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21th WCC, Shenzhen, China, Aug 19, 2010 Guo-Liang Jiang, MD, FACR Min Fan, MD, Jiayan Chen, MD

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

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21th WCC, Shenzhen, China, Aug 19, 2010 Guo-Liang Jiang, MD, FACR Min Fan, MD, Jiayan Chen, MD

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

  2. Outcome of non-small cell carcinoma 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/IVnon-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 Control RT Iressa Iressa + RT Bianco et al. Clin Cancer Res 2002;8:3250-3258

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

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

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

  9. 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 Iressa+RT in Oral SCC (Western blot) Gefitinib could inhibit multistep phosphorylation of EGFR signaling pathway, so slow down the tumor cell proliferation and enhance the radiation sterilization. Shintani S. Int J Cancer 2003; 107:1030–1037

  10. Possible mechanisms for radiosensitization of Gefitinib • Decrease percentage of S phase and increase G2/M phases of tumor cells • Enhance tumor cell apoptosis after RT • Inhibit radiation induced DNA repair • 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 eligibilityNSCLC histologically or cytologically confirmedIIIbIV: brain metsECOG 1-2 No contraindication for RT Tolerable for RT and Gefitinib

  14. TreatmentConcurrent Gefitinib (250mg, qd) and RT and continuously Gefitinib for 2 months after RT. RT target: Gross tumor volume in thorax on CT2Gy/fx, 5 fx/wk,Total dose escalation54Gy, 56Gy, 58Gy, 60GyDose limit toxicity (DLT) in 2 months after completion of RTCTCAE V3 >=3 for lungCTCAE V3 >=4 for othersWhen >=2/8 patients occurred DLT, dose escalation terminated and MTD was one dose level before.

  15. Dose level No. pts 54Gy 8 56Gy 8 58Gy 8 60Gy 8+8 ResultStatus of dose escalation One patient in 60Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days

  16. Clinical characteristics of patients (n=40)

  17. Safety (MFT: 9.7 mos)

  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 • IIIB/IV NSCLC patients could tolerate concurrent RT (MTD 60Gy) and Gefitinib. • 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. • MST of 13.9 mos and 62% of 1-yr OS were encouraging. • Clinical phase II trial was warranted, especially for non-smoker and adnocarcinoma (EGFR mutated).

  20. Shanghai 2010 EXPO Thanks for your attention !

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