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

Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC. David H. Harpole, Jr., M.D. Professor of Surgery Associate Professor of Pathology Vice-chairman, Faculty Affairs Duke University Medical Center. Who to Treat: LACE Meta-analysis: Chemotherapy Effect.

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

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  1. Evolution in Thoracic Oncology: Genomics and Treatment for Early Stage NSCLC David H. Harpole, Jr., M.D. Professor of Surgery Associate Professor of Pathology Vice-chairman, Faculty Affairs Duke University Medical Center

  2. Who to Treat: LACEMeta-analysis: Chemotherapy Effect Recommended for stage II-IIIA Not recommended for stage I (A or B)

  3. Multivariate Risk ratio p Value Vascular invasion 2.36 0.001 T2 tumor size 1.88 0.002 Visceral pleural + 1.75 0.022 > 15 mitoses / HPF 1.51 0.074 Risk Model in Stage I NSCLC: Histopathology (n=410) 1.0 0.75 Survival 0.50 Size (cm) (n) 5-Year Surv 0 to 2 159 74% 2 to 4 207 60% > 4 42 45% 0.25 p=.0002 0.0 12 24 36 48 60 72 Months Who to treat: Tumor Biology Harpole et al., Cancer 1995

  4. Protein Expression (IHC) Stage 1 (n=408) Multivariate Survival Analysis Risk ratio p Value p53 1.63 0.0037 Angiogenesis factor VIII 1.470 0.0333 Her2-neu 1.429 0.0440 CD-44 1.399 0.0500 Rb 0.747 0.0738 1.0 0.75 Survival p=0.0001 0.50 Total Markers (n) 5-yr. Median 0 to 1 140 77% Not reached 2 124 62% Not reached 3 to 5 144 49% 58 months 0.25 12 24 36 48 60 72 Months Who to treat: Tumor Biology D’Amico et al. J Thor & Cardiovasc Surg, 1999

  5. Who to treat: Early Stage NSCLC Patients Current Tools for Prognosis • Clinical and histopathologic factors • Single molecular biomarkers But, the challenge is to provide an individualized patient prognosis Gene expression profiles

  6. Current Therapy for Clinical Stage I NSCLC Clinical Stage 1 (45,000 patients in U.S.) Resection Stage I Stage II and IIIA Identify Patients at Higher Risk Adjuvant Chemotherapy (> 30% relapse) Observation (40% relapse)

  7. Current Therapy for Clinical Stage I NSCLC Clinical Stage 1 (45,000 patients in U.S.) Resection Stage I Stage II and IIIA Observation (40% relapse) Adjuvant Chemotherapy (> 30% relapse) Develop gene expression profiles that refine risk prediction

  8. What is a ‘Genomic Signature’ Phenotype A (Ph A) Phenotype B (Ph B) Microarray analysis Ph APh B Probability of Ph A ‘Signature’

  9. A Signature of Lung Cancer Recurrence Low Risk > 5yr DFS High Risk < 2yr DFS Measure gene expression in tumors Low Risk High Risk “Metagene” NEJM 2006

  10. Metagene Tree Analysis: First 5 of 100 Steps Dead Alive Model has 2100 Genes

  11. Early Stage NSCLCGenomic Predictor of Recurrence Stage I Lung Cancer Predicted Low Risk StageI CALGB 30506 Predicted High Risk NEJM 2006

  12. Prediction Models by Pathologic Stage Clinical-Pathology Prediction Model Lung Metagene Predictor 2100 Genes Accuracy > 90%, Sensitivity > 90% For all stages

  13. Lung Metagene Predictor by Histology

  14. Minnesota + CALGB 9761 Validation Set (n=85) Accuracy > 90%, Sensitivity > 90% Median F/U 59 mo.

  15. Additional Metagene Validation Studies • ACOSOG Z0030; n=25 Stage 1 • Mayo Clinic; Stage 1; n=15 Stage 1 • Washington University; n=71 Stage 1 All together, a total of 4 independent sample sets comprising 195 samples have been used for validation

  16. NCI Director’s Challenge Blinded Dataset 1.0 .75 N=143 (73 Stage1A and 70 Stage 1B) Deaths=47 Black (high risk) 31 Red (low risk) 16 Censored=96 p=0.003 Survival .25 Overall Survival censored at 5 Years 0.0 12 24 36 48 60 72 Months

  17. CALGB 30506: Trial Objectives • Hypothesis: A genomics prediction model (LUNG METAGENE SCORE; LMS) provides a method for selecting stage I non-small cell lung cancer (NSCLC) patients for adjuvant chemotherapy • Primary Objectives • To demonstrate a survival advantage for patients randomized to adjuvant chemotherapy compared to an observation arm (present standard of care). • Observe a more significant survival advantage for High-score patients treated with chemotherapy • To prospectively validate a prognostic indicator of survival in stage I NSCLC patients identified with LMS who are observed after resection.

  18. CALGB 30506: Trial Objectives • Secondary Objectives • Evaluate all other existing gene-based prognostic models • Compare the LMS with best clinico-pathologic model for survival • Validate of gene expression signatures from archived paraffin-embedded tumor samples • Quality of Life / Economics: • To assess QOL/Cost in all stage I patients before and periodically after resection for NSCLC. • To examine the impact of chemotherapy on QOL/Cost for patients in the chemotherapy arm, as compared to patients in the observation arm(s)

  19. CALGB 30506: Inclusion Criteria • Pre-resection • Clinical T2N0 NSCLC • Suspicious tumor on CT size: 2.0 to 6.0 cm • (6 cm by CT translates to < 5.0 cm by path) • Mediastinal node assessment if • CT > 1cm • PET suspicious • Pre-registration after Informed Consent • No other cancer or chemotherapy in 3 years • At Operation • Verified NSCLC (if no Pre-op Dx) • Resectable by lobectomy (VATS or Open) • No clinically evidence of N2 or N1 + • Send frozen sections on nodes prior to enroll • Fresh-frozen Tumor to Duke • Using simple 5mm Dermal punch biopsy

  20. 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 sterile scalpel blade.

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

  22. 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 punch.

  23. Using the forceps, immediately place one tumor biopsy sample per Cryomold onto the frozen layer of OCT. 123456-B 123456-C 123456-A

  24. With the cryomold still on the cold plate, place a top layer of OCT onto the tumor specimen. * The sample should be acquired / frozen within 30 minutes.* 123456-B 123456-A 123456-C

  25. CALGB 30506: Sample/Information Flow TISSUE CALGB Site Harpole Lab PT CAN REGISTER RANDOMIZED REGISTERED TISSUE Genome Trials Support Facility MAW-3 TISSUE 3 days Rejected H&E RNA Rejected RNA Quality RNA Rejected EA: Arrays 10-14 business days DATA LMS SCORE IGSP CALGB

  26. CALGB 30506: Inclusion Criteria: Con’t. • After Operation • Pathologic T1N0 and T2N0 (5% dropout) • N2 and N1 negative • Tumor >1.70 cm (up to 6.0 cm) • Visceral pleural invasion included • Inadequate tumor sample (10% Dropout) • > 50% necrosis • < 12 µg quality RNA • Good quality Array data generated • Formal Registration

  27. CALGB 30506: Statistical Assumptions • Observation arm Survival for 1.7 to 6.0 cm stage I 60% at 5-years • Low-score observation survival = 70+% • (10+% increase) • High-score observation survival = <50% • (10+% decrease) • Chemotherapy Treatment arm survival 68-70%*(10-15% increase = HR 1.3 to 1.5) • High-score chemotherapy advantage • (15+% increase = HR 1.67-2.0) *Based on ANITA and NCI-C JBR-10 30506 is powered based on the chemotherapy treatment study: 85% with a two-sided p<0.05. Patients and treating physicians are Blinded to LMS

  28. CALGB 30506Schema (Stage IA/IB) Resection T (1.70 to 6.0) N0 Patients + Array LM Score <0.55; 60% LM Score > 0.55; 40% Randomize Randomize Adjuvant Chemotherapy Adjuvant Chemotherapy Observation Observation LM Scores Blinded to Investigators, n=1525 (1296 after 15% Ineligibility)

  29. CALGB 30506: Treatment Plan • Assignment to Treatment Arm by Stats • Observation or Treatment • Chemotherapy within 12 weeks of resection • Platinum Doublets to mirror ECOG 1505 • Cisplatin + Docetaxel • Cisplatin + Gemcitabine • Cisplatin + Vinorelbine • Cisplatin + Pemetrexed - added soon This will allow combining these data with the ECOG 1505 chemotherapy-alone arm

  30. Conclusions 1. CALGB 30506 is NCI-CTEP approved and activated in the CTSU. It has been endorsed by ACOSOG, ECOG, RTOG and Canadian sites. The tissue acquisition, processing, Affymetrix Genechip array generation and data analysis are funded by an NCI RO1. 2. It is hopeful that the use of this genomic prediction model will aid in the appropriate selection of stage 1 patients who will benefit from adjuvant chemotherapy.

  31. Enrollment Tips • It is known that node + patients have up to 15% increased survival with adjuvant chemotherapy • It might be the case for node-negative tumors, but we need a trial to show that (standard is no chemo) • Everyone gets an equal chance of observation or chemotherapy • Everyone is does not know the score of your tumor except the NCI statisticians • You can pick the pair of drugs with your medical oncologist These are FDA-approved Standard Doses of Standard Drugs for adjuvant therapy in NSCLC. No experimental use. These are covered by insurance and mandated coverage by Medicare/Medicaid.

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