Supported by Grants U10 CA21661 and U10 CA37422 from the National Cancer Institute

1. Phase III Trial of Accelerated versus Standard Fractionation Plus Concurrent Cisplatin for HNSCC (RTOG 0129): Report of Secondary Analyses Ang KK*, Zhang QE, Wheeler R, Rosenthal DI*, Nguyen-Tan F, Lu C, Kim H, Axelrod R, Silverman C , Weber RS Supported by Grants U10 CA21661 and U10 CA37422 from the National Cancer Institute Acknowledgment: Patients, Participating Teams, RTOG staff, etc. *Served on Advisory Board of BMS

2. Risk reduction Absolute benefit at 5 years p Regimens Survival All group 3.4 % 8 % 0.003 Local-regional Control Hyperfractionation AFX ( Total Dose) ( Total Dose) 24 % 21 % 10 % 9.4 % 7.3 % 2.3 % <0.0001 <0.0001 NS Bourhis (Pignon), Lancet 368:843, 2006 Background & RationaleAltered Fractionation vs Standard Fractionation

3. Risk reduction Absolute benefit at 5 years p Regimens Adjuvant Neoadjuvant Concurrent Cisplatin 2.3 % 2.2 % 6.3 % 9.4 % 2 % 5 % 19 % 24 % NS NS < 0.0001 < 0.00001 Background & RationaleRadiation + Chemotherapy vs Radiotherapy Alone Pignon (Designé), Lancet 335:949, 2000 Pignon & Bourhis, Multidisciplinary H&N Meeting, 2007

4. RTOG 0129: Objective & Study Design Test relative efficacy of combining accelerated fractionation (AFX-C) or standard fractionation (SFX) with cisplatin for the treatment of LA-HNSCC R A N D O M I Z E Stage III & IV* SCC of: • Oral cavity • Oropharynx • Larynx • Hypopharynx Stratify : • Lx vs Non-Lx • No vs N+ • KPS 60-80 VS 90-100 1. AFX-CB: 72 Gy/42 F/6 W + CDDP: 100 mg/m2, q3W x 2 2. SFX: 70 Gy/35 F/7 W +CDDP: 100 mg/m2, q3W x 3 1° endpoint: overall survival Sample size: 720 patients to detect 25% reduction in the death rate (80% power) Excluded T1N+, T2N1

5. RTOG 0129: Study Population Enrolled: 743 patientsin 3 years (7/’02 - 6/’05) Found Ineligibleon Review: 17 Withdrew Consent: 5 Analyzed: 721 (97%) SFX + CDDP: 361 AFX-C + CDDP: 360

6. RTOG 0129: Study Population • CDDP plus AFX-C SFX • Age 55 (26-82) 56 (34-82) • Gender - Male 288 (80%) 309 (86%) • Zubrod: 0 - 1 59% - 41 % 57% - 43% • Primary site • Oropharynx 217 (60%) 216 (60%) • Larynx 98 (27%) 90 (25%) • T3-4 261 (73%) 292 (81%) • N+ 291 (81%) 294 (81%) • AJCC stage IV 279 (78%) 284 (79%)

7. RTOG 0129: Outcome Endpoints by ITT Primary Endpoint ASTRO 2009

8. RTOG 0129: Secondary AnalysesRelative Impact of Tumor, Patient, and Therapy Variables • Patients meeting following criteria: • Alive >3 months without disease progression • Received therapy per protocol or with minor variations • Cycles of cisplatin received: 1-3 • RT dose: >63 Gy (≥90% of prescription) • Overall RT Duration: ≤9 week Total number: 656 (91%) patients Median FU (living patients): 4.8 (0.3 – 6.5) Years ASCO 2010

9. RTOG 0129: Secondary AnalysesRelapse Pattern 1Assumed as having LRR; 2Counted as LRR. ASCO 2010

10. RTOG 0129: Secondary Analyses Overall Survival Progression-Free Survival 100 1º Endpoint 75 50 AFX-C + DDPx2 (303) AFX-C + DDPx2 (303) P=0.50 P=0.55 P=0.66 P=0.22 P=0.0003 P=0.0031 25 SFX + DDPx3 (231) SFX + DDPx3 (231) SFX + DDPx2 (76) SFX + DDPx2 (76) SFX or AFX-C + DDPx1 (46) SFX or AFX-C + DDPx1 (46) Log-rank test 0 0 1 2 3 4 5 0 1 2 3 4 5 Years after Randomization Years after Randomization ASCO 2010

11. RTOG 0129: Secondary Analyses Local-Regional Relapse1 Distant Metastasis 100 Gray’s test 75 50 AFX-C + DDPx2 (303) AFX-C + DDPx2 (303) P=0.33 P=0.91 P=0.047 P=0.11 P=0.63 P=0.049 25 SFX + DDPx3 (231) SFX + DDPx3 (231) SFX + DDPx2 (76) SFX + DDPx2 (76) SFX or AFX-C + DDPx1 (46) SFX or AFX-C + DDPx1 (46) 0 0 1 2 3 4 5 0 1 2 3 4 5 Years after Randomization Years after Randomization 1Includes patients dying of cancer NOS or having LRR+DM ASCO 2010

12. RTOG 0129: Secondary AnalysesMultivariate Analysis without Therapy Variables 1With 20 imputations of missing HPV and smoking data ASCO 2010

13. RTOG 0129: Secondary AnalysesMultivariate Analysis with Therapy Variables ASCO 2010

14. RTOG 0129: Secondary AnalysesGrade 3-4 Late Morbidity ASCO 2010

15. RTOG 0129 – Summary of Planned Endpoints • Strong investigator support – enrollment of 743 patients in 3 years • Compliance to therapy regimens was excellent (91% received therapy per protocol or with minor variations) • No differences in tumor outcome or toxicity were detected between the two regimens

16. RTOG 0129 – Summary of Secondary Analyses • LRR was the main cause of cancer mortality • HPV status was the strongest prognostic factor - Confirming our previous finding that HPV+ OPSCC is a distinct HNSCC entity • Receiving only 1 cisplatin cycle was associated with significantly worse OS, PFS, and LRR rates • The third cisplatin cycle had no significant impact on OS or PFS rate but was associated with a higher LRC rate1 1as defined in this study

17. RTOG 0129 – Summary of Secondary Analyses • Within the range of 64 to 76 Gy, a trend for dose-response relationship was detected for grade 3-4 late morbidity (P=0.063) but not for OS or other endpoints • 2-3 weeks of RT prolongation correlated with poorer OS but not with other endpoints • Only N-category and HPV-status were found to have significant impact on the DM rate