NSCLC AdiuvanteNSCLC Adiuvante

Dott. Domenico Galetta

20 03 2004 2005 2006

~6

ALPIHR = .96N=1207

ALPIHR = .96N=1207

ANITAHR = .76N=840

ANITAHR = .76N=840

JBR.10HR = .69N=482

JBR.10HR = .69N=482

IALTHR = .86N=467

IALTHR = .86N=467

CALGB 9633

HR = .83N=344

CALGB 9633

HR = .83N=344

RADIANTRADIANT

MAGRITMAGRIT

E1505Closed to Accrual

E1505Closed to Accrual

20 08 20 13 2014

ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182

IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97

ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51

BLTHR = 1.02

N=381

BLTHR = 1.02

N=381

Adjuvant Therapy TimelineAdjuvant Therapy TimelineKelly K USA EO3.4

~6

ALPIHR = .96N=1207

ALPIHR = .96N=1207

ANITAHR = .76N=840

ANITAHR = .76N=840

JBR.10HR = .69N=482

JBR.10HR = .69N=482

IALTHR = .86N=467

IALTHR = .86N=467

CALGB 9633

HR = .83N=344

CALGB 9633

HR = .83N=344

RADIANTRADIANT

MAGRITMAGRIT

E1505Closed to Accrual

E1505Closed to Accrual

ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182

IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97

ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51

BLTHR = 1.02

N=381

BLTHR = 1.02

N=381

20032003 20042004 20052005 20062006 20082008 20132013 20142014

Adjuvant Therapy TimelineAdjuvant Therapy Timeline

?

ITACAITACA

CALGB 30506CALGB 30506

ALCHEMIST

ALCHEMIST

CTONG1104

CTONG1104

Afatinib Adjuv

Afatinib Adjuv

EURECAEURECA

adapted

Adjuvant CT ± post-op RT, in operable NSCLC: two meta-analyses of individual patient dataAdjuvant CT ± post-op RT, in operable NSCLC: two meta-analyses of individual patient data

NSCLC Meta-analyses Collaborative Group Lancet 2010; 375:1267

34 trials, 8447 patientsHR 0.86 (95 CI : 0.81-0.92)P<0.0001

13 trials, 2660 patientsHR 0.88 (95 CI : 0.81-0.97)P<0.009

4% benefit

4% benefit

Pignon JP, et al. J Clin Oncol 2008; 26:3552-9

Adjuvant chemo has greatest benefit for stage II and III and is detrimental for stage IA patients

LACE Analysis by StageLACE Analysis by Stage

T 3 - 4 cm T ≥ 4 cm

HR OS p HR OS p

CALGB 9633 1.02 0.51 0.66 0.04

JBR.10 1.73 0.07 0.66 0.13

No Chemo Benefit Potential Chemo Benefit

CALGB Stage IB and Tumor Diameter > 4 cm JBR .10

7th edition of TNM staging Tumors > 5 -7 cm are Stage IIA Tumors > 7 cm are Stage IIB

Strauss GM,et al. J Clin Oncol 2008; 31: 5043-51Butts CA, et al. J Clin Oncol 2010; 28: 29-34

Stage IB T Size AnalysisStage IB T Size Analysis

1. CDDP based adjuvant chemotherapy improves the cure rate for patients with Stage II-IIIA NSCLC with a PS of 0-1.

3. No role for adjuvant chemotherapy in patients with a tumor size < 3 cm (Stage IA in both 6th and 7th Staging classification).

4. Controversial role for adjuvant chemotherapy in patients with a tumor size of > 4 cm with subset analyses suggesting a benefit.

4. Non-cancer mortality may be increased in patients receiving chemotherapy.

What Have We Learned?What Have We Learned?Kelly K USA EO3.4

Early Stage NSCLCNo Biomarker, Unselected Population

Early Stage NSCLCNo Biomarker, Unselected Population

Survival Time

patients with residual micrometastasessensitive to adjuvant therapy

patients with residual micrometastasessensitive to adjuvant therapy

Probability

Predictive Factors

Prognostic Factors

Scagliotti GV Ita

ly MS 13.3

Do «good prognosis»lung cancer exist?Do «good prognosis»lung cancer exist?

5 Year Survival

5 year survival

T stage(all N0M0)

Primary size

N Clinical Stage

Pathological stage

T1a ≤ 2 cm 1816 53% 77%T1b > 2-3 cm 1583 47% 71%T2a > 3-5 cm 2822 43% 58%T2b > 5-7 cm 825 36% 49%T3 > 7 cm 364 28% 35%

Rami-Porta J Thor Oncology 2007

Mark G Kris

, USA

, PC02.4

Prognostic factors in lung cancerPrognostic factors in lung cancerThere are no “good prognosis lung cancers”

23% of patients with tumor less than 2 cm (stage pT1aN0M0) are dead at 5 years. All patients with breast cancer with this degree of risk are reccomended additional therapy with primary treatment

• Phase II “proof of concept” studies less applicable to adjuvant setting.• In adjuvant studies overall response rate is NOT an endpoint. • Survival is much longer and potentially impacted by additional lines of

therapy at relapse.• Quality of life issues and adverse events.• Early stage NSCLC are less frequently reported than in other types of

tumors (e.g. breast).

Kris M

USA PC 02.4

Scagliotti GV Ita

ly MS 13.3

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

Use of microarrays in NSCLCUse of microarrays in NSCLC

• Need for complicated methods.• Large number of genes used in gene profilings.• In most of the studies need of fresh tissue.• Lack of both reproducibility and independent

validation of the results.• Genes varied considerably and only few genes have

been consistently included.• Gene expression profiles can vary according to the

microarray platform and the analytic strategy used.

Scagliotti GV Ita

ly MS 13.3

CALGB 30506 Schema (Stage IA/IB)CALGB 30506 Schema (Stage IA/IB)

Adjuvant Chemotherapy

N=425

Resection T (1.75 to 4.0) N0 Patients + Array

ObservationN=223

Randomize

LM Scores Blinded to Investigators

Randomize

ObservationN=425

Adjuvant Chemotherapy

N=223

N=1296

LM Score <0.55; 850 LM Score > 0.55; 446

Gene Expression Survival Prediction in Lung Adenocarcinoma : Validation Study

Gene Expression Survival Prediction in Lung Adenocarcinoma : Validation Study

• Training-testing multi-institution validation study (UM,HLM,CAN/DF,MSK), 442 adenocarcinoma• Eight Classifiers

All stages All stages with covariates

Stage I only with covariates

Stage I only

Shedden K. et al. Nature Med. 2008; 14::822

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

Early Stage NSCLC Prognostic Biomarkers

Early Stage NSCLC Prognostic Biomarkers

Reference Marker Trial N Marker Status

HR for Survival (P Value)

Fouret 2009[1] MSH2 IALT 768 Positive 0.66 (.01)

Olaussen 2006[2] ERCC1 IALT 761 Positive 0.66 (.009)

Filipits 2007[3] MRP2 IALT 782 Positive 1.37 (.007)

Tsao 2007[4] p53 JBR.10 253 Positive 1.89 (.03)

Seve 2007, 2012[5] β-tubulin III

JBR.10 265 Positive 1.72 (.04)

Cappuzzo 2009[6] MET Retrospective 447 Negative 0.66 (.04)

Rosell 2007[7] BRCA1 Retrospective 12658

Positive 1.98 (.02)2.4 (.04)

1. Fouret P, et al. ASCO 2009. Abstract CRA7502. 2. Olaussen KA, et al. N Engl J Med. 2006;355:983-991. 3. Filipits M, et al. Clin Cancer Res. 2007;13:3892-3898. 4. Tsao MS, et al. J Clin Oncol. 2007;25: 5240-5247. 5. Seve P, et al. Clin Cancer Res. 2007;13:994-999, Annals Onc 2012. 6. Cappuzzo F, et al. J Clin Oncol. 2009;27:1667-1674. 7. Rosell R, et al. PLoS One. 2007;2:e1129.

Scagliotti GV Ita

ly MS 13.3

Erlotinib

CDDP-Pemetrexed

Observation

TASTE -Adjuvant Trial IFCT0704: Non Squamous Stage II and IIIA

ERCC1-

ERCC1+

EGFR wt

ARM B(Experimental)

customized

ARM A (Control)

CDDP pemetrexed

EGFRmutated

TASTE: biomarker distributionTASTE: biomarker distribution

Biomarker distribution

Expected Observed

10%

56%

44%

9%

75%

25%

• Study was stopped at 150 patients due to ERCC1 IHC which behavior during TASTE trial was significantly different from the one observed in IALT-bio analysis1

• Phase III did not proceed due to the unexpected lack of reliability of ERCC1 IHC 2

• ERCC1 IHC is unable to distinguish the different isoforms. Only isoform 2 is active in DNA repair. (Friboulet NEJM 2013)

1Olaussen K et al. NEJM 2006

ERCC1-or UND

ERCC1+

EGFR WTor UND

ARM B(Experimental)

customized

EGFRmutated

2Soria JC ASCO 2013 Abst# 7507)

First analysis of toxicity and treament compliance in customized postoperative chemotherapy based on BRCA1

levels after NSCLC resection: SCAT (Spanish Customized Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP

First analysis of toxicity and treament compliance in customized postoperative chemotherapy based on BRCA1

levels after NSCLC resection: SCAT (Spanish Customized Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP

Bartomeu Massuti1, Manuel Cobo2, Manuel Rodriguez-Paniagua1, Isabel Ballesteros3, Teresa Moran4, Ricardo Arrabal2, Jose Luis Gonzalez Larriba5, Isidoro Barneto6, Yat Wah Pun3, Javier de. Castro Carpeño7, Lara Iglesias8, Carlos Baamonde6, Miguel Angel Muñoz9, Guillermo Lopez-Vivanco10, JJ Rivas de Andres11, Dolores Isla12, Rafael Lopez13, Ramon De Las Peñas14, Delvis Rodriguez15, Pedro Lopez De Castro16, Angel Artal17,

Emilio Esteban Gonzalez18, Florentino Hernando Trancho19, Mariano Provencio20, J Valdivia21, Prudencio Diaz Agero7, Jose Luis Martin De Nicolas8, Eva Pereira22, Jose Miguel Sanchez23, Rafael Rosell16;

1Alicante University Hospital, Alicante/SPAIN, 2Hospital Carlos Haya, Malaga/SPAIN, 3Hospital La Princesa, Madrid/SPAIN, 4Catalan Institute of Oncology, Badalona/SPAIN, 5Hospital Clínico San Carlos, Madrid/SPAIN, 6Hospital Reina Sofia, Cordoba/SPAIN, 7Hospital Universitario La Paz, Madrid/SPAIN, 8Hospital 12 de Octubre, Madrid/SPAIN, 9Instituto Valenciano Oncología, Valencia/SPAIN, 10Hospital de Cruces de Barakaldo,

Vizcaya/SPAIN, 11Hospital Miguel Servet, Zaragoza/SPAIN, 12Hospital Lozano Blesa, Zaragoza/SPAIN, 13Hospital Clinico Universitario de Santiago de Compostela, Santiago De Compostela/SPAIN, 14Hospital Provincial de Castellón, Castellón/SPAIN, 15Hospital Universitario Insular

de Gran Canaria, Las Palmas De Gran Canaria/SPAIN, 16Hospital Germans Trias i Pujol, Badalona/SPAIN, 17Hospital Universitario Miguel Servet, Zaragoza/SPAIN, 18Hospital Universitario Central de Asturias, Oviedo/SPAIN, 19Hospital Clinico San Carlos, Madrid/SPAIN, 20Hospital Puerta de Hierro, Madrid/SPAIN, 21Hospital Virgen de las Nieves, Granada/SPAIN, 22Grupo Español de Cancer de Pulmon (GECP), Barcelona/SPAIN, 23MD

Anderson Cancer Center, Madrid/SPAIN

Massuti B Spain M

Oo8.01

Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)

Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)

Resected NSCLC pN1 / pN2

Q 2 & 3 BRCA1

Q 4 BRCA1

Gem/Cis

Docetaxel

Docetaxel/Cis

Q 1 BRCA1

Planned number of patients: 432 (ammended)

CT should start until 8 weeks after surgery

PORT in N2 patients

CONTROL

EXPERIMENTAL

Docetaxel/Cis

Statification factors: - Stage: N1 vs. N2- Age <65 vs > 65 y - Histology: Non-SCC vs. SCC - Type of resection: Lobectomy vs Pneumonectomy

Eudract: 2007-000067-15NCTgov: 00478699

1

:

3

Massuti B Spain M

Oo8.01

SCAT: BRCA1 expressionSCAT: BRCA1 expression

• Median mRNA BRCA1 levels: 15.78 (0.73-132)• Quartiles distribution:

– Q1: 212 (42.4%)– Q2-3: 150 (30%)– Q4: 138 (27.6%)

• Mean BRCA1:– Adenocarcinoma: 6.95 vs Squamous 20.29 (p<0.001)

• EGFR mut: 5.6% (incomplete data)

Massuti B Spain M

Oo8.01

SCAT trialSCAT trial

Le Chevalier T

, France MO08.06

ITACA Adjuvant Trial Pharmacogenomics: Yes or No?

ITACA Adjuvant Trial Pharmacogenomics: Yes or No?

Radically Resected II-IIIANo priorChemotherapy or Radiation Therapy prior surgery

Stratification Factors Pathological stage (II vs. III) Smoking status (current vs. former vs. never smoker)

ERCC1 and TS Assessment by RT-PCRERCC1 and TS Assessment by RT-PCR

HIGH ERCC1 & HIGH TSHIGH ERCC1 & HIGH TS

HIGH ERCC1 & LOW TSHIGH ERCC1 & LOW TS

LOW ERCC1 & HIGH TSLOW ERCC1 & HIGH TS

LOW ERCC1 & LOW TSLOW ERCC1 & LOW TS

DocetaxelDocetaxel

Standard ChemotherapyStandard Chemotherapy

PemetrexedPemetrexed

Standard ChemotherapyStandard Chemotherapy

Standard ChemotherapyStandard Chemotherapy

Standard ChemotherapyStandard Chemotherapy

Cispplatin/PemetrexedCispplatin/Pemetrexed

Cisplatin/GemcitabineCisplatin/Gemcitabine

R

R

R

RN= 700

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

- 27 -

MMAGE-A3 as AAdjuvant Non-Small Cell LunGG CanceR IR ImmunoTTherapy

Powered for efficacy

No chemo

MAGE-A3 ASCI PlaceboPowered for efficacy

Phase III Study in NSCLC: MAGRITPhase III Study in NSCLC: MAGRIT

MAGE-A3 ASCI Placebo

Randomization

Pathological stage IB, II, IIIA

Resected MAGE-A3 (+) NSCLC

Up to 4 cycles of platinum-based chemo

Randomization

Chemo

N= 2300

2011 accrual completed 2014 ASCO results awaited

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

•Path stage IB - III NSCLC•Complete surgical resection•PS 0-2•Adjuvant chemo and /or XRT allowed

Gefitinib 250 mg po q dayx 2 years

PlaceboPO q dayx 2 years

R

N = 503

All patients EGFR Mutated

Adjuvant Gefitinib: JBR.19

Goss GD, et al. J Clin Oncol 2013; 31: 3320-26

Unselected for EGFR mut+

Stage IB-IIIA Surgery

CTX4/ No CT

Erlotinib

Placebo

R*

* Selection FISH + and/or IHC+

RADIANT

Primary endpoint: Disease Free Survival

N = 945

Adjuvant Therapy: ErlotinibUnselected for EGFR mut+

EGFR mutation in early stage Lung Cancer: Rationale

EGFR mutation in early stage Lung Cancer: Rationale

• All stages need more cure• Eradicating metastases the goal• EGFR as target• Results in patients with early stages• Trials in progress• Seizing the opportunities

Mark G Kris

, USA

, PC02.4

Adjuvant Imatinib in GIST1 year vs 3 Years

Adjuvant Imatinib in GIST1 year vs 3 Years

Joensuu H et al JAMA. 2012;307(12):1265-1272. doi:10.1001/jama.2012.347

SELECT TrialSELECT Trial

EGFR mutation positiveSurgically resectedStage I-IIIA NSCLC

< 6-9 months following adjuvant chemo ± XRT

Initial 36, expanded to 100

ERLOTINIB 150 mg/daily, 2 years total

Scan every 6 months for 3 years, annually yr 4-5

Primary End point : Disease Free Survival

Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)

A multicenter phase II trial of adjuvant erlotinib in 100 EGFR-mutant lung cancer

SELECT: Adjuvant ErlotinibSELECT: Adjuvant Erlotinib

Patients surgically reected stage I-IIIA harboring activating EGFR mutations

Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)

Further hurdles to be considered with molecular alterations…..

Further hurdles to be considered with molecular alterations…..

• Is the alteration equally present in early disease?

• Is the molecular alteration stable overtime?• Is the targeted treatment equally effective as

adjuvant (maintenance) treatment or should be reserved at relapse?

• Are long term toxicities tolerable?

TTP and OS from start of TKI retreatment, in patients who develop a recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI. A portion of patients gain durable disease

control on TKI despite prior adjuvant exposure.Oxnard G R et al. Clin Cancer Res 2011;17:6322-6328

Mark G Kris

, USA

, PC02.4

EURECAEErlotinib Used as Adjuvant Therapy in

Resected EGFR mutant Lung Carcinoma

EURECAEErlotinib Used as Adjuvant Therapy in

Resected EGFR mutant Lung Carcinoma

• Resected stage I-III EGFR-mutation positive lung cancer with activating EGFR mutation(exon 19 deletion, L858R, L861Q, G719X)

• Perioperative citotoxyc chemotherapy and radiation therapy as indicated

• Stratified by staging and perioperative chemotherapy

N=286

Adjuvant erlotinib up to 24 months with CT chest every 6 months than yearly

N=190

CT chest every 6 months than yearly

N=96

• CT scan at 30 months• Follow patients for

recurrence or death• Patients with recurrence

will be biopsed to confirm recurrence and test for molecular determination of acquired resistance

• Record of subsequent chemotherapies

Lung Cancer Mutation Consortium PI Cristopher Azzoli

Mark G Kris

, USA

, PC02.4

Adjuvant Afatinib: 3 months vs 2 yearsAdjuvant Afatinib: 3 months vs 2 years

Resected stage I-IIIEGFR+ lung cancers/p completion of standard adjuvant chemotherapy +/- RT

92 patients will be stratified for pathological stage (I,II,III) powered to detect a recurrence free survival improvement of 20%

Afatinib oral daily x 3 months

Afatinib oral daily x 2 years

CT Chest every 6 months x 3 years and then annualy RFS at 5 yearsRFS at 5 years

Adjuvant Afatinib PI Lecia Sequist

RANDOMIZE

Baseline CT need

Mark G Kris

, USA

, PC02.4

Consent & Register: A151216Screening& Follow-up Protocol

CLIA-approved LAB•EGFR mutation test

•ALK rearrangement

TCGA•Genomic sequencing•Transciptome•Methylation

Pre-opCohort

Post-op Cohort

•SOP-driven FF/FFPE•After resection, buffy coat

•Assess FFPE•buffy coat

E4512:Crizotinib

Other AdjuvantStudies

AllianceAlliancePI: Govindan R.PI: Govindan R.

ECOG 4512ECOG 4512PI: Ramalingam S.PI: Ramalingam S.

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial)

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial)

A081105

Erlotinib

Placebo

R*

N = 410

A151216 Registry StudyScreening and Follow up protocol

N= 6000 -8000

Primary Endpoint: OS

E4512 N= 360

Actionable target and trial identified

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial)

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial)

Adjuvant Therapy: Molecular SelectionAdjuvant Therapy: Molecular SelectionKelly K USA EO3.4

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

Strategies to select Drugs for use with surgery in Early Stage Lung Cancer

• Gene expression profiles (microarrays)• Repair/Metabolism genotype• Immunotherapy• Molecular driven mutation• New targets• Assess radiographic response in induction

“window of opportunity”

WCLC 2013: what’s newWCLC 2013: what’s new

Besse B, France M

O08.02

IFCT-0703: phase II study resultsIFCT-0703: phase II study resultsBesse

B, France MO08.02

~6

ALPIHR = .96N=1207

ALPIHR = .96N=1207

ANITAHR = .76N=840

ANITAHR = .76N=840

JBR.10HR = .69N=482

JBR.10HR = .69N=482

IALTHR = .86N=467

IALTHR = .86N=467

CALGB 9633

HR = .83N=344

CALGB 9633

HR = .83N=344

RADIANTRADIANT

MAGRITMAGRIT

E1505Closed to Accrual

E1505Closed to Accrual

ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182

IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97

ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51

BLTHR = 1.02

N=381

BLTHR = 1.02

N=381

20032003 20042004 20052005 20062006 20082008 20132013 20142014

Adjuvant Therapy TimelineAdjuvant Therapy Timeline

?

ITACAITACA

CALGB 30506CALGB 30506

ALCHEMIST

ALCHEMIST

CTONG1104

CTONG1104

Afatinib Adjuv

Afatinib Adjuv

EURECAEURECA

adapted

Knowledge GapsKnowledge Gaps

>70<65

N % N %

# Non-lung cancer deaths

195 12 54 22

Overall toxicities

grade 3-5 559 72 62 76

grade 4-5 470 34 65 41

Deaths from toxicities

grade 5 10 0.7 3 1.9

Fruh M, et al. J Clin Oncol 2008; 26:3573-81Elderly patients should receive adjuvant chemotherapy

No treatment interaction

Phase II Cis/Pemetrexed vs. Cis/Vinorelbine (TREAT)

Cis/Vb N-67 Cis/Pem N-65

Feasibility 74% 96%

Completion of Therapy 63% 22%

Grade 3-4 hematological toxicity 78% 11%

Grade 3-4 non-hematological toxicity 33% 31%

Dose Delivery (% Planned) Cis 66% Cis 90%

Vb 64% Pem 90%

p =.001; p<.0001

Kueter M et al. Ann Oncol 24: 986-992;2012

Adjuvant Chemotherapy – Optimal RegimenAdjuvant Chemotherapy – Optimal Regimen

Most extensively studied regimen is Vinorelbine and Cisplatin

LACE meta-analysis showed a benefit of VNR/CDDP over“other” CDDP regimens

pStage IB-IIIAIB > 4 cm

RANDOMIZE

Cisplatin – based Chemotherapy

Cisplatin – basedChemotherapy

Bevacizumab: 15 mg/kg

REGIMEN N= 636 % Use

Vinorelbine + CDDP 27%

Doxetaxel + CDDP 33%

Gemcitabine + CDDP 25%

Pemetrexed + CDDP 16%

E1505

Wakelee ASCO 2012, Abstr 7013

Adjuvant Chemotherapy – Optimal RegimenAdjuvant Chemotherapy – Optimal Regimen

Primary endpoint: Overall Survival

Yanagawa N et al European J Cardio-Thoracic Surgery 44:e200-e206, 2013N = 433 patients (1995-2010; 7th edition TNM staging)

Variables HR 95% CI P-value Variables HR 95% CI P-value

Lymphovascular Invasion in Stage ILymphovascular Invasion in Stage I

Induction (Neoadjuvant) vs AdjuvantFactors Favoring Induction

Chemotherapy

Induction (Neoadjuvant) vs AdjuvantFactors Favoring Induction

Chemotherapy• Attacks micrometastases at earliest time• Better drug delivery and tolerability• Ability to assess sensitivity of agents used in

induction and planned for adjuvant• Platform for new agent testing• Surgical findings an outcome surrogate• Time to identify unsuspected metastases and

comorbidities before local therapy• Randomized trials equivalent or better• Provide quick answers

Major pathologic response (≤10% viable tumor) following

neoadjuvant chemotherapy as a surrogate for overall survival in

patients with pathologically documented stage IIIA (N2) lung

adenocarcinomasJamie E. Chaft1, Matthew D. Hellmann1, William

D. Travis2, Valerie Rusch3, Mark G. Kris1

Memorial Sloan-KetteringDepartments of 1Medicine, 2Pathology, 3Surgery

Chaft JE, U

SA O02.05

Survival Results

0 12 24 36 48 60 720

20

40

60

80

100

Survival by Nodal Downstaging

Months

Per

cen

t su

rviv

al

Nodal downstagingPersistent N2

0 12 24 36 48 60 720

20

40

60

80

100

Survival by Nodal Clearance

Months

Per

cen

t su

rviv

al

Nodal clearancePersistant Nodal disease

Nodal Downstaging

N=16

Persistent N2

N=30

Median survival

Undefined 64 months

Hazard ratio (95% CI)

1.4 (0.5 – 4.2) 0.7 (0.2 - 2.1)

Nodal Clearance

N=14

Persistent N2N=32

Median survival

Undefined 64 months

Hazard ratio (95% CI)

1.0 (0.4 – 3.1) 0.9 (0.3 – 2.8)

Major pathologic response as a surrogate for survivalMajor pathologic response as a surrogate for survival

Survival by Major Pathologic Response

0 12 24 36 48 60 720

20

40

60

80

100

Survival by Major Pathologic Response

Months

Per

cen

t su

rviv

al MPR

>10% tumor cells

≥90% path response N=5

<90% path response N=41

Median survival undefined 40.5 months

Hazard ratio (95% CI) 0.3 (0.07-0.95) 3.9 (1.1-14)

(N=5)(N=41)

Major pathologic response as a surrogate for survivalMajor pathologic response as a surrogate for survival

Adjuvant Therapy: Molecular SelectionAdjuvant Therapy: Molecular Selection

Proportion of patients with surgically resected non–small-cell lung cancer diagnosed in Ontario (N = 6,304) from 2001 to 2006 who received adjuvant chemotherapy.

Booth C M et al. JCO 2010;28:3472-3478

Adjuvant chemotherapy uptakeAdjuvant chemotherapy uptake

~ 25%

ConclusionConclusion

• Patient selection & drug selection based on gene expression arrays, gene mutation and amplification and/or proteomics will quite likely improve the efficacy of adjuvant chemotherapy

• Phase II studies are marginally appropriate• In this setting alternative efficacy outcomes instead of

OS are needed.• Marker-based or marker by treatment interaction are

eagerly encouraged.• In the context of rare oncogene-addicted tumors a

close multidisciplinary, international collaboration is needed.

Scagliotti GV Ita

ly MS 13.3