Weekly paclitaxel combined with monthly carboplatin versus single agent therapy in patients aged 70

to 89 : IFCT-0501 randomized phase III study in advanced non-small cell

lung cancer

Elisabeth Quoix, JP Oster, V Westeel, E Pichon, G Zalcman, L Baudrin, A

Lavolé, J Dauba, MP Lebitasy & B Milleron

on behalf of the French Intergroup (IFCT)

• Rapid increase in lung cancer in elderly

• Association of two phenomenons : – Increased life expectancy : population older than 65 years = fastest

growing segment

– Increased incidence of cancers with age

• Median age ~ 65-69 years• At least one third > 70 years

Rationale of the study (1)

Rationale of the study (2)

MST 28 vs 21 weeks1-year survival 32 vs. 14%

MST 28 vs 21 weeks1-year survival 32 vs. 14%

Elderly Lung Cancer Vinorelbine Italian Study Group, J Natl Cancer Inst 1999; 91 : 66-72Gridelli et al, J Nat Cancer Instit 2003; 95 : 365-72

Rationale of the study (3)

• Phase II study of gemcitabine 1125 mg/m2 D1 and 8 : RR 28.2%, MST 6.83 months (95% CI, 4.16-11.46)

• Phase II study of the doublet carboplatin (AUC 6, D1) + weekly paclitaxel (90 mg/m2, D1, 8, 15) well tolerated and effective :

RR 43%, MST 13.6 months (95% CI 7.5-17.5)

• No trial devoted to elderly comparing single agent versus platin-based doublet however a subset analysis of elderly in a phase III trial comparing paclitaxel alone to carboplatine + paclitaxel trial favored the doublet

E. Quoix Lung Cancer 2005 ;47 : 405-12JL Pujol J Thorac Oncol 2006; 1 : 328-34R. Lilenbaum J Clin Oncol 2005; 23 : 190-6

Erlotinib:PlaceboPS 0-1

PS 2-3

Male

Female

<65 years

>65 years

Adenoca

Squamous

Other Histology

Weight loss <5%

Weight loss 5-10%

Weight loss >10%

Never smoker

Smoker

1 prior regimen

2+ prior regimens

Hazard Ratio

Rationale of the study (4)

F. Shepherd N Engl J Med 2005;353:123-32

Erlotinib in second line therapy as efficient in patients aged 65 or more and in younger counterparts

0 1 2 3 4

Study scheme

*Choice of the center at the beginning of the study** In case of PD or excessive toxicity

NSCLC

Stage III-IV

Age 70-89 years

PS 0-2

n = 451

Vinorelbine

or

Gemcitabine*

Carboplatin +

paclitaxel

Erlotinib**

150 mg/d

RANDOM

Stratification by centre, PS 0-1 vs. 2, age ≤80 vs. >80 and stage III vs. IV

First-line Treatment

ARM A

V V V V V V V V V V

G G G G G G G G G G

WEEKS 1 2 3 4 5 6 7 8 910

11

12

13

14

15

16

17

18

ARM BCP

P PCP

P PCP

P PCP

P P

EVALUATION

V : Vinorelbine : 30 mg/m2

G : Gemcitabine : 1150 mg/m2

C : Carboplatin : AUC 6P : Paclitaxel : 90 mg/m2

Choice ofthe center

Statistical considerations

• Sample size of 522 pts : power of 80% and a two-sided overall type I error α of 5%

• To show an improvement in 1-year survival rate of 10% (30 to 40%) and of MST from 7 months in the single agent arm to 9 months in the doublet arm, 336 deaths had to be observed

• 1st planned interim analysis (173 pts) did not meet the stopping rule criteria of Peto-Haybittle (p = 0.0001)

• At the 2nd planned analysis (two-third of the expected events)p value for survival was < 0.001 and thus the IDMC recommended the closure of the study with 451 pts included

Objectives of the study• Primary : overall survival• Secondary :

– Progression-free survival (first line)– Response rate (first line)– Response rate (second line)– Response duration to first line chemotherapy– Response duration to second line erlotinib– Quality of life– Survival after first line– Grade 3 and 4 toxicities (CTC-NCIC)

Inclusion criteria• Age 70-89 • With Stage III (not amenable to RT) or Stage IV

NSCLC• PS 0-2• No prior treatment except surgery or palliative

radiation therapy• At least 3 weeks after must have elapsed after

radiation therapy or major surgery.• Adequate hematological, renal and hepatic function• Life expectancy of at least 12 weeks• Signed informed consent• Geographically near enough for follow-up

Exclusion criteria• Previous mediastinal radiation therapy• Symptomatic brain metastases• Previous malignancy within the last 5 years or with

chemotherapy at any time• Serious active infection or underlying conditions

that would impair the ability of the patient to receive protocol treatment

• Motor or sensory neuropathy ≥ grade 2 CTC• Treatment with any investigational drug within 4

weeks prior to inclusion• Prior allergic reactions to Cremophor EL® excipient

Population of patients

• 451 pts enrolled from April 2006 to December 2009

• 16 ineligible pts (8 with serious underlying condition, 6 prior cancers, 2 PS 3).

• Median follow-up : 21.3 months (range : 3.7- 40.8)

• Data cut off : March 2010• Survival and PFS analyses all 451 patients (ITT)• Response rate, toxicity analyses on 421

patients included before September 2009

Patients characteristics (1)

Patients characteristics (2)

Chemotherapy administered

*Analysis performed on the 421 pts included before 9/10/2009**1 patient received 6 cycles, 1 received 7 cyles and 1, 8 cycles*** 1 patient received 6 cycles

Response rate at 6 weeks (ITT)

*Main causes : deaths (20 in arm A and 23 in arm B), reduced general condition (respectively 7 and 4), toxicity0 and 4 cases respectively and withdrawal of consent (6 cases)

*Main causes : deaths (20 in arm A and 23 in arm B), reduced general condition (respectively 7 and 4), toxicity0 and 4 cases respectively and withdrawal of consent (6 cases)

Hematological toxicity (418* evaluable pts)

*3 patients did not receive any dose of CT

Non hematological toxicity(418 evaluable patients)

DeathsCauses of deaths

Early deaths (within 3  months)

Doublet

Single

Doublet

Single

Months 0 6 12 18 24 30 36 42

Single 226 50 4 1 1 1 0

Doublet 225 107 27 12 7 4 3

PFS probabilIty

Median : 6.1 months (95% CI 5.5-6.9)1-year PFS : 15.4% (95% CI 10.8-20.8)

Median : 3.0 months (95% CI 2.6-3.9)1-year PFS : 2.3% (95% CI 0.8-5.3)

p <10-6

PFS (ITT)

Doublet

Single agent

Months 0 6 12 18 24 30 36 42

Single 226 112 45 24 11 4 1

Doublet 225 150 78 46 30 14 7

Doublet

Single

survival

probability

MST = 10.3 months (95% CI 8.3-13.31-year survival 45.1% (95% CI 38.2-51.8)

MST = 6.2 months (95% CI 5.3-7.4)1-year survival 26.9% (95% CI 21-33.1)

p= 0.00004

Overall survival (ITT)

Univariate analysis of survival (1)

Univariate analysis of survival (2)

Not significant variables : age ≤ 80 vs > 80; stage (IIIA-B vs IV) and Charlson’s index >2 vs ≤ 2

Multivariate analysis of survival (Cox model) N=407 (patients without any missing data)

Stepwise variable selection procedure, entry level=0.20, stay level=0.05

Exploratory Sub-group analysis

OS – The univariate hazard ratio was derived from a Cox model with a single treatment covariate

Favorsdoublet

Favorssingle

Conclusions (1)

• First study entirely devoted to elderly patients showing the superiority of a carboplatin doublet over single agent therapy in advanced NSCLC

• Recommendations of ASCO 2003 at the beginning of the study were to give single agent therapy based on the studies by the Italian Group

Conclusions (2)• Carboplatin-based doublet resulted in a doubling of

median PFS from 3 to 6.1 months, an improvement of median OS from 6.2 months to 10.3 and of 1-year survival rate from 27% to 45%.

• Carbo-based doublet had a beneficial effect on survival in most of the subgroups tested even those with lower prognosis

• At the expense of manageable toxicity

• New paradigm for elderly patients with advanced NSCLC: monthly carboplatin + weekly paclitaxel

Acknowledgments• Investigators, patients and their families

• Institut national du cancer (INCa)

• Ligue nationale contre le cancer

• Independent Data Monitoring Committee (Martine Extermann, Bruno Housset, Marianne Paesmans, Joseph Gligorov)

• Peter Harper for thoughtful comments

• Roche, BMS, Pierre Fabre.

List of the investigators

Jean-Luc Breton, Jean-Philippe Oster, Lionel Moreau, Eric Pichon, Gerard Zalcman, Bernard Milleron, Armelle Lavole, Virginie Westeel, Jerome Dauba, Didier Debieuvre, Pierre-Jean Souquet, Laurence Bigay-Game, Olivier Molinier, Eric Dansin, Michel Poudenx, Fabien Vaylet, Jaafar Bennouna, Jean Tredaniel, Denis Moro-Sibilot, Dominique Herman, Helene Laize, Philippe Masson, Jean-Paul Duhamel, Marc Derollez, Yves Martinet, Claude Vidal, Beatrice Gentil-Lepecq, Pierre Bombaron, Alain Prevost, Daniel Coetmeur, Cedric Galichet, Alain Ducolone, Sylvie Labrune, Marc Zaegel, Philippe Bonnefoy, Jean-Michel Vannetzel, Nadine Paillot, Jean-Louis Pujol, Jerome Meunier, Bruno Stach, Sophie Schneider, Laure Gautier-Felizot , Denis Braun, Francois Lebargy, Pierre Nouyrigat, Michel Farny, Corinne Sarda, Francis Martin, Jacques Hermann, Ghislaine Fraboulet, Philippe Richard, Sylvie Friard, Frederic Goutorbe, Antoine Levy, Yannick Duval, Marc Angebault, Philippe CharvolinMagali Roa, Michel Vincent, Sebastien Larive, William Jacot, Marie Boutemy, Nicole Le Flour