1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

4. Adjuvant Therapy of NSCLC Winter Lung Cancer Conference 2012 Rogerio Lilenbaum, MD, FACP Cleveland Clinic Florida Weston, FL

5. Adjuvant Therapy of NSCLC Stage IB Chemotherapy choices PORT

6. LACE – Benefit by Stage CT may be detrimental for stage IA, but stage IA patients were generally not given cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages) Test for trend: p = 0.051 Category No. Deaths / No. Entered Hazard Ratio (Chemotherapy / Control)[95% CI] Stage IA102 / 3471.41[0.96;2.09] Stage IB509 / 13710.92[0.78;1.10] Stage II880 / 16160.83[0.73;0.95] Stage III865 / 12470.83[0.73;0.95]

7. Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2008 CALGB 9633 Overall Survival by Tumor Size Chemotherapy (N = 99) Control (N = 97) –HR = 0.69 –90% CI: 0.48 to 0.99 –P =.043 Chemotherapy (N = 63) Control (N = 71) –HR = 1.12 –90% CI: 0.75 to 1.07 –P =.32 Tumor ≥4 cmTumor <4 cm

8. Stage IB Analysis T < 4 cmT ≥ 4 cm HR OSp p CALGB 96331.02.510.66.04 JBR.101.73.070.66.13 No Chemo BenefitPotential Chemo Benefit Strauss JCO 2008, Vincent ASCO 2009

9. Stage-Specific Hazard Ratios Recent Adjuvant Trials Trial IB < 4 cm IB > 4 cm IIIIIA IALT0.95 0.930.79 BR-101.730.660.59N/A ANITA1.100.100.710.69 CALGB1.020.66N/A LACE0.92 0.83 Negative Positive Indeterminate Not studied

10. Adjuvant Therapy of NSCLC Stage IB –Tumor size matters –Use 4 cm as a parameter Chemotherapy choices PORT

11. Adjuvant Therapy of NSCLC Stage IB Chemotherapy choices PORT

12. E1505 Chemotherapy Regimens Therapy to start 6-12 weeks post-operatively –Investigator Choice of Chemo - 4 cycles (12 wks) Cisplatin/Vinorelbine –Cis 75 mg/m 2 d1, Vin 25 mg/m 2 d1,8 q21 d Cisplatin/Docetaxel –Cis 75 mg/m 2 d1, Docetaxel 75 mg/m 2 d1 q21 d Cisplatin/Gemcitabine –Cis 75 mg/m 2 d1, Gem 1250 mg/m 2 d1,8 q21 d Cisplatin/Pemetrexed –Cis 75 mg/m 2 d1, Pem 500 mg/m 2 d1 q21 d

13. E1505 – Adjuvant Chemotherapy Wakelee et al - ASCO 2011 Between Aug 2007 and Jan 2010, 557 patients were enrolled: –median age 61 –52% female –54% adeno, 31% squamous –23% IB, 43% II, 29% IIIA (N2), 4% IIIA (T3N1) Adjuvant regimens: –28% C-V –34% C-D –26% C-G –12% C-P (added later) Overall Gr 3/4 toxicities are increased in Bev arm; Gr 5 toxicity was 2.5% vs. 3.8% without or with Bev

14. 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 Tage postoperatively, R0, systematic LN-dissection ECOG 0, 1 - amenable to cisplatin treatment Rationale: Need: reduction of toxicity, improvement of dose delivery & compliance Cisplatin / pemetrexed in thoracic malignancies: high dose intensity, low toxicities

15. 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

16. 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

17. TREAT: Time to treatment failure TREAT: Time to treatment failure Time from surgery to withdrawal due to AE AE progression / relapse / death progression / relapse / death failure to return to therapy failure to return to therapy refusal of treatment / withdrawal of consent refusal of treatment / withdrawal of consent Time to treatment failure also in favor of cisplatin/pemetrexed, p<0.001

18. Adjuvant Therapy of NSCLC Stage IB Chemotherapy choices –Use cisplatin whenever possible –Cis-Vnb is associated with greater toxicity PORT

19. Adjuvant Therapy of NSCLC Stage IB Chemotherapy choices PORT

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

21. Overall survival for N2 pts stratified by postoperative radiotherapy (PORT) use – SEER data – SEER data There is benefit of PORT in stage IIIA-N2 disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials.

22. “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

23. Adjuvant Therapy of NSCLC Stage IB Chemotherapy choices PORT –No benefit in N0 and N1 disease –Consider in N2 patients – especially with multi- station involvement and/or extra-capsular spread –Do it sequentially

24. 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