1. Current Strategies for Adjuvant Therapy: Ongoing and Future Trial Research Tracey Evans, MD Abramson Cancer Center University of Pennsylvania, Philadelphia

2. Current Status of Adjuvant Chemotherapy in NSCLC It is STANDARD OF CARE How did we get here?

3. Early Adjuvant Trials in NSCLC No benefitBusulfan + Cyclophosphamide 726Girling 1985 No benefitCCNU + Hydrea865Shields 1982 No benefitCyclophosphamide + MTX417Shields 1977 No benefitCyclophosphamide IV + IP909Shields 1974 No benefit higher recurrence in treatment arm Cyclophosphamide IV189Brunner 1973 No benefitCyclophosphamide orally502Miller 1971 No benefitNitrogen mustard IV + IP1192Slack 1970 No benefitCyclophosphamide IV1035Higgins 1969 No benefitNitrogen mustard IV + IP1002Hughes 1962 ResultsChemotherapy# ptsInvestigator

4. Limitations of Earlier Adjuvant Trials Regimens with marginal activity in advanced NSCLC Inclusion of patients with compromised PS and multiple co-morbidities Difficulty administering systemic therapy in the post-op setting Inadequate power/overly ambitious survival endpoints

5. BMJ Meta-analysis: Adjuvant Cisplatin-based Chemotherapy Overall Survival at risk Months 706590462371295206Surgery+CT Surgery 688548433353258177 S u r v i v a l 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 1.0 0.9 01224364860 Surgery 316 688 298706 EventsTotal Surgery+CT Survival benefit with cisplatin- based chemotherapy: 3% at 2 years, 5% at 5 years BMJ 311:899-901, 1995.

6. IALT Schema Surgically resected non- small cell lung cancer Observation Cisplatin 300-400mg/m2 over 3-4 cycles with Etoposide, vinorelbine, vinblastine, or vindesine Within 60 days post-op RandomizeRandomize Radiation optional, predetermined by N stage for each center

7. IALT Results Chemo (932)No Chemo (935) 5 yr OS 44.5%40.4% 5 yr DFS39.4%34.3% MS50.8 mos44.4 mos MDFS40.2 mos30.5 mos NEJM 350; 351-60, 2004.

8. 935 775 619 520 447372282208 125 932 780 650550 487 399300 208133 0% 20% 40% 60% 80% 100% 01234 5678 years chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years HR: 0.91 (0.81-1.02, P = 0.10) Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507. IALT: 7.5-Year Median Follow-Up

9. NCIC-BR10 Select inclusion criteria: Stage IB-II NSCLC Complete surgical resection N=482 RANDOMIZERANDOMIZE Vinorelbine, IV, 25 mg/m2, weekly  16 wk Cisplatin, 50 mg/m2, d 1, 8 q 4 wk  4 cycles No chemotherapy

10. Overall Survival by Treatment Arm Absolute improvement in 5 yr OS = 11% (67% vs. 56%); benefit persists at 9+ yrs Vincent, Butts et al, 2009. All Patients Absolute improvement in 5 yr OS = 15% (69% vs. 54%) Winton et al. NEJM 2005. HR 0.69 5 yr: 69% vs 54% MST 94 m vs 73 m 5 yr: 67% vs 56% MST 94m vs 72m

11. NCIC-CTG JBR.10 NCIC-CTG JBR.10 Elderly Analysis Elderly received less chemotherapy overall Toxicity differences not seen in this trial by age group Adjuvant chemotherapy should be offered to the fit elderly Pepe, J Clin Oncol Vol 25: 1553-1561, 2007. Age (N)HR OS (Chemo vs obs) CIp ≤65 (327)0.77[0.54-1.09]0.14 >65 (155)0.61[0.38-0.98]0.04 >75 (23)2.35[0.84-6.58]0.09

12. CALGB 9633: RCT of Adjuvant Chemotherapy in Stage IB NSCLC T2N0MO stage IB NSCLC COMPLETE SURGICAL RESECTION ADJUVANT CHEMOTHERAPY Paclitaxel, 200 mg/m 2 Carboplatin, AUC=6 mg/ml x min 4 cycles over 12 weeks OBSERVATION randomization within 4 to 8 wks of resection STRATIFIED squamous vs other poorly differentiated vs other mediastinoscopy: yes vs no Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

13. Overall Survival: THEN AND NOW ASCO: 2004 ASCO: 2006 HR=0.62; 90% CI: 0.44- 0.89; P=0.01 HR=0.80; 90% CI: 0.60-1.07; P=0.10 Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007. 02468 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0123456789 02468 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0123456789

14. Disease-Free Survival: Then and Now ASCO: 2004ASCO: 2006 HR=0.69; 90% CI: 0.51- 0.92; P=0.02 HR=0.74; 90% CI: 0.57-0.96; P=0.03 Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007. 02468 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 012345678902468 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo

15. LACE* Meta-analysis 5 trials including 4,584 patients Median follow-up: 5.1 years (3.1 – 5.9) 80% male Median age 59 years, 9% > 70 years old Pathological Stage: IA: 8%, IB: 30%, II: 35%, III: 27% Surgery: 31% pneumonectomy Histology: 49% squamous cell, 39% adenocarcinoma, 12% other *Lung Adjuvant Cisplatin Evaluation Pignon Proc ASCO 2006 abs 7008.

16. Pignon J et al. JCO 2008;26:3552-3559. The absolute effect of chemotherapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death. LACE Meta-analysis Overall Survival (%) Disease-free Survival (%) Overall Survival (%)

17. LACE Meta-analysis P=.005P<.001 0.89 (0.82-0.96) 0.84 (0.78-0.91) Pignon J et al. JCO 2008;26:3552-3559.

19. NCCN Guidelines

20. Controversies Which regimen? –Cisplatin vs Carboplatin? Stage IB? Predictive/prognostic biomarkers? Post-operative XRT (PORT)?

21. Which regimen?

22. Regimens: LACE Meta-analysis Cisplatin/vinorelbine: regimen for 41% LACE pts –Regimen for Anita and JBR10 –86% patients received >300mg/m2 cisplatin –13% of IA’s cis/vinorelbine vs. 43% other stages Drugs used with cisplatin other studies –IALT: vinorelbine, vindesine, vinblastin, etoposide –BLT: vinorelbine, vindesine, mitomycin/vindesine, mitomycin/ifosfamide –ALPI: vindesine/mitomycin.04.02.10.09

23. Extrapolating Stage IV: Not Vinorelbine? Survival Time (Mos.) Cumulative Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 03691215182124273033 Docetaxel Cisplatin Vinorelbine Cisplatin P = 0.044 (adjusted log-rank) Fossella FV et al. JCO 22, 2003.

24. Schiller et al. NEJM.2002; 346:92-98. Extrapolating Stage IV: It’s all the Same?

25. Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857. Extrapolating stage IV: Cisplatin ≠ Carboplatin: Response Rate

26. Extrapolating Stage IV: Cisplatin ≠ Carboplatin: Overall Survival Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857.

27. M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas on behalf of the TREAT investigators

28. LACE-MetaanalysisNCIC-JBR.10 No treatment9%4.5% Treatment incomplete24 % (≤ 2 cycles) 50% (< 4 cycles) early death or progression9%5% toxicity34%13% patient refusal35%29% Therapy delay55% Dose reductions77% Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009. TREAT Rationale: Adjuvant CTX: mainly Cisplatin / Vinorelbine Need: reduction of toxicity, improvement of dose delivery & compliance Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low toxicities Rationale: Dose delivery: Adjuvant CTX

29. TREAT: Design Cisplatin / Vinorelbine (CVrb) Cisplatin / Pemetrexed (CPx) 50 mg/m 2 d1+8 / 25 mg/m 2 d1, 8, 15, 22 q d 29 x 4 75 mg/m 2 d1 / 500 mg/m 2 d1 q d 22 x 4 R0 Winton et al., N Engl J Med (2005) 352: 258 Inclusion NSCLC stages IB, IIA, IIB, T3N1M0 ≤ 42 days postoperative, R0, systematic LN-dissection ECOG 0, 1 amenable to Cisplatin treatment Stratification Center Nodal status (N0 versus N1) Surgical procedure (lobectomy versus pneumonectomy)

30. Study conduct: Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132 patients) Treatment until 2/2010, primary endpoint analysis 12/2010 Primary endpoint: Clinical Feasibility considered promising if > 80% No death due to cancer, toxicity, comorbidity No Non-acceptance by patients leading to premature withdrawal No observation of DLT  Neutropenia grade 4 > 7 d  Neutropenia grade 3/4 with fever/infection  Thrombocytopenia grade 4 > 7 d  Thrombocytopenia any grade with bleeding  Non-hematologic toxicity grade 3/4 related to CTX Secondary endpoints: Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse TREAT: Conduct / Endpoints

31. CharacteristicsCPx(n=67)CVb(n=65)Total(n=132) Age (years [range])58 [40-73]60 [38-74]59 [38-74] Gender (%) male female 72 28 77 23 74 26 Smoking status (%) Smoker Ex-smoker Non-smoker Not available 33 61 6 0 26 71 1.5 29 66 4 1 Stage (%) IB3738 IIA128 10 IIB4648 47 T3N1565 TREAT: Characteristics

32. CharacteristicsCPx(n=67)CVb(n=65)Total(n=132) Surgical procedures (%) Lobectomy848283 Pneumonectomy121514 Complex resections433 Histology (%) Squamous cell carcinoma 454243 Non-squamous555857 Adenocarcinoma374441 Large cell carcinoma999 Mixed cell carcinoma957 TREAT : Characteristics

33. CPxCVb Feasibility rate (%) 95.5 (CI 87.5-99.1) 75.4 (CI 63.1-85.2) Death (%)1.5 3.1 Withdrawal of consent (%)06.2 DLT (%)3.015.4 Reasons for DLT (events) * patients (n=2) patients (n=10) G4 neutropenia >7d04 G4 thrombocytopenia >7d00 G3/4 febrile neutropenia15 Thrombocytopenia with bleeding00 G3/4 non-hematologic toxicity21 Results: Primary Endpoint - Feasibility * multiple reasons possible p = 0.0010

34. EOTCPxCVb Regular EOT (%)77.6 36.9 Earlier termination of therapy (%)22.463.1 Reasons for earlier termination (events)* patients (n=15) patients (n=41) Unacceptable toxicity according to protocol**419 Unacceptable toxicity perceived by patient67 Relapse of disease0 2 Withdrawal of consent04 Death (therapy related)1 (0) 2 (0) Non-compliance to protocol02 Medical decision by investigator45 Major protocol violation01 Other reasons04 Results: End of Therapy *multiple reasons possible **delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

35. ToxicityCPxCVb Mean Number (AE / SAE) 6.8 / 0.36.9 / 0.2 Hematologic Toxicity G3/4 (%) 10.576.5 Non-hematologic Toxicity G3/4 (%) 3331 Hematologic Toxicity (%) G3/4 Anemia01.5 Thrombocytopenia00 Neutropenia969 Febrile Neutropenia1.56 TREAT: Toxicity p<0.0001 p=0.7988

36. TREAT: Time to Treatment Failure TtTF: Time from surgery to withdrawal due to AE progression / relapse / death failure to return to therapy refusal of treatment / withdrawal of consent p<0.001 Withdrawal probability

37. CPx safe and feasible  less toxicity compared to CVb  superior dose delivery compared to CVb  high dose density (mg/m 2 /week) Dose delivery failure in CVb mostly due to Vb (delivery d15, d22) Efficacy: longer follow up to be awaited TREAT: Conclusions

38. E1505 Chemotherapy Regimens Therapy to start 6-12 weeks post-operatively –Investigator Choice of Chemo - 4 cycles (12 wks) Cisplatin/Vinorelbine –Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d Cisplatin/Docetaxel –Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d Cisplatin/Gemcitabine –Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d Cisplatin/Pemetrexed –Cis 75 mg/m2 d 1; Pem 500 mg/m2 d 1 Q 21 d Bevacizumab 15 mg/kg q 21 days x 12 months

39. ECOG 1505: Adjuvant Bevacizumab RANDOMIZERANDOMIZE STRATIFIED: Stage Histology Gender Chemo regimen* Chemotherapy X 4 cycles ELIGIBLE: Resected IB^-IIIA Squamous Allowed!  Lobectomy No prior chemo No planned XRT No h/o CVA/TIA No ATE w/in 1 yr Chemotherapy x 4 cycles Plus Bevacizumab X 1 year ^ Now revised to exclude IB < 4cm Completed accrual/study closed Sept 20, 2013

40. ECOG 4599: Overall Survival 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Surviving 0642481830 122436 Months HR=0.80; P=0.013 BV/PC12.3 mo PC10.3 mo Median Survival 1-year survival 51% vs. 44% 2-year survival 23% vs. 15% Sandler, et al. NEJM. 355;24. Dec 14 2006.

41. Stage IB

42. LACE Meta-analysis: Stage Effects CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients versus ~43% for other stages)

43. Stage-Specific Hazard Ratios Recent Adjuvant Trials TrialIBIIIIIA IALT0.950.930.79 BR-100.940.59N/A ANITA1.100.710.69 CALGB0.8N/A LACE0.920.83 NegativePositive Indeterminate Not studied

44. Stage-Specific Hazard Ratios Recent Adjuvant Trials Trial IB < 4 cm IB > 4 cm IIIIIA IALT0.950.930.79 BR-101.730.660.59N/A ANITA1.100.710.69 CALGB1.020.66N/A LACE1.41*0.91*0.83 NegativePositive Indeterminate Not studied * Using 3 cm as cut off

45. UICC6 T/M DescriptorProposed T/MN0N1N2N3 T1 (< 2 cm)T1aIAIIAIIIAIIIB T1 (> 2-3 cm)T1bIAIIAIIIAIIIB T2 ( 3 to < 5 cm)T2aIBIIAIIIAIIIB T2 (>5-7)T2bIIAIIBIIIAIIIB T2 (> 7 cm)T3IIBIIIA IIIB T3 invasionT3IIBIIIA IIIB T4 (same lobe nodules)T3IIBIIIA IIIB T4 (extension)T4IIIA IIIB M1 (ipsilateral Lung)T4IIIA IIIB T4 (pleural effusion)M1aIV M1 (contralateral lung)M1aIV M1 (distant)M1bIV New Staging System (IASLC ’07) Staging alteration

46. Prognostic/Predictive Biomarkers Using prognostic data to treat fewer patients who are probably cured, more who are probably not Using predictive data to treat only those likely to benefit with drugs most likely to work

47. ERCC-1 DNA repair mechanisms important for resistance to cisplatin Excision repair cross-complementation group 1 (ERCC1) enzyme plays rate-limiting role in the nucleotide excision repair pathway ERCC-1 Negative ERCC-1 Positive

48. IALT: ERCC-1 Survival Olaussen et al, NEJM 2006; 355: 983-991

49. Prospective Biomarker NSCLC Studies

50. Evaluation of 16 commercially available ERCC1 antibiodies could not distinguish between active and inactive ERCC1 isoforms. 8F1 antibody in IALT data set Friboulet, et al, NEJM 2013; 368: 1101-1110.

51. Erlotinib CDDP-Pemetrexed Observation ERCC1- ERCC1+ EGFR wt Experimental Arm Customized Control Arm CDDP - pemetrexed EGFR mutated TASTE: TAilored Post-Surgical Therapy in Early stage NSCLC: Non-squamous cell NSCLC stage II and IIIA (non-N2)

52. [TITLE] Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

53. [TITLE] Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

54. [TITLE] Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

55. Spanish Customized Adjuvant Treatment (SCAT) Resected NSCLC pN1/pN2 Control Experimental Q 1 BRCA1 Q 2,3 BRCA1 Q 4 BRCA1 Docetaxel/Cisplatin Gemcitabine/Cisplatin Docetaxel/Cisplatin Docetaxel RANDOMIZERANDOMIZE Stratification Age ( 65) Histology (squam vs non-squam) Extent of surgery (lobe vs pneumo) Nodal involvement (pN1/pN2) PORT mandatory N2 3 1 BRCA1: mismatch repair pathway, High levels sensitize to apoptosis by antimicrotubulin agents (taxanes) and inhibit apoptosis with platinum

56. [TITLE] Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

57. [TITLE] Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

58. [TITLE] Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

59. RRMI > 40.5 AND ERCC1> 66.0 Active Monitoring All Others (RRM1< 40.5 OR ERCC1 < 66.0 ) Cisplatin-Gemcitabine S0720: Biomarker-directed Adjuvant Therapy of Stage I NSCLC Assignment Good Prognosis Less benefit from Chemotherapy Poor Prognosis More benefit from Chemotherapy Primary Endpoint = Feasibilty (>75% of patients assigned)

60. High Low TS Low High Profile 4 Profile 3 Profile 2 Profile 1 Taxane Pemetrexed Cis/Gem Cis/Pem Control* High/Low ERCC1 & TS selected according to median level of mRNA expression in historical series ; * Control arm – Investigator choice of a DDP-based doublet ERCC1 ITACA* : Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 & TS * International TAilored Chemotherapy Adjuvant Trial

61. Completely resected stage II-IIIA Primary endpoint: overall survival Secondary endpoints: recurrence free survival, therapeutic compliance, toxicity profile, comparative evaluation of ERCC1 and TS mRNA vs protein Plan for 700 pts (90% power to detect 30% improvement in survival) As of ASCO 2011 annual meeting, 180 patients enrolled from 24 institutions (mostly Italy and Germany) ITACA Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 & TS Novello et al, 2011 ASCO Annual Meeting, abstract e17514.

62. CALGB 30506: Phase III Randomized Study of Adjuvant Chemotherapy vs. Observation in Patients with Stage I NSCLC D. Harpole, PI Stage I NSCLC (2-6 cm, node negative) N=1525 Primary Outcome: Overall survival chemo vs observation Collection of high-quality fresh frozen tissue for gene expression array generation Secondary Evaluate selected genomic-based prognostic models using data from the patients randomized to observation after resection. Rate of toxicity for different chemo regimens. QOL and impact of chemo on QOL Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed x 4 cycles Observation RANDOMIZERANDOMIZE Start date: 3/09 Estimated completion: 1/2014

63. SELECT Trial: Phase II Trial of Adjuvant Erlotinib in Patients with Resected, Early Stage NSCLC with EGFR Mutations PI L Sequist Resected stage IA-IIIA NSCLC Screen tumor for activating EGFR mutations (del_19, L858R) Adjuvant erlotinib x 2 years +/- adjuvant chemo Enroll if: screen + or documented EGFR mutation positive –and- No evidence recurrence on baseline CT scans Surveillance CT scans and CTC analysis q 6 mos x 3 years then q 12 mos x 2 years Biopsy at recurrence, sequence EGFR gene for new mutations, FISH for EGFR and MET copy number surveillance SCREENING PHASE TREATMENT PHASE N=100 Primary Endpoint: Two year disease-free survival

64. SELECT*: First 36 Patients Surgically resected EGFR mutant Lung cancer with adjuvant Erlotinib Cancer Treatment Neal et al, ASCO 2012, abstract 7010.

65. SELECT: Stage and Mutation Distribution StageEGFR Mutation

66. SELECT: Toxicities Toxicity Any (%) Grade 3 (%)Grade 4 (%) Rash * 8917- Diarrhea *783- Fatigue *616- Nausea/vomiting39-- Dry skin39-- Cough (unrelated except 1 gr 2)423- Nail changes36-- Dyspnea (unrelated)28-- Alopecia/Scalp irritation25-- Eye irritation25-- (Any relationship, >25% frequency or grade 3+) * Toxicities leading to dose reductions

67. SELECT: Toxicities (cont) Toxicity Any (%) Grade 3 (%) Grade 4 (%) Pruritis193- Mucositis19-- Transaminitis*19-- Hyperbilirubinemia*173- Anorexia/dysguesia14-- Nosebleed14-- Constipation14-- Neuropathy14-- Urticaria*33- Venous thrombosis (unrelated)33- Pneumonitis (none observed)--- (Any relationship, 10-25% frequency or grade 3+) * Toxicities leading to dose reductions

68. SELECT: Treatment Length Treatment duration and dose reductions 1 Travel precluded participation 2 Diarrhea 3 Rash/Diarrhea 4 Diarrhea/fatigue 5 Prostate cancer radiotherapy Months on Erlotinib 6 Patient preference 7 Rash 8 Disease progression 9 Patient preference 10 Rash Reasons for discontinuation

69. Disease Free Survival

70. Disease Free Survival, by Stage DFS, by stage Disease Free Probability Stage I Censored Stage II Censored Stage III Censored Time (years) 12340 1.0 0.8 0.6 0.4 0.2 0

71. Overall Survival

72. SELECT: Conclusions Feasible, some patients required dose reduction or discontinuation Primary endpoint of 2 year DFS > 86% met. Observed 2 year DFS: 94% Only one patient progressed while receiving adjuvant erlotinib Ten patients progressed ≥6 months after stopping adjuvant erlotinib 6 of 8 rebiopsies did not identify a TKI resistance mechanism All 5 evaluable patients were sensitive to further treatment with erlotinib Taken together, this suggests that adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease Based on the demonstrated role of EGFR TKIs in advanced NSCLC with EGFR mutations, this trial has been expanded to 100 patients total

73. RADIANT: Adjuvant Erlotinib in Resected NSCLC Stage IB, II, or IIIA NSCLC* Complete surgical resection And subsequent adjuvant chemo No prior or concurrent neoadjuvant or adjuvant N=945 Arm A Erlotinib qd  2 years Arm B Placebo qd  2 years RANDOMIZERANDOMIZE *Enriched Population: FISH and/or IHC (+) Primary endpoint: disease free survival 240 sites (US, Canada,Europe, Asia, Argentina) Completed enrollment 4/2010 Interim results expected soon 2 1

74. BR 19: Adjuvant Trial of Gefitinib in NSCLC Stage IB, II, or IIIA NSCLC Complete surgical resection No prior or concurrent neoadjuvant or adjuvant N=1242 ٭ Modified 2004 to allow adjuvant chemotherapy Arm A Gefitinib qd  2 years Arm B Placebo qd  2 years CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol. Clinical Trials (PDQ ® ). At: www.cancer.gov. Commenced October 2002. RANDOMIZE٭RANDOMIZE٭

75. BR 19: Results ArmBSCGefitinibP value No252251 Female46% Adenoca59%60% Stage IB50%53% MSNR5.1 y0.14 [HR1.24] DFSNR4.20.15 [HR 1.22] Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.5] Goss et al, ASCO 2010, abstract LBA7005.

76. Vaccines

77. MAGE-A3 Antigen (melanoma antigen family A, 3) Truly tumor-specific –Not expressed on normal cells (RT-PCR) –Expressed by various tumor types Lung 35-50% Bladder35% Head & Neck 49% Melanoma74% May be associated with poor prognosis (Bolli et al.,2002; Gure et al.,2005) Member of a large family of genes (portfolio)

78. MAGE A3 ASCI* Randomized Phase II stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo. Vaccination was started >6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Other anti-cancer adjuvant therapy was not allowed. Primary endpoint was disease-free interval, other endpoints were recurrence rates at different times, and survival. N=182 * antigen-specific cancer immune therapeutic Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

79. Safety Status 182 patients / 1214 MAGE-A3 doses administered Overall well tolerated Mild grade 1 or 2 Local or systemic reactions,  48 hours 29 grade 3 or 4 adverse events in 21 patients Three grade 3 events, possibly related to treatment Leading to withdrawal of 2 patients –(local pain, COPD exacerbation)

80. Median follow up 44 mos Induction of anti-MAGE-A3 IgG antibody response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response) T cell response in 41% immunized pts, 14% placebo No correlation of immune response and clinical outcome MAGE-A3 Vaccine Phase II: Efficacy Endpoints Overview Hazard Ratio95% CIp Disease-free interval 0.75[0.46-1.23]0.127 Disease-free survival 0.76[0.48-1.21] Overall survival0.81[0.47-1.40] Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

81. Median follow up 44 mos Induction of anti-AMGE-A3 IgG antibody response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response) T cell response in 41% immunized pts, 14% placebo No correlation of immune response and clinical out MAGE-A3 Vaccine Phase II: Efficacy Endpoints Overview Hazard Ratio95% CIp Disease-free interval 0.75[0.46-1.23]0.127 Disease-free survival 0.76[0.48-1.21] Overall survival0.81[0.47-1.40] Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

82. Resectable NSCLC Surgery Pathological stage IB, II, IIIA N=2,270* R MAGE-A3 +AS15Placebo No chemotherapy Chemotherapy Up to 4 cycles platinum based chemotherapy R MAGE-A3 +AS15Placebo MAGRIT: Phase III *MAGE-A3 as Adjuvant non-small cell LunG Cancer ImmunoTherapy

83. PEARL Randomized, double blind phase II study of PRAME (PReferentially Expressed Antigen of MElanoma Immunotherapy) after resection in NSCLC Recombinant PRAME protein combined with AS15 adjuvant system, 13 doses N= 220, stage IA-T1b, IB, II, IIIA, PRAME positive (~30-40%) Open 6/13, primary endpoint DFS

84. Post-operative Radiation Therapy

85. Adjuvant Radiotherapy: Adjuvant Radiotherapy: Meta-analysis 1998 Individual data from 9 randomized trials including 2128 patients Treatment details (staging, surgery, RT) highly variable among series PORT: better local control: 29% fewer local recurrences - 195 LR vs 276 LR for no RT Overall HR = 1.21 (1.08-1.34) ~ survival decrement of 7 % at two years (55% vs 48%) Increase risk greater for early stage patients(Stage I/II vs. III) Lancet 25 July 1998.

86. PORT Meta-analysis PORT Meta-analysis Survival Curves Stewart et al Lancet 1998.

87. PORT – Results by Stage/Nodal Status No increased risk for patients with N2 disease Patients with the least to gain have the most to lose Stewart et al Lancet 1998

88. PORT Meta-analysis PORT Meta-analysis Methodologic Flaws Variable and unspecified staging Variable and unspecified interval between resection and PORT Inadequate RT –Suboptimal doses; large fields –Poor treatment planning –Outmoded techniques (e.g.: use of low-energy photons or 60 Co for a substantial proportion of patients) Inclusion of node negative patients Unpublished data (2 of 9 studies) Relatively short follow up (< 4 yrs)

89. Risks of PORT Risks of PORT Modern Technology Retrospective review –202 patients treated with surgery and PORT for Stage II and III disease –Median dose 55 Gy –Actuarial rate of death from intercurrent disease was 13.5% compared to expected rate of 10% Machtay et al JCO 2001.

90. ANITA - PORT Evaluation PORT: 33% on obs, 22% on chemo For all Chemo > XRT = chemo/XRT > 0 For N2 Chemo/XRT > chemo > XRT > 0 XRTNo Yes ChemoNoYesNoYes All pts MST26mo93mo50mo46mo N2 MST13mo24mo23mo47mo Rosell, IASLC 11, Abs Pr3, 2005.

91. ANITA TRIAL: N2 Disease – Influence of RT

92. Lally, B. E. et al. J Clin Oncol; 24:2998-3006 2006. Plot of Overall Survival for N2 pts Stratified by Postoperative Radiotherapy (PORT) use SEER Data SEER Data

93. “Lung ART” “Lung ART” P.I. Dr Cécile Le Pechoux Completely resected N2 NSCLC SURGERY Conformal RT No post-op RT 54 Gy/27-30 fxs Primary end-point: DFS (Sample size: 700 patients) Pre or post-op chemotherapy allowed Concomitant chemo not allowed Sponsors: FNCLCC, IFCT, LARS-G, EORTC

94. Controversies Which regimen? –Cisplatin vs Carboplatin? Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed (non-squam), or nab- paclitaxel, carboplatin regimens if not cis candidate Stage IB? If at least 4 cm. Predictive/prognostic biomarkers? Not ready for prime time, clinical trials ongoing Post-operative XRT (PORT)? Consider if N2 disease