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3. David Jablons, M.D. Professor and Chief, Section of General Thoracic Surgery Ada Distinguished Professor and Program Leader Thoracic Oncology Laboratory Helen Diller Family Comprehensive Cancer Center University of California, San Francisco Large-Scale International Validation of a qPCR-Based Genetic Assay Prognostic of Survival in Resected Non- Squamous Cell NSCLC

4. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory)

5. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm

6. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm Analytical Assay Validation (CLIA-certified Laboratory)

7. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm Analytical Assay Validation (CLIA-certified Laboratory) Independent Validation Kaiser Northern California 433 stage I China Clinical Trials Consortium 1006 stage I-III

8. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm Analytical Assay Validation (CLIA-certified Laboratory) Independent Validation Kaiser Northern California 433 stage I China Clinical Trials Consortium 1006 stage I-III paraffin-tissues

9. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm Analytical Assay Validation (CLIA-certified Laboratory) Independent Validation Kaiser Northern California 433 stage I China Clinical Trials Consortium 1006 stage I-III qPCR paraffin-tissues

10. A practical genomic prognostic assay 361 stage I-IV non- squamous FFPE samples (UCSF Training Cohort) Measure expression of 14 cancer pathways + reference genes (CLIA-certified Laboratory) L2-penalized Cox Proportional Hazards Modeling Prognostic Algorithm Analytical Assay Validation (CLIA-certified Laboratory) Independent Validation Kaiser Northern California 433 stage I China Clinical Trials Consortium 1006 stage I-III qPCR paraffin-tissues blinded

12. Study Cohorts (n=1800) UCSF Training CohortKaiser Validation CohortChina Validation Cohort Eligible Patients3614331006 Successful RNA recovery337 (93.4%)420 (97.0%)967 (96.1%) Age at Resection67.4 (10.5) § 66.6(9.3) § 58.3(10.8) § Females200 (59.3%)229 (54.5%)366 (37.9%) Smoking History Yes224 (66.5%)355 (84.5%)492 (48.9%) No57 (16.9%)36 (8.6%)403 (40.1%) Unknown56 (16.6%)29 (6.9%)72 (7.2%) Median follow-up (months)46.470.037.8 Deaths at 5 years139 (41.2%)179 (42.6%)406 (42.0%) Histology Adenocarcinoma278 (82.5%)325 (77.4%)881 (87.6%) Large Cell17 (5.0%)15 (3.6%)17 (1.7%) Mixed10 (3.0%)15 (3.6%)46 (4.6%) NSCLC NOS32 (9.5%)65 (15.5%)23 (2.3%) AJCC Stage I223 (66.2%)420 (100%)471 (46.8%) II41 (12.2%)0222 (22.1%) III58 (17.2%)0266 (26.4%) IV9 (2.7%)00 Undetermined6 (1.8%)08 (0.8%) § Cohort Mean (Standard Deviation)

13. Algorithm Development – UCSF Cohort Overall survival (%):80% versus 35%, based on 14 cancer-related oncogenes

14. Blinded Assay Validation Kaiser Cohort (n = 420)China Cohort (n = 967) Overall Survival 75% versus 48% 80% versus 45%

15. Stage Independence (China) Stage I disease (low risk = 83.0% [73.8–89.1]; intermediate risk = 67.7% [54.8–77.7]; high risk = 64.6% [57.9–70.5]) Stage II disease (low risk = 54.2% [30.1–73.2]; intermediate risk = 45.8% [26.2–63.4]; high risk = 38.1% [29.4–46.8]) Stage III disease (low risk = 53.3% [32.6–70.3]; intermediate risk = 43.3% [27.2–58.5]; high risk = 24.0% [17.5–30.9])

16. Multivariate Models Kaiser cohort (n = 420) China cohort (n = 967) PredictorHR95% CILR test p-value High Risk Category*1.931.23-3.040.010 Female Sex0.650.48-0.870.004 Age (years) § 1.041.02-1.06<0.001 Tumor Size (cm) § 1.091.00-1.190.057 *Compared to Low Risk Category § Modeled as Continuous Variables PredictorHR95% CILR test p-value High Risk Category*3.252.25-4.70<0.001 Female Sex0.960.73-1.280.798 Never smoker0.840.64-1.110.214 Tumor Size (cm) § 1.011.00-1.030.197 *Compared to Low Risk Category § Modeled as Continuous Variables

17. China stage I-IIA (n=540) New TNMM Staging TNM StageMulti-Gene AssayNew TNMM Stage IALow RiskTNMM IA IBLow Risk IAIntermediate + High RiskTNMM IB IBIntermediate + High Risk IIALow Risk IIAIntermediate + High RiskTNMM IIA

18. Conventional Staging No data support the use of adjuvant treatment in patients with stage IA tumors as defined by conventional criteria Use of such treatment in patients with stage IB disease is lent support by only controversial evidence

19. New TNMM Staging The addition of the molecular assay gave better risk discrimination than did NCCN risk criteria alone

20. Genetic Assay Outperforms Conventional Methods The molecular assay was the strongest predictor of 5 year mortality compared with standard criteria (sex, age, smoking status, etc) Outperformed the NCCN guidelines used to identify high-risk patients with stage I disease

21. Conclusions There is a clear need to improve NSCLC staging A robust, practical assay prognostic of survival after resection has been developed using qPCR and paraffin-tissues This multi-gene assay has been independently validated in two large international cohorts The multi-gene assay can outperform conventional risk factors / staging and may lead to personalized therapies for patients with early stage non-squamous NSCLC

22. Thank you UCSF Thoracic Oncology Laboratory David JablonsMichael Mann Patrick PhamMike Mulvihill Marc SegalRoshni Ray Kirk JonesDan Raz Zhidong XuThierry Jahan Biao He Kaiser Northern California Stephen Van Den Eeden Charles QuesenberryLaurel Habel China Clinical Trials Consortium Jianxing HeZhi-Hua Zhu Wen GaoHuanrong Zhang Bo SuQiuhua Deng Zongfei WangJiangfen Zhou Huiling LiMei-Chun Huang Che-Chung Yeh Pinpoint Genomics David Berryman Jerry Hurst Fatemeh Zaiei

23. Sunday, February 12, 2012 Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Walter J Curran Jr, MD David Jablons, MD Mark G Kris, MD Suresh Ramalingam, MD Alan B Sandler, MD