Abstract # 7507

1. Randomized Trial of Gemcitabine-Carboplatin (G-Cb) Therapy Followed by Gemcitabine (G) Maintenance or Best Supportive Care (BSC) in Advanced NSCLC C.P. Belani1,D.M. Waterhouse2, H.H. Ghazal3, S. Ramalingam 4 , J.M. Waples5, R.E. Bordoni6, G.A. Reznikoff7, C.P. Curran8, R. H. Greenberg9 1Penn State Hershey Cancer Institute, Hershey, PA, USA; 2Oncology Hematology Care, Cincinnati, OH; 3Kentucky Cancer Clinic, Hazard, KY); 4Emory University Winship Cancer Institute, Atlanta, GA, 5 Clearview Cancer Institute, Huntsville, AL; 6Georgia Cancer Specialists, Atlanta, GA; 7Medical Specialists of Fairfield, Fairfield, CT; 8 Palmetto Hematology Oncology, Spartanburg, SC; 9The Center for Cancer and Hematologic Disease, Cherry Hill, NJ Abstract# 7507

2. Maintenance Therapy in Advanced NSCLC • Maintenance therapy represents a useful strategy to improve patient outcomes in advanced stage NSCLC • Recent studies of maintenance therapy (sequential, consolidation, ‘switch’ to a new agent), immediately following first-line therapy, have demonstrated a statistically significant survival benefit

3. Rationale • Single-agent Gemcitabine maintenance results in significantly longer time to progression (TTP) compared to BSC (6.6 mos. vs 5.0 mos., P<0.001) (Brodowicz et al, Lung Cancer, 2006; 52:155-163) • Given its ease of administration and favorable safety profile, we evaluated maintenance Gemcitabine + BSC vs. BSC in non-progressors following 4 cycles of Gemcitabine/Carboplatin (G-Cb) in patients with advanced stage IIIB/IV NSCLC

4. Study Design • Chemonaïve Stage IIIB/IV NSCLC • Randomization factors: • PS • stage • best tumor response Arm A Gemcitabine 1000 mg/m2 d 1,8 q 21 days + Best supportive care (BSC) CR PR SD Gemcitabine 1000 mg/m2 d 1,8 Carboplatin AUC 5 d 1 q 21 days X 4 cycles 1:1 Randomization Primary Endpoint = OS Arm B Best supportive care (BSC) PD Off study

5. BSC was the same in both arms and was defined as treatment given with the intent to maximize QOL without a specific antineoplastic regimen Acceptable therapies included were: Treatment with antibiotics, analgesics, antimetics, thoracentesis pleurodesis, blood transfusions, nutritional support (enteral or parenteral) BSC specifically excluded: Surgery, immunotherapy, radiotherapy (exception of palliative RT), anticancer hormonal therapy, and systemic chemotherapy Best Supportive Care Patients were evaluated every 9 wks (or three cycles) on both GEM+BSC and BSC alone arms for tumor assessment

6. Eligibility Criteria • Histologic or cytologic diagnosis of stage IIIB with pleural effusion and/or positive supraclavicular nodes or stage IV NSCLC • Age ≥ 18 years • ECOG performance status of 0 - 2 • Adequate renal, hepatic and bone marrow function • Patients with asymptomatic / treated & controlled brain metastases were allowed • Presence of measurable disease • No prior chemotherapy for NSCLC • Signed informed consent

7. Objectives Primary Objective • Overall survival comparing Gemcitabine maintenance +BSC vs. BSC following randomization Secondary Objectives • Objective response rate • Progression-free survival following randomization • Safety and tolerability

8. Statistical Design • Sample size of 600 patients for initial therapy with G-Cb was planned to allow 332 patients to be randomized to maintenance Gemcitabine + BSC vs. BSC (assuming 45% progression to initial therapy) based on 80% power using two-sided alpha level of 0.05 • Overall survival (OS) analysis planned after 238 events to achieve full power • Assumed hazard ratio of 0.69 comparing Gemcitabine + BSC vs. BSC on OS • Planned patient accrual time was 18 months

9. Study Accrual • Patient enrollment was from January 2002 to August 2007 • 519 patients were enrolled to G-Cb phase of trial (87% of plan) • 255 patients were randomized to maintenance Gemcitabine + BSC vs. BSC following initial treatment • Study was closed in September 2008 due to slow accrual • Final Analysis at 179 events amongst 255 randomized patients

10. Baseline Characteristics Initial Phase

11. Best Tumor Response to Therapy Initial Phase

12. Study Treatment Initial Phase

13. Baseline Characteristics Maintenance Phase

14. BestTumor Response to Therapy Maintenance Phase

15. Study Treatment Maintenance Phase

16. Overall Survival (Intent-to-treat Population) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 HR=0.97 (95% CI:0.72, 1.30) P =0.838 BSC 9.3 mos. Survival Probability Gemcitabine 8.0 mos. 0 6 12 18 24 30 36 42 48 54 60 Overall Survival (months)

17. Progression-free Survival (Intent-to-treat Population) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 HR=1.09 (95% CI:0.81, 1.45) P =0.575 Progression-free Probability BSC 7.7 months Gemcitabine 7.4 months 0 6 12 18 24 30 36 42 48 54 60 Progression-free Survival (months)

18. Cox Regression Analysis Significant variables in final model *Modeling hazard ratio associated with worsened survival

19. Treatment-related Toxicities ‡P <0.05 for grade 3/4 rates of neutropenia, anemia

20. Systemic Post-study Therapy

21. Lack of sub-histology information Most of the patients categorized as NSCLC High proportion of patients with PS 2 Low post-study treatment-rate Study Limitations

22. Conclusions • This study failed to show a survival benefit for maintenance Gemcitabine in non-progressors following standard treatment of G-Cb for patients with advanced NSCLC • Nearly two thirds of patients were ECOG PS 2 at study entry • Gemcitabine in the maintenance setting was well tolerated • Few patients received post-study therapy likely due to poor PS

23. The authors would like to thank: All the patients and their families The investigators and the staff at each participating center Pharmatech and their research staff Acknowledgements