21th WCC, Shenzhen, China, Aug 19, 2010

Guo-Liang Jiang, MD, FACRGuo-Liang Jiang, MD, FACRMin Fan, MD, Jiayan Chen, MD Min Fan, MD, Jiayan Chen, MD

Fudan University Shanghai Cancer CenterFudan University Shanghai Cancer Center

Combination of radiation therapy and Combination of radiation therapy and Gefitinib for non-small cell lung carcinomaGefitinib for non-small cell lung carcinoma

Outcome of non-small cell carcinomaOutcome of non-small cell carcinoma

Stage and tmt Stage and tmt 55-yr survival -yr survival I-II surgeryI-II surgery 48-70% 48-70%I-II inoperable, SBRT I-II inoperable, SBRT ～～ 40%40%IIIa (surgery ±other Tmt) 15-27%IIIa (surgery ±other Tmt) 15-27%IIIa (RTIIIa (RT ＋＋ Chemo) 14-20%Chemo) 14-20%IIIb (RTIIIb (RT ＋＋ Chemo) 5-7%Chemo) 5-7%

Predominant failure pattern: Local and distant failures

Combination of radiation therapy and Gefitinib for

stage IIIb/IV non-small cell lung carcinoma

Clinical phase I trial

Irradiation dose escalation (NCT00497250)

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)

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 RTIressa

The percentage of S phase decreased after IressaIressa+RT (GEO in vivo)

Bianco C. Clin Cancer Res 2002;8:3250-3258

Mechanism of Gefitinib radiosensitization

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

Gefitinib inhibits RT induced damage repairOral 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

Iressa+RT in Oral SCC (Western blot)

RT could activate EGFR-TK signaling pathway (Ras-Raf-MAPK). And 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.

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 repair4. Inhibit multistep phosphorylation of EGFR

signaling pathway, so reduce the tumor cell proliferation after RT

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

Goal of the trialMain 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

Patient eligibility

NSCLC histologically or cytologically confirmed

IIIbIV: brain metsECOG 1-2 No contraindication for RT Tolerable for RT and Gefitinib

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, 60Gy

Dose 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.

ResultStatus of dose escalation

Dose level No. pts

54Gy 8

56Gy 8

58Gy 8

60Gy 8+8

One patient in 60Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days

Male/Female 28/12Medium age (yr)Medium cycle of chemo

55 (32–79)3.5 (1-5)

ECOG 01

1030

Stage IIIB IV

1822

Histology Adeno-SqPoor differentiated

35 (86%)4

1Smoker/non-smoker 20/20

Clinical characteristics of patients (n=40）

Safety (MFT: 9.7 mos)

CTCAE 3.0 Incidence Rash 1-2 24 (60%)

≥3 0Pulmonary 1-2 29 (73%)

3G5

01 (3%)

Espophageal 1-2 23 (58%) ≥3 0Hematological

1-2 16 (40%)

≥3 0

OutcomeAt last follow-up visitSD 8 (20%); PD 32 (80%)Median progression-free time: 7 mosMedian survival time: 13.9 mos (11.4-16.4)1-yr OS 62%

Conclusion

1. IIIB/IV NSCLC patients could tolerate concurrent RT (MTD 60Gy) and Gefitinib.

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. MST of 13.9 mos and 62% of 1-yr OS were encouraging.

4. Clinical phase II trial was warranted, especially for non-smoker and adnocarcinoma (EGFR mutated).

Thanks for your attention !

Shanghai 2010Shanghai 2010EXPOEXPO