1. 21th WCC, Shenzhen, China, Aug 19, 2010 Guo-Liang Jiang, MD, FACR Min Fan, MD, Jiayan Chen, MD Fudan University Shanghai Cancer Center Combination of radiation therapy and Gefitinib for non-small cell lung carcinoma

2. Outcome of non-small cell carcinoma Stage and tmt 5-yr survival Stage and tmt 5-yr survival I-II surgery 48-70% I-II inoperable, SBRT ～ 40% IIIa (surgery ±other Tmt) 15-27% IIIa (RT ＋ Chemo) 14-20% IIIb (RT ＋ Chemo) 5-7% Predominant failure pattern: Local and distant failures

3. Combination of radiation therapy and Gefitinib for stage IIIb/IV non-small cell lung carcinoma Clinical phase I trial Irradiation dose escalation (NCT00497250)

4. Gefitinib enhanced radiosensitivity of tumor cells Survival curve of Oral SCC (in vitro) Shintani S. Int J Cancer 2003; 107:1030–37 Shoulder of survival curve disappear (inhibition for SLD repair) Slop of survival curve reduced (intrinsic radiosensitivity increased)

5. Gefitinib enhanced radiosensitivity of tumor cells GEO (rectal carcinoma) in vivo (tumor re-growth delay) 10Gy/fx×4fx + Iressa 2.5mg ip d1-5×4 wks Bianco et al. Clin Cancer Res 2002;8:3250-3258 Iressa + RT Control RT Iressa

6. The percentage of S phase decreased after Iressa Iressa+RT (GEO in vivo) Bianco C. Clin Cancer Res 2002;8:3250-3258 Mechanism of Gefitinib radiosensitization

7. Gefitinib speeds up apoptosis of tumor cells after RT GEO in vivo Bianco C. Clin Cancer Res 2002;8:3250-3258 RT+Iressa RT Iressa

8. Gefitinib inhibits RT induced damage repair Oral SCC (Western blot) Shintani S. et al. Int J Cancer 2003; 107:1030–1037 RT damage DNA Need DNA repair enzyme RT enzyme  DNA repair  Gefitinib enzyme  DNA repair 

9. Iressa+RT in Oral SCC (Western blot) And RT could activate EGFR-TK signaling pathway (Ras-Raf-MAPK). And initiates a multistep phosphorylation cascade that leads to activation the pathway, and stimulates cell-cycle progression Shintani S. Int J Cancer 2003; 107:1030–1037 Gefitinib could inhibit multistep phosphorylation of EGFR signaling pathway, so slow down the tumor cell proliferation and enhance the radiation sterilization.

10. Possible mechanisms for radiosensitization of Gefitinib 1.Decrease percentage of S phase and increase G2/M phases of tumor cells 2.Enhance tumor cell apoptosis after RT 3.Inhibit radiation induced DNA repair 4.Inhibit multistep phosphorylation of EGFR signaling pathway, so reduce the tumor cell proliferation after RT

11. Rationales: Gefitinib as radiosensitizer to enhance local tumor sterilization. Inhibit or delay the growth of micrometastases What is concerned most for concurrent RT and Gefitinib for NSCLC? Pulmonary toxicity: Interstitial pneumonitis by Gefitinib Radiation pneumonitis

12. Goal of the trial Main endpoint Side-effect and toxicity, safety and MTD of concurrent therapy of Gefitinib and RT for advanced non-small cell lung carcinoma. Second endpoint Acute response (RECIST) and survival

13. Patient eligibility NSCLC histologically or cytologically confirmed IIIb IV: brain mets ECOG 1-2 No contraindication for RT Tolerable for RT and Gefitinib

14. Treatment Concurrent Gefitinib (250mg, qd) and RT and continuously Gefitinib for 2 months after RT. RT target: Gross tumor volume in thorax on CT 2Gy/fx, 5 fx/wk, Total dose escalation 54Gy, 56Gy, 58Gy, 60Gy Dose limit toxicity (DLT) in 2 months after completion of RT CTCAE V3 >=3 for lung CTCAE V3 >=4 for others When >=2/8 patients occurred DLT, dose escalation terminated and MTD was one dose level before.

15. Result Status of dose escalation Dose levelNo. pts 54Gy8 56Gy8 58Gy8 60Gy8+8 One patient in 60Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days

16. Male/Female28/12 Medium age (yr) Medium cycle of chemo 55 (32–79) 3.5 (1-5) ECOG0101 10 30 StageIIIB IV 18 22 Histology Adeno- Sq Poor differentiated 35 (86%) 4 1 Smoker/non-smoker20/20 Clinical characteristics of patients (n=40 ）

17. Safety (MFT: 9.7 mos) CTCAE 3.0 Incidence Rash1-224 (60%) ≥3≥30 Pulmonary1-229 (73%) 3 G5 0 1 (3%) Espophageal1-223 (58%) ≥3≥30 Hematological1-216 (40%) ≥3≥30

18. Outcome At last follow-up visit SD 8 (20%); PD 32 (80%) Median progression-free time: 7 mos Median survival time: 13.9 mos (11.4-16.4) 1-yr OS 62%

19. Conclusion 1. 1. IIIB/IV NSCLC patients could tolerate concurrent RT (MTD 60Gy) and Gefitinib. 2. 2. There was no excessive toxicity in NSCLC patients treated with concurrent RT and daily Gefitinib, except for pulmonary toxicity, which seemed like increased, especially the low grades (1-2) of CTCAE. 3. 3. MST of 13.9 mos and 62% of 1-yr OS were encouraging. 4. 4. Clinical phase II trial was warranted, especially for non- smoker and adnocarcinoma (EGFR mutated).

20. Thanks for your attention ! Shanghai 2010 EXPO