1NCIC CTG JBR.10

NCIC CTG BR.10NCIC CTG BR.10((SWOG JBR10, ECOG JBR10, CALGB 9795)SWOG JBR10, ECOG JBR10, CALGB 9795)

Phase III Randomized Trial of Adjuvant Vinorelbine and

Cisplatin in Completely Resected Stage IB and II

Non Small Cell Lung Cancer

Timothy Winton, Robert Livingston, David Johnson, James Rigas, Yvon Cormier, Charles Butts, Keyue Ding, Lesley

Seymour, Nadine Magoski, Frances Shepherd.

2NCIC CTG JBR.10

JBR.10 JBR.10 -- ObjectivesObjectives

• Prospective, randomized controlled trial designed to determine whether adjuvant vinorelbine and cisplatin is superior to observation alone, in terms of overall survival, in patients who have undergone complete resection of early stage (IB and II) Non Small Cell Lung Cancer

• Secondary Endpoints– Recurrence free survival– Evaluate Toxicity of the Regimen– Health related Quality of Life Analysis– Explore the prognostic significance of ras mutations

3NCIC CTG JBR.10

JBR.10 JBR.10 -- Study DesignStudy Design

RANDOM I SE

Stratified byNodal* N0* N1

ras* Neg* Pos* UNK

T

I SSUE

REGI STER

ObservationOnly

CisplatinVinorelbine

4NCIC CTG JBR.10

JBR.10 JBR.10 -- Statistical DesignStatistical Design

• Expected 3 year survival - 60%• To detect an improvement of 10%

(HR 1.43)– 198 events– Require 450 patients randomised over 7

years• Two planned interim analyses

– 66 events– 132 events

5NCIC CTG JBR.10

JBR.10 JBR.10 -- Inclusion CriteriaInclusion Criteria

• T2N0, T1N1 or T2N1 NSCLC• Complete resection

– Segmentectomy/wedge resection not eligible

• Tissue submission (fresh/paraffin)• ECOG PS ≤ 1• QoL (mandatory Canada)• Acceptable hematology / biochemistry• Randomised within 40 days of surgery

6NCIC CTG JBR.10

JBR.10 JBR.10 -- Exclusion CriteriaExclusion Criteria

• Prior malignancy– Any breast, melanoma or renal cell– Any Other Malignancy within 5 years

• BAC (unless discrete nodule)• Mixed NSCLC/SCLC• Multiple site, T3, Level 10 nodes (N2)• Severe co-morbid disorders

7NCIC CTG JBR.10

JBR.10 JBR.10 -- ChemotherapyChemotherapy

Agent Dose Schedule

Cisplatin 50 mg/m2 D 1 & 8 Q 4 weeks X 4 cycles

30 mg/m2 * Weekly 16 weeks

25 mg/m2 Weekly 16 weeksVinorelbine

Doses adjusted for hematologic, renal and neurologic toxicity* Protocol Modification August 1995 because of hematologic

toxicity/patient compliance

NCIC CTG JBR.10

JBR.10 JBR.10 -- ResultsResults• Opened July 1994, closed April 2001• Randomized: 482

– 41 patients - ineligible post randomization• Incomplete staging/screening: 7• N2/M1/T4 disease: 15• Incomplete resection: 1• Inadequate / abnormal labs 18

• Analyses: – Interim # 1: March 2000– Interim # 2: March 2002 – Final, ITT, March 2004

9NCIC CTG JBR.10

Completely Resected Early Stage NSCLCCompletely Resected Early Stage NSCLCStage IB Stage IB --IIII

482

Randomized to

ChemotherapyCisplatin –Vinorelbine

243

Standard of CareObservation Only

239VS

10NCIC CTG JBR.10

JBR.10 JBR.10 -- Patient CharacteristicsPatient CharacteristicsObservation

(239)Vin/Cis(243)

Median Age (yrs) 61 61Male 64% 66%Female0 49% 49%

Undifferentiated 7% 8%Mixed 2% 2%

1 51% 51%Adenocarcinoma 54% 53%Squamous 38% 37%

Histology

35% 34%ECOG PS

Gender

11NCIC CTG JBR.10

JBR.10 JBR.10 -- Patient CharacteristicsPatient CharacteristicsObservation

(239)Vin/Cis(243)

1 13 % 16 %2 87 % 84 %

I 45 % 46 %IIA 13 % 16 %

Stage

IIB 41 % 39 %

T

0 45 % 46 %N1 55 % 54 %

Lobectomy 71 % 66 %Bilobectomy 7 % 8 %

Extent of Resection

Pneumonectomy 22 % 26 %

12NCIC CTG JBR.10

JBR.10 JBR.10 -- Patient CharacteristicsPatient Characteristics

Observation(239)

Vin/Cis(243)

Present 23% 24%Absent 63% 60%Unknown/pending 14% 15%

Ras Mutation*

* Subset analysis of prognostic significance of Ras and other molecular markers continues

13NCIC CTG JBR.10

JBR.10 JBR.10 –– Chemotherapy Chemotherapy -- Dose DeliveryDose Delivery

• 65 % of patients received 3 or 4 cycles of chemotherapy

• Median number of cycles of chemotherapy therapy received was 3

• All patients on chemotherapy required at least one dose reduction or treatment delay

• 77% of patients required at least one dose reduction

• 74% of dose reductions were required because of Neutropenia

14NCIC CTG JBR.10

JBR.10 JBR.10 –– ChemotherapyChemotherapy--Related ToxicityRelated ToxicityVin/Cis N= 243

Total % Grade 3 or 4 %Fatigue 77% 14%Anorexia 53% 9%Local Toxicity 33% 3%Dyspnea 17% 4%

Nausea 76% 10%Vomiting 46% 7%Constipation 44% 3%

Diarrhea 22% <1%

15NCIC CTG JBR.10

JBR.10 JBR.10 –– ChemotherapyChemotherapy--Related ToxicityRelated Toxicity

Vin/Cis N= 243Total % Grade 3 or 4 %

Hearing 20% 1.5%

Alopecia 31% 0%Hemoglobin 91% 7.3%Granulocytes 98% 73%Infection 21% 1%Febrile Neutropenia 7% * 7%

Sensory 45% 2%

* 6% after dose reduction

16NCIC CTG JBR.10

JBR.10 JBR.10 -- Reasons Off StudyReasons Off StudyVin/Cis

Number off study ProgressionToxicity 30 (12%)

Treatment complete 120 (49%)

RefusalDeathIntercurrent IllnessOther 4 (2%)

123Reason 9 (4%)

72 (30%)3 (1%)5 (2%)

17NCIC CTG JBR.10

QOL Results: During TreatmentQOL Results: During Treatment

• Clinically and statistically significant differences during treatment in :

– Global QOL– Physical, Role, Social, Cognitive function– Fatigue, Nausea, Dyspnea, Appetite,

Alopecia

18NCIC CTG JBR.10

QOL Results: After Completion of QOL Results: After Completion of TreatmentTreatment

• No differences in global or any of the QoL performance scales

• Clinically and statistically significant differences after completion of treatment in :– Parasthesias, numbness, hearing

19NCIC CTG JBR.10

0

20

40

60

80

100

0.0 2.0 4.0 6.0 8.0

JBR.10 RecurrenceJBR.10 Recurrence--Free SurvivalFree Survival

____ Vin/Cis, ____ Observation

*HR 0.61, p=0.0002

61%

48%

Years

20NCIC CTG JBR.10

JBR.10 JBR.10 –– Recurrence Free SurvivalRecurrence Free Survival

Observation(95% CI)

Vin/Cis(95% CI)

HR p

MedianSurvival

46.7 months Not reached

0.61 0.0002

RF 5 yr Survival

48%(42-55%)

61%(54-68%)

0.012

21NCIC CTG JBR.10

JBR.10 JBR.10 -- Overall SurvivalOverall Survival

0

20

40

60

80

100

0.0239

2.0182

4.094

6.047

8.013

____ Vin/Cis, ____ Observation

*HR 0.7, p=0.012

69%

54%

Years

22NCIC CTG JBR.10

JBR.10 JBR.10 -- Causes of DeathCauses of Death

Observation Vin/CisAlive 127 155

Lost to Follow UP 1 2

Died 111 86Disease - NSCLC 92 70Toxicity 0 2*Disease and non-protocol toxicity 3 0Other primary malignancy 5 4Other 11 10

* Sepsis, Pulmonary Fibrosis.

23NCIC CTG JBR.10

JBR.10 JBR.10 -- SurvivalSurvival

Observation(95% CI)

Vin/Cis(95% CI)

HR p

MedianSurvival

73 months(48 - ~ )

94 months(CI 75 - ~)

0.7 0.012

5 Year Survival

54%(48-61%)

69%(CI 62-75%)

0.0022

24NCIC CTG JBR.10

JBR.10 JBR.10 -- ConclusionsConclusions• Vinorelbine and Cisplatin can be administered

safely post resection of NSCLC

• Impact on QoL was limited and generally reversiblewith the exception of neurotoxicity

• Adjuvant treatment with this 3rd generation chemotherapy combination significantly improves disease free and overall survival as compared to observation alone post complete resection of Stage IB and Stage II Non Small Cell Lung Cancer

25NCIC CTG JBR.10

JBR.10 JBR.10 --Intergroup PartnersIntergroup Partners

• National Cancer Institute of Canada Clinical Trials Group

• Eastern Cooperative Oncology Group• Southwest Oncology Group• Cancer and Leukemia Group B

26NCIC CTG JBR.10

AcknowledgmentsAcknowledgments

• Financial support– National Cancer Institute of Canada– Medical Research Council of Canada– Glaxo-Smith-Kline Canada– National Cancer Institute (USA)

• Ras Mutation / Tissue Bank– Dr Ming Sound Tsao, PMH/UHN, Toronto

Canada

27NCIC CTG JBR.10

AknowledgementsAknowledgements• Thanks to the many patients and their families that

agreed to enter the trial and help pave the way for improved treatment for future Lung Cancer patients

• Thanks to our many collaborators around North America – Canada and USA - who participated and supported this trial

• Personal thanks to Dr Joe Pater and Leslie Seymour & Staff of the NCIC – CTG and Dr Frances Shepherd, Chair of the NCIC Lung Site Group, for their leadership and support