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

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; 52:155-163)

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

Arm B

Gemcitabine 1000 mg/m2 d 1,8

q 21 days+

Best supportive care (BSC)

Arm A

Gemcitabine 1000 mg/m2 d 1,8

Carboplatin AUC 5 d 1q 21 days X 4 cycles

PD

Off study

CRPRSD

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 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

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 CharacteristicsInitial Phase

Gemcitabine/Carboplatin(G-Cb)

Initial PhaseN=519

Median age, years 66.6

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 PhaseN=519

Response rate (CR+PR) 28%

Complete response 1%

Partial response 27%

Stable disease 37%

Progressive disease 9%

Unknown/not done 26%

Best Tumor Response to Therapy

Initial Phase

Gemcitabine/Carboplatin(G-Cb)

N=519

No. patients treated 518

Median no. cycles (range) 4 (1-4)

Dose reductions 32 %Discontinuations due to drug-related toxicities

5%

Dose intensity 92% for G

89% for Cb

Study TreatmentInitial Phase

Maintenance PhaseGEM

N=128%

BSCN=127

%

Median age, years 67.2 67.5

Age ≥65 years /<65 years

61/39 59/41

Stage IIIB/IV disease 22/78 9/91

Male/Female 60/40 67/33

Caucasian/AA/Other 83/13/4 88/6/6

ECOG PS 0/1/2/3 0/44/52/4 0/43/54/4

Baseline CharacteristicsMaintenance Phase

Best Tumor Response to Therapy

Maintenance Phase

Maintenance PhaseGEM

N=128BSC

N=127

Response rate (CR+PR) 28% 6 %

Complete response 5 % 0

Partial response 23 % 6 %

Stable disease 40 % 25 %

Progressive disease 9 % 17 %

Unknown/not done 23 % 53 %

Study TreatmentMaintenance Phase

Maintenance PhaseGEM

N=112BSC

N=127

No. patients treated 112 -

Median no. cycles (range) 4 (1-9) -

Dose reductions 26 % - Discontinuations due to drug-related toxicities

6 % -

Patients completing ≥6 cycles 31 % -

Patients completing 9 cycles 19 % -

Dose intensity 91 % -

Overall Survival (Intent-to-treat Population)

Overall Survival (months)0 6 12 18 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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)0 6 12 18 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Cox Regression Analysis

Variable Reference level

Hazard Ratio* 95% CI P value

PS ≥2 PS=1 1.50 1.10, 2.03 0.009

Male Female 1.59 1.15, 2.18 0.005

Significant variables in final model

*Modeling hazard ratio associated with worsened survival

Toxicities

Gemcitabine(N=112)

%

BSC

(N=127)

%Grade 3-4 Grade 3-4

Neutropenia‡ 15 2

Anemia‡ 9 2

Thrombocytopenia 9 4

Fatigue 5 2

Nausea 0 <1

Vomiting 0 <1

‡P <0.05 for grade 3/4 rates of neutropenia, anemia

Treatment-related Toxicities

Post-study TherapyGemcitabine

(N=128)

%

BSC (N=127)

%

Patients with known post-study therapy

16 17

Most common post-study therapies

Pemetrexed 9 10

Bevacizumab 2 2

Carboplatin 2 6

Gemcitabine 2 3

Docetaxel 3 6

Vinorelbine 2 2

Paclitaxel 2 2

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