Rationale for EGFR Inhibition in Combined Modality Therapy in NSCLC

1. Rationale for EGFR Inhibition in Combined Modality Therapy in NSCLC Francisco Robert,M.D. UAB Cancer Center

2. Locally Advanced Stage III NSCLC • Represents approx 35-40% of cases • During the past 2 decades,the management of these pts has undergone considerable change • RT was the Std therapy prior to 1980,current management entails the combination of ChemRT in selected pts with good PS • RTOG data showed that 60 Gy was superior to other doses(40Gy,split 40Gy,50Gy) for local control and overall survival—no difference at 5 Yr

3. Locally Advanced Stage III NSCLC • Progress in the management of stage III disease came about in part because of the recognition that cisplatin-based CT imparts a modest but real survival benefit even in pts with far advanced disease • CALGB/RTOG/ECOG have established that 2 cycles of induction CT with CISP/VLB followed by RT(60Gy) leads to an approx 4-months increased in median survival when compared to RT alone

4. Theoretical Advantages of Combined Modality ChemoRT in NSCLC • SpatialCooperation—RT and CT work in different disease compartments:RT-Local disease,CT-distant micro-metastatic disease • Non-overlapping Txs—CT does exacerbate RT Tx • CellularInteractions—Changes in the shape of the RT response curve;Altered cell cycle distribution( cell in a RT sensitive phase) • Cytoreduction of the mass: tumor hypoxia •  Tumor cell repopulation during Tx

5. Approaches to Combining Chemotherapy and Thoracic Radiation • CT  RT: Full doses of each modality can be delivered w/o combined toxicity • CT+RT: Exploit potential synergy between the modalities • CT  CT/RT: Induction CT may allow ↓RT ports and ↓systemic micrometastatic disease • CT/RT  CT: Delivering maximal anti-tumor efficacy upfront; exploit potential synergy;intense Tx is given early when the pt is able to handle it better

6. Current Status of ChemoRT in Stage IIINSCLC: Randomized Studies

7. Current Status of Combined Modality Therapy in Stage III NSCLC:Conclusions • Using a concurrent CT/RT component of a CMT(platinum-based)regimen is the current Std of care in good PS patients • Concurrent CT/RT increases toxicity • An obvious need exists for improved systemic Tx,but there is also a need for better local control5yr survival rate is still poor (15-16%) • Is there any role of surgery in the combined modality therapy? • Have we reached a plateau with current therapy?

8. Rationale for EGFR Inhibition in NSCLC •Major role of EGFR expression and signal activation in Bronchial Carcinogenesis • Overexpression of EGFR in early bronchial neoplastic transformation (metaplasia,dysplasia, ca in situ) • NNK-mediated transformation of BEAS-2B cells increased EGFR expression • EGFR as a chemoprevention target

9. Rationale for EGFR Inhibition in NSCLC •EGFR and TGF-α are frequently expressed or overexpressed in NSCLC (ICH) • EGFR (40-80%) →TGF-α (80-90%) •In some studies,EGFR expression has been associated with ↓survival,poor prognosis and increased risk of metastasis •In combination with MVD and MMP-9 expression, elevated EGFR expression was found to provide prognostic information independent of TNM STG

10. Rationale for EGFR Inhibition in CMT in NSCLC:Pre-Clinical Observations p27  CDK2/p27  G1 EGFR Blockage Angiogenesis Apoptosis EGFR Inhibition prevents repair and survival Of tumor cells damaged by CT and RT: Chemosensitization,  Radiosensitization

11. Enhanced antitumor effects both in vitro and in vivo using xenografts: Cisplatin,Paclitaxel, CPT-11,Gemcitabine,Doxorubicin,and 5-FU Enhanced inhibition of growth of tumor cells Increased cell cycle effects indicative of apoptosis Inhibition of cellular proliferation  expression of EGFR and  receptor activation Induction of tumor remission and  survival Preclinical Combination Studies Demonstrating Enhanced Activity of C225+CT

12. Antitumor Activity of Cisplatin and C225 on A-431 Xenograft Ciardello F:Clin Ca Res-Oct01

13. •Inhibit tumor cell proliferation •Induces cell cycle arrest (Radiosensitive cell cycle phase) - C225: G1 phase - RT: G2/M phase •Promotes RT-induced apoptosis -  bcl-xl and bcl-2 expression - suppression of the activated(-p) form of akt •Inhibit RT-induced damage repair •Inhibit tumor angiogenesis:  VEGF,  bFGF •Effects on invasion EGFR Blockage and Radiation Interaction

14. Antitumor Activity of C225 in Combination with RT in Squamous Cell Ca Xenografts Ciardiello F: Clin Ca Res(Oct/01)

15. Rationale for EGFR Inhibition in CMT in NSCLC:Clinical Observations •Activity of EGFR Inhibitors in Adv NSCLC >ZD 1839 (gefitinib) - IDEAL ½ Studies(N=426): Obj Resp 12-18%; CR/PR/SD49% >OSI-774 (erlotinib) - Phase II (N=56) Obj resp 15.8%; MS=37wks

16. Rationale for EGFR Inhibition in CMT in NSCLC:Clinical Observations •Tolerability of C225 with 1st and 2nd-Line Chemotherapy - Gemcitabine/Carboplatin - Docetaxel •Enhanced activity and tolerability in Head-Neck Cancer  C225+RT (UAB Experience)

17. Rationale for EGFR Inhibition in NSCLC:Issues of Concern •Interaction of Chemotherapy+EGFR inhibitors  Negatives Studies(INTACT 1 / 2) with ZD1839+CT  A role for maintenance therapy(?) •Potential enhancement of RT-related Tx (e.g.Esophageal/Lung/CV)  No Phase I data of RT/EGFR Inh

18. Phase II Study of C225 in Combination with ChemoRT in Stage IIIa/b NSCLC* C225:250mg/m2 Paclitaxel 45mg/m2/w Carbo:AUC2/w RT:63GY(7w) C225: 250mg/m2 wk3 C225-d1 400mg/m2 Objectivesl:Safety/TX,Survival Rate,Potential correlation of EGFR/Survival • Carbo/Paclitaxel Q 3w • 2 cycles C225:250mg/m2/w * Proposed RTOG Phase II Study