1. Head and Neck Cancer CCO Independent Conference Coverage of the 2006 Annual Meeting of the American Society of Clinical Oncology* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an unrestricted educational grant from June 2-6, 2006 Atlanta, Georgia

2. clinicaloptions.com/oncology Head and Neck Cancer About These Slides  These slides accompany CCO’s comprehensive online Independent Conference Coverage of the 2006 Annual Meeting of the American Society of Clinical Oncology  Our thanks to the presenters who gave permission to include their original data  The full program is available on the Clinical Care Options for Hematology/Oncology Web site: clinicaloptions.com/Atlanta2006  Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Head and Neck Cancer Corey J. Langer, MD Coordinator Head and Neck Medical Oncology Fox Chase Cancer Center Associate Professor Temple University Philadelphia, Pennsylvania Faculty Participating in Slide Development

4. Induction Chemotherapy in Head and Neck Cancer

5. clinicaloptions.com/oncology Head and Neck Cancer TAX 324: Phase III Induction Study Patients with SCCHN No prior chemotherapy, radiotherapy, surgery; PS 0/1, Stage III/IV disease (N = 539) Primary endpoint: OS Secondary endpoints: PFS, safety TPF Docetaxel 75 mg/m 2 IV Cisplatin 100 mg/m 2 IV 5-FU 1000 mg/m 2 /d IV x 4 days Every 3 wks for 3 cycles (n = 280) CRT Carboplatin AUC 1.5, weekly Daily radiotherapy, 5 days/wk, followed by surgery as needed Posner M, et al. ASCO 2006. Oral presentation. PF Cisplatin 100 mg/m 2 IV 5-FU 1000 mg/m 2 /d CI x 5 days Every 3 wks for 3 cycles (n = 259)

6. clinicaloptions.com/oncology Head and Neck Cancer TAX 324 : Survival Log-rank P =.0058 Hazard ratio (HR) = 0.70 Survival Time (Mos) Survival Probability (%) 06 1218243036424854606672 0 10 20 30 40 50 60 70 80 90 100 TPF (n = 255) PF (n = 246) Posner M, et al. ASCO 2006. Oral presentation. TPF 62% PF 48% TPF 67% PF 54%

7. clinicaloptions.com/oncology Head and Neck Cancer TAX 324: Other Efficacy Results  Fewer deaths in TPF arm: 103 (41%) vs 130 (54%)  Improved PFS with TPF vs PF –PFS at 24 and 36 mos –53% vs 42% at 2 yrs –49% v 37% at 3 yrs; P =.004  Postinduction: overall response trend favors TPF vs PF –72% vs 64%; P =.07  No difference in response after CRT –TPF vs PF: ORR, 77% vs 72%; P =.21 Posner M, et al. ASCO 2006. Oral presentation.

8. clinicaloptions.com/oncology Head and Neck Cancer TAX 324: Safety  TPF tolerable and safe compared with PF –Increased hematologic toxicity with TPF during induction  Similar toxicity profile between groups during CRT Posner M, et al. ASCO 2006. Oral presentation. Grade 3/4 Toxicity TPF, % (n = 251) PF, % (n = 243) Neutropenia8456 Febrile neutropenia127 Neutropenic infection129 Stomatitis2127 Nausea/vomiting2224 Anorexia12 Lethargy510

9. clinicaloptions.com/oncology Head and Neck Cancer TAX 324: Conclusions  TPF significantly improved survival (3-year OS: 62%); post-CRT response equivalent to response with PF –Safe and tolerable  New standard of care for induction in SCCHN  Effect of TPF on freedom from distant metastases or with full-dose CRT after induction unknown  Ongoing studies will investigate –Integration of targeted therapies into the induction setting –The role of TPF induction followed by full-dose CRT Posner M, et al. ASCO 2006. Oral presentation.

10. clinicaloptions.com/oncology Head and Neck Cancer EORTC 24971 Patients with newly diagnosed, locally advanced stage III or IV inoperable SCCHN (N = 358) Primary endpoint: PFS Secondary endpoints: RR, OS, toxicity, QOL *Total dose. RT Conventional: 66-70 Gy* OR Accelerated: 70 Gy* OR Hyperfractionated: 74 Gy* Remenar E, et al. ASCO 2006. Abstract 5516. TPF Docetaxel 75 mg/m 2 IV Day 1 Cisplatin 75 mg/m 2 IV Day 1 5-FU 750 mg/m 2 /d IV x 5 days Every 3 wks for 4 cycles (n = 177) PF Cisplatin 100 mg/m 2 IV Day 1 5-FU 1000 mg/m 2 /d x 5 days Every 3 wks for 4 cycles (n = 181) Follow-up every 3 mos Surgery for residual disease permitted 3 mos after RT

11. clinicaloptions.com/oncology Head and Neck Cancer EORTC 24971: Survival  Patients treated with TPF experienced longer PFS compared with PF –Median PFS: 11 mos vs 8.2 mos (P =.015) –HR:.74 (95% CI: 0.59-0.95)  Improved OS with TPF over PF –Median OS: 18.6 mos vs 14.2 mos (P =.0052) –HR: 0.73 (95% CI: 0.56-0.90)

12. clinicaloptions.com/oncology Head and Neck Cancer TPF (n = 173)PF (n = 179) Response, %* Chemotherapy  ORR  CR 67.8 8.5 53.6 6.6 Chemotherapy plus RT  ORR  CR 72.3 33.3 58.6 19.9 Grade 3/4 adverse events, % Chemotherapy  Neutropenia  Leukopenia  Thrombocytopenia  Anemia  Alopecia (including grade 2)  Stomatitis/oral 77 42 3 9 55 5 53 23 18 13 12 11 *Chemotherapy; P =.006 for ORR, >.05 for CR. Chemotherapy + RT; P =.0063 for ORR,.004 for CR. Remenar E, et al. ASCO 2006. Abstract 5516. EORTC 24971: Response and Safety

13. clinicaloptions.com/oncology Head and Neck Cancer EORTC 24971: Quality of Life  QOL assessed at baseline, 2, 4, 6, and 9 mos after RT –GHS/QOL, PSS-HN scores assessed  GHS/QOL scores comparable at baseline; remained stable with TPF, decreased in PF group after RT  PSS-HN scores favored TPF over PF –Normal diet (P =.0064), eating in public (P =.0004), clarity of speech (P =.0003)  Patients in TPF group had 30% risk reduction for WHO PS deterioration (P =.0004) Bernier J, et al. ASCO 2006. Abstract 5522.

14. clinicaloptions.com/oncology Head and Neck Cancer GORTEC Phase III Trial Previously untreated head and neck cancer patients with resectable larynx or hypopharynx tumors* (N = 220) Primary endpoint: 3-year larynx preservation rate TPF Docetaxel 75 mg/m 2 IV Day 1 Cisplatin 75 mg/m 2 IV Day 1 5-FU 750 mg/m 2 /d CI Days 1-5 Every 3 wks for 3 cycles (n = 112) Total laryngectomy then RT 54-66 Gy Responders † Nonresponders † *T3-T4; patients with T2 tumors included if not suitable for partial laryngectomy. † Response: tumor regression > 50% and recovering larynx function; nonresponse: < 50% tumor regression and persistent larynx fixation. Calais G, et al. ASCO 2006. Abstract 5506. RT 70 Gy PF Cisplatin 100 mg/m 2 IV Day 1 5-FU 1000 mg/m 2 /d CI Days 1-5 Every 3 wks for 3 cycles (n = 108)

15. clinicaloptions.com/oncology Head and Neck Cancer GORTEC 2000-01: Preliminary Results TPF, %PF, %P Value Larynx preserved (current rate) 63.241.4NR Response  CR  PR 43.4 39.4 30.4.0013 Calais G, et al. ASCO 2006. Abstract 5506.  Increase in larynx preservation with TPF vs PF –Larynx preservation observed in 80% and 58% of patients following TPF and PF treatment, respectively (P =.036) –Overall survival trend favors TPF over PF (P =.096)

16. clinicaloptions.com/oncology Head and Neck Cancer GORTEC 2000-01: Preliminary Results (cont’d) Grade 3/4 Adverse Events TPF, %PF, %P Value Neutropenia Alopecia Mucositis Febrile neutropenia 57 19 5 2 35 2 9 7.03.002.04.045 Calais G, et al. ASCO 2006. Abstract 5506.  TPF safe, tolerable compared with PF – More grade 3/4 neutropenia, alopecia in TPF arm

17. clinicaloptions.com/oncology Head and Neck Cancer EORTC 24971 and GORTEC 2000-01: Conclusions  EORTC 24971: improved PFS and OS with TPF + RT vs PF + RT –11 mos vs 8.2 mos (P =.015) and 18.6 mos vs 14.2 mos (P =.0052), respectively –Better toxicity profile, QOL for TPF over PF  GORTEC 2000-01: higher rate of larynx preservation in TPF arm vs PF arm –Current preservation rate: 63.2% vs 41.4% –TPF safe and tolerable compared with PF Remenar E, et al. ASCO 2006. Abstract 5516. Calais G, et al. ASCO 2006. Abstract 5506.

18. clinicaloptions.com/oncology Head and Neck Cancer Phase II/III 3-Arm Induction Study TPF Docetaxel 75 mg/m 2 Day1 Cisplatin 75 mg/m 2 Day 1 5-FU 750 mg/m 2 Days1-5 (infusion) 4 cycles every 3 wks PF Cisplatin 100 mg/m 2 Day 1 5-FU 1000 mg/m 2 Day 1-5 (infusion) 4 cycles every 3 wks Treatment-naive patients with unresectable, locally advanced SCCHN ECOG PS < 2 18-70 years old (N = 310) CRT* RT 66-70 Gy Cisplatin 100 mg/m 2 Day 1, 22, 43 Primary endpoints: TTF, CR Secondary endpoints: DFS, OS, safety *Surgery for residual disease or neck dissection allowed before or after CRT. Hitt R, et al. ASCO 2006. Abstract 5515. No induction

19. clinicaloptions.com/oncology Head and Neck Cancer Induction Plus CRT: Efficacy  Longer median TTF with induction + CRT vs CRT alone (P =.031) –TPF + CRT: 16 mos; PF + CRT: 12 mos –CRT: 8 mos  Higher CR with induction + CRT vs CRT alone (P =.02) –Induction + CRT: 68%; CRT: 51%  Longer TTP in complete responders vs nonresponders (P =.0001) –Median TTP: 32 mos vs 12 mos Hitt R, et al. ASCO 2006. Abstract 5515.

20. clinicaloptions.com/oncology Head and Neck Cancer Induction Plus CRT: Safety  Some postinduction toxicity increased with TPF vs PF –Leukopenia: 15% vs 3%; febrile neutropenia: 19% vs 2%  Post-CRT toxicity similar in all groups Hitt R, et al. ASCO 2006. Abstract 5515. Post-CRT Grade 3/4 Adverse Events TPF, Then CRT, %PF, Then CRT, %CRT Only, % Neutropenia Leukopenia Febrile neutropenia Asthenia Mucositis Renal Diarrhea 28 9 6 11 53 2 7 18 11 1 9 58 4 22 18 11 2 5 35 6 13

21. clinicaloptions.com/oncology Head and Neck Cancer Induction With Novel Agents  Phase II study: treatment-naive patients (N = 47) with head and neck cancer –Induction: cetuximab 400 mg/m 2 /wk then 250 mg/m 2 weekly; paclitaxel 135 mg/m 2 ; carboplatin AUC 2 –Subsequent therapy based on tumor stage, site at diagnosis (surgery ± RT, or RT, or CRT)  43 of 44 evaluable patients achieved nodal response (97%) –PR: 70%; CR: 27% –11 of 45 patients disease-free postinduction Kies MS, et al. ASCO 2006. Abstract 5520.

22. Organ Preservation

23. clinicaloptions.com/oncology Head and Neck Cancer RTOG 91-11: Phase III Induction/Larynx Preservation Study Concurrent CRT RT 70 Gy Cisplatin 100 mg/m 2 Day 1, 22, 43 (n = 171) RT alone 70 Gy (2.0 Gy/wk x 5 days/wk) for 7 weeks (n =171) Treatment-naive patients with resectable SCC of the glottis/ supraglottis (N = 547)* *515 patients eligible. Forastiere AA, et al. ASCO 2006. Abstract 5517. Primary endpoint: larynx preservation Induction PF Cisplatin 100 mg/m 2 Day 1 5-FU 1000 mg/m2 CI Day 1-5 3 cycles every 3 wks (n = 173) Third course of PF followed by RT Laryngectomy followed by RT CR or PR < PR

24. clinicaloptions.com/oncology Head and Neck Cancer Forastiere AA, et al. ASCO 2006. Abstract 5517. RTOG 91-11: 5-Year Results  Concurrent CRT improved larynx preservation compared with induction or RT alone  Chemotherapy increased laryngectomy-free survival Concurrent CRT, %Induction, %RT Alone, % Laryngectomy-free survival 47 P =.98 vs induction P =.011 vs RT 45 P =.011 vs RT 34 Larynx preservation 84 P =.0029 vs induction P =.00017 vs RT 70 P =.37 vs RT 66

25. clinicaloptions.com/oncology Head and Neck Cancer ECOG 2399: Phase II Study of Organ Preservation in SCCHN  Chemotherapy/radiation-naive patients with stage III/IV resectable SCCHN –Induction: paclitaxel 175 mg/m 2 plus carboplatin AUC 6; 2 cycles every 21 days –CRT (if no progression): RT 70 Gy x 35 with concurrent paclitaxel 30 mg/m 2 /wk Day 1 for 7 wks  Organ preservation rate at 1 year assessed –Defined as avoidance of salvage surgery, ability to speak and swallow –Separate analysis for treatment effect on swallowing function Cmelak AJ, et al. ASCO 2006. Abstract 5527. Murphy B, et al. ASCO 2006. Abstract 5524.

26. clinicaloptions.com/oncology Head and Neck Cancer ECOG 2399: Results  105 patients with oropharyngeal (OP) and laryngeal cancer (L) evaluable for results  Induction followed by concurrent CRT appears feasible and safe in patients with resectable SCCHN –65% ORR (CR + PR) to induction –12% required surgery at primary site 1 year post-treatment –Acceptable toxicity  2-year event-free survival (EFS): 57% –EFS higher in OP vs L patients: 68% vs 34%; P =.02 Cmelak AJ, et al. ASCO 2006. Abstract 5527.

27. clinicaloptions.com/oncology Head and Neck Cancer ECOG 2399: Results (cont’d)  Correlative study of swallowing function with evaluations at baseline, 3, 12, and 24 mos  DOSS and FCM tools used to assess swallowing abnormality and function  Severe abnormalities, function impairment by DOSS, FCM, noted on treatment (3 mos) in 38% and 45% of patients, respectively  Improvement in abnormality and function by 12 mos –< 10% patients with swallowing abnormalities at 12, 24 mos Murphy B, et al. ASCO 2006. Abstract 5524.

28. Novel Strategies in Advanced Head and Neck Cancer

29. clinicaloptions.com/oncology Head and Neck Cancer Erlotinib Plus Chemotherapy in Advanced SCCHN  EGFR blockade may provide benefit in SCCHN  Phase II study investigated EGFR-inhibitor erlotinib combined with cisplatin/docetaxel in advanced disease –Primary endpoint: response  Eligibility criteria –ECOG PS ≤ 2, no acute comorbidities/infections –Adequate marrow/organ function; no prior EGFR therapy –No brain metastases, no nonmelanoma skin cancer or other malignancies within past 5 years Kim ES, et al. ASCO 2006. Abstract 5521.

30. clinicaloptions.com/oncology Head and Neck Cancer Erlotinib Plus Chemotherapy in Advanced SCCHN: Results  Planned accrual: 50 patients –Treatment with 2 cycles of erlotinib plus cisplatin/docetaxel –42 patients enrolled to date; preliminary results available in 37 patients  Objective response: 59% (CR: 8%; PR: 51%) –Low rate of disease progression: 16%  Acceptable toxicity –Grade 3/4 neutropenia, 14%  Results warrant phase III investigation Kim ES, et al. ASCO 2006. Abstract 5521.

31. Postoperative Strategies

32. clinicaloptions.com/oncology Head and Neck Cancer ARO 96-3: Study Design Postoperative, high-risk SCCHN patients (N = 440) Stratification by primary tumor site and study center Primary endpoint: OS Secondary endpoints: local control, distant metastases, safety Fietkau R, et al. ASCO 2006. Abstract 5507. CRT (n = 214) Radiotherapy (identical to RT arm) Cisplatin 20 mg/m 2 and 5-FU 600 mg/m 2 continuous infusion Days 1-5, 29-33 RT arm (n = 226) Tumor classification Radiation dose N0 50 Gy pN+, no ECS 56 Gy PT + pN+ with ECS 64 Gy

33. clinicaloptions.com/oncology Head and Neck Cancer ARO 96-3: Results Fietkau R, et al. ASCO 2006. Abstract 5507.  Improved DFS, locoregional control for CRT over RT –DFS: 62.4% vs 50.1% (P =.023) –Locoregional control: 83.3% vs 61.9% (P =.0006)  CRT vs RT: no statistically significant difference in OS (P =.11) or freedom from distant metastases (P =.73) –Multivariate survival analysis: HR, 0.7 (P =.034)  Increased grade 3/4 toxicity with CRT –Mucositis 21% vs 13% (P =.038) –Leukopenia 4.4% vs 0% (P =.007)

34. clinicaloptions.com/oncology Head and Neck Cancer Postoperative Treatment: Conclusions  ARO 96-3 results suggest addition of chemotherapy to RT improves DFS, locoregional control  Toxicity concerns with CRT –RTOG 9501: grade 3/4 toxicity higher with CRT vs RT (75% vs 46%) Cooper J, et al. N Engl J Med. 2004;350:1937-1944.

35. clinicaloptions.com/oncology Head and Neck Cancer Postoperative Treatment: Conclusions  Effect of chemotherapy on efficacy of adjuvant RT investigated in several studies –Ongoing OCAT trial Cooper J, et al. N Engl J Med. 2004;350:1937-1944. Bernier J, et al. N Engl J Med. 2004;350:1945-1952. Bachaud J, et al. Int J Rad Oncol Biol Phys. 1996;36:999-1004 Study, CRT vs RT, % DFSLocoregional control OS RTOG 9501 33 vs 25 P =.04 81 vs 70 P =.01 45 vs 38 P =.19 EORTC 22931 47 vs 36 P =.04 82 vs 69 P =.007 53 vs 40 P =.002 Bachaud et al 45 vs 23 P <.02 70 vs 55 P =.05 36 vs 13 P <.01

36. Prognostic Factors for Survival and Toxicity

37. clinicaloptions.com/oncology Head and Neck Cancer MARCH/MACH-NC Meta-Analysis  No treatment benefit with Alt-RT or concomitant CRT in older patients (> 71 years of age) –Advanced age is barrier to effective treatment in SCCHN Age, Yrs MARCH Alt-RT vs RT MACH-NS Concomitant CRT vs RT ≤ 50 HR: 0.78 (95% CI: 0.65-0.94) n = 1311 P =.007 HR: 0.76 (95% CI: 0.66-0.86) n = 2584 P =.003 51-60 HR: 0.95 (95% CI: 0.83-1.09) n = 2300 HR: 0.78 (95% CI: 0.70-0.87) n = 3306 61-70 HR: 0.92 (95% CI: 0.81-1.06) n = 2346 HR: 0.88 (95% CI: 0.78-1.00) n = 2698 > 71 HR: 1.08 (95% CI: 0.89-1.30) n = 1085 HR: 0.97 (95% CI: 0.76-1.23) n = 692 Bourhis, et al. ASCO 2006. Abstract 5501.

38. clinicaloptions.com/oncology Head and Neck Cancer RTOG Risk Analysis for Late Toxicity in SCCHN  Risk factors associated with late toxicity according to RTOG case-control study Machtay, et al. ASCO 2006. Abstract 5500. FactorIncreased Risk of Late Toxicity, OR (95% CI) P Value Older age1.05 (1.02-1.09).001 T3-4 tumor stage (vs T1-2)3.08 (1.44-6.56).004 Site of tumor in larynx/ hypopharynx (vs oral cavity) 4.41 (1.67-11.63).003 Neck dissection performed*2.55 (1.24-5.23).011 *Neck dissection predicted prolonged feeding tube dependence in patients with advanced SCCNH (P =.013; Lango M, et al. ASCO 2006. Abstract 5525).

39. Studies in Patients With Poor Prognosis

40. clinicaloptions.com/oncology Head and Neck Cancer GETTEC/GORTEC: Reirradiation Study in Postoperative Setting CRT RT 60 Gy Chemotherapy Hydroxyurea 1 g twice daily 5-FU 800 mg/m 2 /day* for 5 days, every 2 weeks (n = 65) 12 Weeks Patients with relapsed head and neck cancer (recurrence or second primary tumor with previous local irradiation ≥ 50 Gy) (N = 130) Salvage surgery Primary endpoint: PFS Secondary endpoints: OS, compliance, safety Janot F, et al. ASCO 2006. Abstract 5508. *University of Chicago regimen; Vokes EE, et al. J Clin Oncol. 1989;7:761-768. Observation (n = 65)

41. clinicaloptions.com/oncology Head and Neck Cancer GETTEC/GORTEC: Results  First phase III reirradiation study in postoperative setting –Poor prognosis patients  Improvement in PFS observed in CRT arm (P <.008) –OS: no statistically significant difference observed –Metastasis more likely in CRT arm –Locoregional relapse more likely in observation group –Compliance: 71% of patients completed 12 weeks of CRT  Systemic therapy from GETTC/GORTEC study likely suboptimal in this setting Janot F, et al. ASCO 2006. Abstract 5508.

42. Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications Expert Highlights: download mp3 files and listen to our experts review the highlights of this conference clinicaloptions.com/Atlanta2006 Go Online for More CCO Coverage of This Conference!