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

 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 Maintenance Therapy in Advanced NSCLC

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: )  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

Arm B Gemcitabine 1000 mg/m 2 d 1,8 q 21 days + Best supportive care (BSC) Arm A Gemcitabine 1000 mg/m 2 d 1,8 Carboplatin AUC 5 d 1 q 21 days X 4 cycles PD Off study CR PR SD Study Design 1:1 Randomization Primary Endpoint = OS  Chemonaïve Stage IIIB/IV NSCLC  Randomization factors: PS stage best tumor response Best supportive care (BSC)

 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

 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  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 Eligibility Criteria

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 Objectives

 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 Statistical Design

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

Baseline Characteristics Initial Phase Gemcitabine/Carboplatin (G-Cb) Initial Phase N=519 Median age, years66.6 Age ≥65 years /<65 years, %57/42 Stage IIIB/IV disease, %15/85 Male/Female, %63/37 Caucasian/AA/Other, %84/10/6 ECOG PS 0/1/2, %0/36/64

Gemcitabine/Carboplatin (G-Cb) Initial Phase N=519 Response rate (CR+PR)28% Complete response1% Partial response27% Stable disease37% Progressive disease9% Unknown/not done26% Best Tumor Response to Therapy Initial Phase

Gemcitabine/Carboplatin (G-Cb) N=519 No. patients treated518 Median no. cycles (range)4 (1-4) Dose reductions32 % Discontinuations due to drug-related toxicities5% Dose intensity 92% for G 89% for Cb Study Treatment Initial Phase

Maintenance Phase GEM N=128 % BSC N=127 % Median age, years Age ≥65 years /<65 years61/3959/41 Stage IIIB/IV disease22/789/91 Male/Female60/4067/33 Caucasian/AA/Other83/13/488/6/6 ECOG PS 0/1/2/30/44/52/40/43/54/4 Baseline Characteristics Maintenance Phase

Best Tumor Response to Therapy Maintenance Phase GEM N=128 BSC N=127 Response rate (CR+PR)28%6 % Complete response5 %0 Partial response23 %6 % Stable disease40 %25 % Progressive disease9 %17 % Unknown/not done23 %53 %

Study Treatment Maintenance Phase GEM N=112 BSC N=127 No. patients treated112 - Median no. cycles (range)4 (1-9) - Dose reductions26 % - Discontinuations due to drug-related toxicities 6 % - Patients completing ≥6 cycles31 % - Patients completing 9 cycles19 % - Dose intensity91 % -

Overall Survival (Intent-to-treat Population) Overall Survival (months) Gemcitabine 8.0 mos. BSC 9.3 mos. HR=0.97 (95% CI:0.72, 1.30) P =0.838

Progression-free Survival (Intent-to-treat Population) Gemcitabine 7.4 months BSC 7.7 months HR=1.09 (95% CI:0.81, 1.45) P =0.575 Progression-free Survival (months)

Cox Regression Analysis VariableReference levelHazard Ratio*95% CIP value PS ≥2PS= , MaleFemale , Significant variables in final model *Modeling hazard ratio associated with worsened survival

Toxicities Gemcitabine (N=112) % BSC (N=127) % Grade 3-4 Neutropenia‡152 Anemia‡92 Thrombocytopenia94 Fatigue52 Nausea0<1 Vomiting0<1 ‡P <0.05 for grade 3/4 rates of neutropenia, anemia Treatment-related Toxicities

Post-study Therapy Gemcitabine (N=128) % BSC (N=127) % Patients with known post-study therapy1617 Most common post-study therapies Pemetrexed910 Bevacizumab22 Carboplatin26 Gemcitabine23 Docetaxel36 Vinorelbine22 Paclitaxel22 Systemic Post-study Therapy

 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

 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 Conclusions

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