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. Walter J Curran, Jr, MD Executive Director Winship Cancer Institute of Emory University Georgia Cancer Coalition Distinguished Scholar RTOG Group Chair Multi-Modality Management of Stage III NSCLC Use of PET Imaging

5. Good PS Stage III NSCLC: Where is There No Randomized Data? Use of Any Advanced Technology RT Tools? Selection of Best Chemo to Give Concurrently with RT Use of Functional Imaging in RT Planning/Assessment Higher RT Dose with a Standardized Chemo Regimen Use of “Targeted Agent” Concurrent with Chemo-RT

6. State III NSCLC Survival by Local Tumor Control Status Median Survival Pts with Local Control (n=674) 18.6 mo 24% Pts without Local Control (n=761) 15.5 mo 6% p < 0.0001

7. RTOG 0617 (CALGB 30609, NCCTG N0628) Randomized Phase III Trial of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal RT w Concurrent and Consolidation Cb/P in Stage IIIA/B NSCLC Primary Endpoint – Survival (n=512) (2 X 2 design evaluating dose and cetuximab independently) Stratified by stage (A vs B), type of RT (3-D vs IMRT) and PS (0 vs 1) Stage IIIA/B PS 0-1 FEV 1 ≥1.5L; V 20 <37% No Supraclav LNs PET recommended RANDOMRANDOMIZEIZERANDOMRANDOMIZEIZE Concurrent ChemoRT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 60 Gy (2 Gy/d) + Cetuximab Concurrent ChemoRT Paclitaxel 45 mg/m 2 Carboplatin AUC 2 Weekly x7 RT 74 Gy (2 Gy/d) + Cetuximab Consolidation Paclitaxel 200mg/m 2 Carboplatin AUC 6 q3wks x2 cycles

8. RTOG 0617 DMC Meeting June 2011 DMC Meeting in early June 2011 High Dose RT Arm (74 Gy) Crossed Futility Boundary Both 74 Gy Arms Closed to Further Accrual Cetuximab Question at 60 Gy to be Completed Accrual will Finish in Late 2011/Early 2012

9. RTOG 0617: Standard vs High RT Dose Question 423 Patients Evaluated in June 2011 DMC Analysis Median Follow-up is 9 months After 90 Deaths, High RT Dose Arm Crossed Futility Boundary 10 Treatment-Related Deaths: – 3 in Standard Dose Arm – 7 in High Dose Arm Most other Deaths Attributed to Disease Progression

10. RTOG 0617 Overall Survival 60 Gy, 58 deaths/213 74 Gy, 70 deaths/204 – – HR=1.45 (1.02, 2.05) – – p=0.02* *One-sided p-value, left tail

11. Can PET/CT Assess RT or ChemoRT Efficacy Earlier? This may be the Most Personalized Care for Stage III Patients!

12. FDG-PET-based Response as an Early Marker of Survival StudyNStagePET response Criteriap MacManus 200373I-IIICR qualitative0.0004 Weber 200357IIIB/IV20% SUV decrease0.005 Hellwig 200447IIB/IIISUV < 40.001 Hoekstra 200547IIIAMR glu < 0.130.0003 Eschmen 200770III80% SUV decrease0.005 deGeus-Oei 200751IB-IV35% SUV decrease0.018 Dooms 200830IIIA60% SUV decrease0.002 Decoster 200831IIICR qualitative0.004 Tanvetyanon 200889IB-IIIBPR qualitativeNS (Hicks J Nuc. Med 2009)

13. REGISTERREGISTER FDG-PET-SUVFDG-PET-SUV Concurrent chemo-XRT (+/- adjuvant chemo as per M.D.) FDG - PET – SUV to be done 12 to 16 weeks following XRT and several wks after adjuvant chemo (if given). Sample size = 250 pts. Completed Accrual 5/14/09 P.I.: Machtay ACRIN 6668/RTOG 0235 Use of PET in Response Assessment

14. SUV peak (c.f. SUV max ) SUVpeak: Circular 1 cm ROI centered around SUVmax. Then, the software is queried to determine the mean SUV within that precisely defined ROI.

15. ACRIN 6668/RTOG 0235 Preliminary Results Assessment Mean SUV peak Pearson Correlation Local Review Central Review Pre-treatment GTV9.4 0.73 Post-treatment GTV2.51.80.86

16. RTOG 0235/ACRIN 6668 Pre and Post- Chemo-RT SUV Median SUV= 9.4 Median SUV= 2.5

17. Major Limitation... 12-16 week waiting period following RT before assessing response/efficacy/prognosis/prediction can seem like an eternity!

18. PET during Weeks 1&2 of RT Aerts HJWL, IJROBP 2008 "The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor."

19. Mid-course FDG-PET & Outcome Kong, JCO 2007 "Although there were not enough patients to perform survival analyses in this study, a significant association of metabolic response and peak FDG activity between during-RT and post-RT scans suggests a potential of using the during-RT PET response (at approximately 45 Gy) to predict long-term survival in lung cancer."

20. PET-based Adaptive Radiotherapy for Stage III NSCLC – RTOG 1106 REGISTERREGISTER FDG-PET Off Study – D/C RT RT to 64 Gy. RANDOMIZERANDOMIZE RT to 64 Gy + 10+ Gy boost based on FDG-PET FDG-PET ChemoRT 44 Gy SD/Response PD

21. FDG-PET based Adaptive RT Feng, IJROBP 2009 "Tumor metabolic activity and volume can change significantly after 40-50 Gy of RT. Using mid-RT PET volumes, tumor dose can be significantly escalated or normal tissue complication probability reduced."

22. Lung Functional Region Classification CT and Ventilation-SPECT Lung quality and ventilation-SPECT is variable between lungs Radiation planning identifying partially functioning, dysfunctional and functional lung can assist in individualizing therapy

23. V/Q SPECT to Individualize Adaptive RT The dose of a functioning lung region decreases from 30-50% to 15-30% after re- optimization.

24. Summary: Stage III NSCLC Chemo-RT   No Fully Personalized Therapy   Thoracic RT is Becoming Anatomy and Response Dependent   RT Optimization of Interest Despite RTOG 0617   Changes in Details of Care not All Subject to Clinical Trials

25. 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