completely resected stage II-IIIA ECOG 0/1

n=700

PE: overall survival

Low

Profile 2

Profile 1

Cis/Pem

Control*

Control*

TS

Low

High

ERCC1: Excision repair cross complementing group 1 geneTS: Thymidilate Synthase

*Investigators choice of a platinum-based doublet

NSCLC - chemotherapy: potential predictive molecular markers for response

Gene Abnormality Drug Response

p53 Mutation Multiple p53 Mutation Multiple

K-ras Mutation Multiple

tubulin Increased Isotype 3 Taxanes

RRM 1 Increased Expression Gemcitabine

ERCC 1 Increased Expression Platinum

TS Increased Expression Antifolates TS Increased Expression Antifolates

EGFR Mutation EGFR-TKI

BRCA 1 Increased Expression Anti - microtubulins

BRCA 1 Increased Expression Platinum

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NSCLC (TASTE trial): tailored (ERCC1, EGFR mut.) adjuvant Therapy

Cis/PemPhase II/III

TAilored Post-Surgical Therapy in Early Stage NSCLC

Stage II-IIIA completeresection,EGFR mutERCC1

Control arm

EGFR WT

/Phase II/III

No treatment

Cis/Pem

ERCC1 high

ERCC1 low

ERCC1

Erlotinibwww.clinicaltrials.gov; NCT00775385

EGFR mutant

Cis/Pem

NSCLC (BR19): adjuvant therapy by Gefitinib - overall survival

S iti i t tiSensitizing mutation

Placebo Gefitinib

Per

cent

age

40

60

80

100

Overall population

at Risk

PlaceboGefitinib

0

20

0

4036

1

3829

2

3226

3Time (Years)

3021

4

2617

5

67

6

10

Goss et al. J Clin Oncol 28 (suppl 15), 516 (abstr 7005), 2011

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NSCLC (SELECT): tailored (EGFR mut.) adjuvant therapy by Erlotinib

Phase II

Stadium II-IIIA nach kompletter Resektion

EGFR-Mutation +

Erlotinib 150 mg/d2 Jahre

Pennell et al. J Clin Oncol 29 (Suppl, Abstr. TPS209) 2011Neal et al. J Clin Oncol 30 (Suppl, Abstr. 7010) 2012

N=36: 2-years DFS 94% (95% CI, 80%-99%)Expansion to 100 pts. to permit analysis by stage

NSCLC (WJOG6410L): tailored (EGFR mut.) adjuvant therapy - Gefitinib vs. CT

WJOG 6410L, Impact study

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NSCLC (SWOG 0720): tailored (ERCC1, RRM1) adjuvant Chemotherapy

Phase II

Stage IA-IB completeresection,RRM1

ERCC1 > 65RRM1 > 40

No treatment

RRM1ERCC1 Cis/Gem

www.clinicaltrials.gov; NCT00792701

ERCC1 < 65RRM1 < 40

NSCLC (SCAT): tailored (BRCA1) adjuvant chemotherapy

T

Spanish customized adjuvant treatment according BRCA1

Stage II-IIIA complete resection

mRNABRCA1 level

High level TaxaneNo Platinum

Phase III

Low level Platinumbased CT

Massuti J Clin Oncol 29 (Suppl, Abstr. TPS208) 2011Trials in progress Poster

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Systemic therapy in early stage NSCLC

Adjuvant chemotherapy is recommended in stage II - III radically resected NSCLC

•Cisplatin-based chemotherapy improves OS and DFS

•Benefit is greatest in stage II and III, and in PS 0-1

• There is no significant interaction between CT and type of surgery, histology, age, gender, or planned RT

• Current trials investigate the role of pharmacogenomics

Neo-adjuvant cisplatin-based chemotherapy is recommended in stage IIIA/N2- radically resected NSCLC

• Benefit similar to adjuvant therapy