Evolution in Thoracic Oncology: Evolution in Thoracic Oncology: Genomics and Treatment for Early Genomics and Treatment for Early

Stage NSCLCStage NSCLC

David H. Harpole, Jr., M.D.David H. Harpole, Jr., M.D.Professor of SurgeryProfessor of Surgery

Associate Professor of PathologyAssociate Professor of PathologyVice-chairman, Faculty AffairsVice-chairman, Faculty Affairs

Duke University Medical CenterDuke University Medical Center

Who to Treat: LACEWho to Treat: LACE Meta-analysis: Meta-analysis: Chemotherapy EffectChemotherapy Effect

Recommended for stage II-IIIARecommended for stage II-IIIA

Not recommended for stage I (A or B)Not recommended for stage I (A or B)

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Multivariate Multivariate Risk ratio Risk ratio p Valuep Value

Vascular invasionVascular invasion 2.36 2.36 0.0010.001

T2 tumor sizeT2 tumor size 1.88 1.88 0.0020.002

Visceral pleural +Visceral pleural + 1.75 1.75 0.0220.022

>> 15 mitoses / HPF 15 mitoses / HPF 1.51 1.51 0.0740.074

12 24 36 48 60 72 Months12 24 36 48 60 72 Months 0.00.0

0.250.25

0.500.50

0.750.75

1.01.0

Size (cm)Size (cm) (n) (n) 5-Year Surv5-Year Surv0 to 20 to 2 159159 74%74%2 to 42 to 4 207207 60%60%> 4> 4 4242 45%45% p=.0002p=.0002

Risk Model in Stage I NSCLC: HistopathologyRisk Model in Stage I NSCLC: Histopathology

Harpole et al., Cancer 1995Harpole et al., Cancer 1995

SurvivalSurvival

(n=410)(n=410)

Who to treat: Tumor BiologyWho to treat: Tumor Biology

Protein Expression (IHC) Stage 1 (n=408)Protein Expression (IHC) Stage 1 (n=408)

Multivariate Survival AnalysisMultivariate Survival Analysis Risk ratioRisk ratio p Valuep Valuep53p53 1.631.63 0.00370.0037Angiogenesis factor VIII Angiogenesis factor VIII 1.4701.470 0.03330.0333Her2-neuHer2-neu 1.4291.429 0.04400.0440CD-44CD-44 1.3991.399 0.05000.0500RbRb 0.747 0.0738

D’Amico et al. J Thor & Cardiovasc Surg, 1999

12 24 36 48 60 72 Months

1.0

0.75

0.50

0.25

Survival

Total Markers (n) 5-yr. Median0 to 1 140 77% Not reached2 124 62% Not reached3 to 5 144 49% 58 months

p=0.0001

Who to treat: Tumor BiologyWho to treat: Tumor Biology

Who to treat: Early Stage NSCLC Patients Who to treat: Early Stage NSCLC Patients

Current Tools for PrognosisCurrent Tools for Prognosis• Clinical and histopathologic factors• Single molecular biomarkers

But, the challenge is to provide an individualizedBut, the challenge is to provide an individualizedpatient prognosispatient prognosis

Gene expression profiles

Current Therapy for Clinical Stage I NSCLCCurrent Therapy for Clinical Stage I NSCLC

Stage I Stage II and IIIAStage I Stage II and IIIA

Adjuvant Chemotherapy(> 30% relapse)

ObservationObservation(40% relapse)(40% relapse)

Resection Resection

Clinical Stage 1 (45,000 patients in U.S.)Clinical Stage 1 (45,000 patients in U.S.)

Identify Patients atIdentify Patients at Higher RiskHigher Risk

Current Therapy for Clinical Stage I NSCLCCurrent Therapy for Clinical Stage I NSCLC

Stage I Stage I Stage II and IIIAStage II and IIIA

Adjuvant Chemotherapy(> 30% relapse)

ObservationObservation(40% relapse)(40% relapse)

Resection Resection

Clinical Stage 1 (45,000 patients in U.S.)Clinical Stage 1 (45,000 patients in U.S.)

Develop gene expression profiles Develop gene expression profiles that refine risk predictionthat refine risk prediction

What is a ‘Genomic Signature’What is a ‘Genomic Signature’

Phenotype A (Ph A)

Phenotype B (Ph B)

Ph A Ph B

Microarray analysis

Pro

babi

lity

of P

h A

‘Signature’

A Signature of Lung Cancer RecurrenceA Signature of Lung Cancer Recurrence

Low Risk High Risk

Low Risk> 5yr DFS

High Risk< 2yr DFS

Measure gene expression in tumors

“Metagene”

NEJM 2006

Metagene Tree Analysis: First 5 of 100 StepsMetagene Tree Analysis: First 5 of 100 Steps

Dead

Alive

Model has 2100 GenesModel has 2100 Genes

Early Stage NSCLCEarly Stage NSCLCGenomic Predictor of RecurrenceGenomic Predictor of Recurrence

CALGB 30506

Stage I Lung Cancer

Stage I

Predicted High Risk

Predicted Low Risk

NEJM 2006

Prediction Models by Pathologic StagePrediction Models by Pathologic StageClinical-Pathology Clinical-Pathology Prediction ModelPrediction Model

Lung Metagene PredictorLung Metagene Predictor2100 Genes2100 Genes

Accuracy > 90%, Sensitivity > 90%Accuracy > 90%, Sensitivity > 90%For all stagesFor all stages

Lung Metagene Predictor by HistologyLung Metagene Predictor by Histology

Minnesota + CALGB 9761 Validation Set (n=85)Minnesota + CALGB 9761 Validation Set (n=85)

Median F/U 59 mo.

Accuracy > 90%, Sensitivity > 90%Accuracy > 90%, Sensitivity > 90%

Additional Metagene Validation StudiesAdditional Metagene Validation Studies• ACOSOG Z0030; n=25 Stage 1ACOSOG Z0030; n=25 Stage 1• Mayo Clinic; Stage 1; n=15 Stage 1Mayo Clinic; Stage 1; n=15 Stage 1• Washington University; n=71 Stage 1Washington University; n=71 Stage 1

All together, a total of 4 independent sample setsAll together, a total of 4 independent sample setscomprising 195 samples have been used for validationcomprising 195 samples have been used for validation

N=143 (73 Stage1A and 70 Stage 1B)Deaths=47

Black (high risk) 31Red (low risk) 16

Censored=96p=0.003

NCI Director’s Challenge Blinded DatasetNCI Director’s Challenge Blinded Dataset

Overall Survival censored at 5 Years

1212 24 24 36 36 48 48 60 72 60 72MonthsMonths

Sur

viva

lS

urvi

val

1.01.0

.25.25

.75.75

0.00.0

CALGB 30506: Trial ObjectivesCALGB 30506: Trial Objectives• Hypothesis: A genomics prediction model (LUNG Hypothesis: A genomics prediction model (LUNG

METAGENE SCORE; LMS) provides a method for METAGENE SCORE; LMS) provides a method for selecting stage I non-small cell lung cancer (NSCLC) selecting stage I non-small cell lung cancer (NSCLC) patients for adjuvant chemotherapypatients for adjuvant chemotherapy

• Primary ObjectivesPrimary Objectives– To demonstrate a survival advantage for patients To demonstrate a survival advantage for patients

randomized to adjuvant chemotherapy compared to an randomized to adjuvant chemotherapy compared to an observation arm (present standard of care).observation arm (present standard of care).• Observe a more significant survival advantage for Observe a more significant survival advantage for

High-score patients treated with chemotherapyHigh-score patients treated with chemotherapy

– To prospectively validate a prognostic indicator of To prospectively validate a prognostic indicator of survival in stage I NSCLC patients identified with LMS survival in stage I NSCLC patients identified with LMS who are observed after resection. who are observed after resection.

CALGB 30506: Trial ObjectivesCALGB 30506: Trial Objectives• Secondary ObjectivesSecondary Objectives

– Evaluate all other existing gene-based prognostic Evaluate all other existing gene-based prognostic modelsmodels

– Compare the LMS with best clinico-pathologic model Compare the LMS with best clinico-pathologic model for survivalfor survival

– Validate of gene expression signatures from archived Validate of gene expression signatures from archived paraffin-embedded tumor samplesparaffin-embedded tumor samples

– Quality of Life / Economics:Quality of Life / Economics:• To assess QOL/Cost in all stage I patients before To assess QOL/Cost in all stage I patients before

and periodically after resection for NSCLC.and periodically after resection for NSCLC.• To examine the impact of chemotherapy on To examine the impact of chemotherapy on

QOL/Cost for patients in the chemotherapy arm, as QOL/Cost for patients in the chemotherapy arm, as compared to patients in the observation arm(s)compared to patients in the observation arm(s)

CALGB 30506: Inclusion CriteriaCALGB 30506: Inclusion Criteria• Pre-resectionPre-resection

– Clinical T2N0 NSCLCClinical T2N0 NSCLC– Suspicious tumor on CT size: 2.0 to 6.0 cmSuspicious tumor on CT size: 2.0 to 6.0 cm

• (6 cm by CT translates to < 5.0 cm by path)(6 cm by CT translates to < 5.0 cm by path)– Mediastinal node assessment if Mediastinal node assessment if

• CT > 1cmCT > 1cm• PET suspiciousPET suspicious

– Pre-registration after Informed ConsentPre-registration after Informed Consent– No other cancer or chemotherapy in 3 yearsNo other cancer or chemotherapy in 3 years

• At OperationAt Operation– Verified NSCLC (if no Pre-op Dx)Verified NSCLC (if no Pre-op Dx)– Resectable by lobectomy (VATS or Open)Resectable by lobectomy (VATS or Open)– No clinically evidence of N2 or N1 +No clinically evidence of N2 or N1 +

• Send frozen sections on nodes prior to enrollSend frozen sections on nodes prior to enroll– Fresh-frozen Tumor to DukeFresh-frozen Tumor to Duke

• Using simple 5mm Dermal punch biopsyUsing simple 5mm Dermal punch biopsy

After the specimen has been released by the pathologist, cut an approximate After the specimen has been released by the pathologist, cut an approximate 1.0 x 1.0 x 0.5 cm block of firm grossly homogeneous lung tumor using a 1.0 x 1.0 x 0.5 cm block of firm grossly homogeneous lung tumor using a sterile scalpel blade.sterile scalpel blade.

Using a 5mm dermal punch biopsy, cut three (3) core Using a 5mm dermal punch biopsy, cut three (3) core biopsies of equal size from the tumor.biopsies of equal size from the tumor.

The core biopsy may be difficult to extract from the dermal punch. If so, it can The core biopsy may be difficult to extract from the dermal punch. If so, it can be pushed out using a wooden applicator stick inserted into the back end of the be pushed out using a wooden applicator stick inserted into the back end of the punch.punch.

Using the forceps, immediately place one tumor biopsy Using the forceps, immediately place one tumor biopsy sample per Cryomold onto the frozen layer of OCT.sample per Cryomold onto the frozen layer of OCT.

123456-A

1234

56-B

123456-C

With the cryomold still on the cold plate, place a top layer of With the cryomold still on the cold plate, place a top layer of OCT onto the tumor specimen.OCT onto the tumor specimen.

* The sample should be acquired / frozen within 30 minutes.** The sample should be acquired / frozen within 30 minutes.*

123456-A

1234

56-B

123456-C

CALGB 30506: Sample/Information Flow

RejectedRejected

RejectedRejected

RejectedRejected

CALGB Site

Genome Trials Support Facility

H&E

Harpole Lab

RNA Quality

MAW-3

EA: Arrays

IGSP CALGB

3 days

TISSUE

TISSUE

RNA

TISSUE

RNA

DATA LMS SCORE

PT CAN

REGISTER

REGISTERED

RANDOMIZED

10-14 business days

CALGB 30506: Inclusion Criteria: Con’t.CALGB 30506: Inclusion Criteria: Con’t.

• After OperationAfter Operation– Pathologic T1N0 and T2N0 (5% dropout) Pathologic T1N0 and T2N0 (5% dropout)

• N2 and N1 negative N2 and N1 negative • Tumor >1.70 cm (up to 6.0 cm)Tumor >1.70 cm (up to 6.0 cm)• Visceral pleural invasion includedVisceral pleural invasion included

– Inadequate tumor sample (10% Dropout)Inadequate tumor sample (10% Dropout)• > 50% necrosis> 50% necrosis• < 12 < 12 µµg quality RNAg quality RNA• Good quality Array data generatedGood quality Array data generated

• Formal RegistrationFormal Registration

CALGB 30506: Statistical AssumptionsCALGB 30506: Statistical Assumptions– Observation arm Survival for 1.7 to 6.0 cm stage IObservation arm Survival for 1.7 to 6.0 cm stage I

60%60% at 5-years at 5-years• Low-score observation survival = Low-score observation survival = 70+%70+%

– (10+% increase)(10+% increase)• High-score observation survival = High-score observation survival = <<50%50%

– (10+% decrease)(10+% decrease)

– Chemotherapy Treatment arm survivalChemotherapy Treatment arm survival68-70%68-70% **(10-15% increase = HR 1.3 to 1.5)(10-15% increase = HR 1.3 to 1.5)

– High-score chemotherapy advantageHigh-score chemotherapy advantage• (15+% increase = HR 1.67-2.0)(15+% increase = HR 1.67-2.0)

** Based on ANITA and NCI-C JBR-10Based on ANITA and NCI-C JBR-1030506 is powered based on the chemotherapy30506 is powered based on the chemotherapytreatment study: 85% with a two-sided p<0.05. treatment study: 85% with a two-sided p<0.05. Patients and treating physicians are Blinded to LMSPatients and treating physicians are Blinded to LMS

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

LM Score <0.55; 60%LM Score <0.55; 60% LM Score LM Score >> 0.55; 40% 0.55; 40%

Adjuvant Adjuvant ChemotherapyChemotherapy

Resection T (1.70 to 6.0) N0 Patients + ArrayResection T (1.70 to 6.0) N0 Patients + Array

ObservationObservation

RandomizeRandomize

LM Scores Blinded to Investigators, n=1525LM Scores Blinded to Investigators, n=1525(1296 after 15% Ineligibility)(1296 after 15% Ineligibility)

RandomizeRandomize

ObservationObservationAdjuvant Adjuvant

ChemotherapyChemotherapy

CALGB 30506: Treatment PlanCALGB 30506: Treatment Plan

• Assignment to Treatment Arm by StatsAssignment to Treatment Arm by Stats– Observation or TreatmentObservation or Treatment

• Chemotherapy within 12 weeks of resectionChemotherapy within 12 weeks of resection

– Platinum Doublets to mirror ECOG 1505Platinum Doublets to mirror ECOG 1505• Cisplatin + DocetaxelCisplatin + Docetaxel• Cisplatin + GemcitabineCisplatin + Gemcitabine• Cisplatin + VinorelbineCisplatin + Vinorelbine• Cisplatin + Pemetrexed - added soonCisplatin + Pemetrexed - added soonThis will allow combining these data with theThis will allow combining these data with theECOG 1505 chemotherapy-alone armECOG 1505 chemotherapy-alone arm

ConclusionsConclusions

1.1. CALGB 30506 is NCI-CTEP approved and CALGB 30506 is NCI-CTEP approved and activated in the CTSU. It has been endorsed activated in the CTSU. It has been endorsed by ACOSOG, ECOG, RTOG and Canadian by ACOSOG, ECOG, RTOG and Canadian sites. The tissue acquisition, processing, sites. The tissue acquisition, processing, Affymetrix Genechip array generation and Affymetrix Genechip array generation and data analysis are funded by an NCI RO1.data analysis are funded by an NCI RO1.

2.2. It is hopeful that the use of this genomic It is hopeful that the use of this genomic prediction model will aid in the appropriate prediction model will aid in the appropriate selection of stage 1 patients who will benefit selection of stage 1 patients who will benefit from adjuvant chemotherapy.from adjuvant chemotherapy.

Enrollment TipsEnrollment Tips

• It is known that node + patients have up to 15% increased It is known that node + patients have up to 15% increased survival with adjuvant chemotherapysurvival with adjuvant chemotherapy

• It might be the case for node-negative tumors, but we need a It might be the case for node-negative tumors, but we need a trial to show that (standard is no chemo)trial to show that (standard is no chemo)

• Everyone gets an equal chance of observation or Everyone gets an equal chance of observation or chemotherapychemotherapy

• Everyone is does not know the score of your tumor except the Everyone is does not know the score of your tumor except the NCI statisticiansNCI statisticians

• You can pick the pair of drugs with your medical oncologist You can pick the pair of drugs with your medical oncologist These are FDA-approved Standard Doses of Standard Drugs These are FDA-approved Standard Doses of Standard Drugs for adjuvant therapy in NSCLC. No experimental use. These for adjuvant therapy in NSCLC. No experimental use. These are covered by insurance and mandated coverage by are covered by insurance and mandated coverage by Medicare/Medicaid.Medicare/Medicaid.