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Paolo G. Casali, John Zalcberg, Jaap Verweij, Axel Le Cesne, Peter Reichardt, Jean-Yves Blay, Lars Lindner, Ian R. Judson,

Elena Fumagalli, Pancras Hogendoorn, Agnes Natukunda, Sandrine Marreaud, Saskia Litière, Winette T.A. Van Der Graaf

LONG-TERM ANALYSIS OF A PHASE III RANDOMIZED, INTERGROUP, INTERNATIONAL TRIAL

ASSESSING THE CLINICAL ACTIVITY OF IMATINIBAT TWO DOSE LEVELS

IN PATIENTS WITH UNRESECTABLE OR METASTATIC GASTROINTESTINAL STROMAL TUMORS (GIST)

Speaker’spotential conflicts of interest

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Empl Cons Stocks Honor Res Test Other

Amgen Dompé l lARIAD lBayer l lGlaxo SK l lImClone lInfinity lJanssen Cilag l lLilly lMerck SD l lMolmed lNovartis l l l lPfizer l l lPharmaMar l l l lSanofi Aventis l lSchering Plough l

Study design

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Rimatinib 800 mg /d

imatinib 400 mg /d

946 eligible pts: GIST (CD117+) metastatic and/or unresectable WHO PS = 0-3 previous chemo accepted

progression

February 2001 / February 2002

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End points

PFS

OS OR TOX

primary

secondary

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6

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Long-term update

Database lock on May 27, 2013• Median follow-up: 10.9 years (IQR: 8.1 - 11.3) • Maximum follow up: 11.8 years

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946 randomized

473: 400mg/day1 did not start treatment

9 ineligible

473: 800mg/day1 did not start treatment

9 ineligible

379 progressed360 died

82 still alive31 lost to follow up

358 progressed339 died

95 still alive39 lost to follow up

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Treatment

Total(N=946)

A-400mg(N=473)

B-800mg(N=473)

  N (%) N (%) N (%)Best overall response                                                       

                                                                                                                                

                      

                                                                                             

       CR                     33 (7.0)                                  

                                                        

  32 (6.8)                                                              

                            

  65 (6.9)                                                                             

             PR                    208 (44.0)                               

                                                          

 239 (50.5)                                                                                         

 447 (47.3)                                                                          

               SD                    160 (33.8)                               

                                                          

 138 (29.2)                                                                                         

 298 (31.5)                                                                          

               PD                     49 (10.4)                                

                                                         

  40 (8.5)                                                              

                            

  89 (9.4)                                                                             

             Early death    7 (1.4)                                   

                                                       

   11 (2.3)                                                             

                             

  18 (1.9)                                                                             

             Un-evaluable 

                16 (3.4)                                                                                    

      

  13 (2.7)                                                              

                            

  29 (3.1)                                                                             

             

Objective response

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(years)0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment417 473 206 111 67 42 30405 473 230 110 67 42 29

A-400mgB-800mg

Overall Logrank test: p=0.202

HR 0.91 (95%CL 0.80, 1.05 )

Median PFS:- 400mg 1.7 years (95% CI 1.5, 2.0)- 800mg 2.0 years (95% CI 1.9, 2.3)

Progression-free survival

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(years)0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment360 473 312 213 146 93 61339 473 326 212 146 96 59

A-400mgB-800mg

Overall Logrank test: p=0.312

HR 0.93(95% CL 0.80,  1.07)

Median OS:- 400mg 3.9 years (95% CI 3.3, 4.4)- 800mg 3.9 years (95% CI 3.4, 4.9

Overall survival

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946 randomized patients

473 at 400mg/day

473 at 800mg/day

61(12.9%) were 10-y survivors62 censored prior to 10 years

350 dead before 10 years

59 (12.5%) were 10-y survivors82 censored prior to 10 years

332 dead before 10 years

10-y survivors (120 pts)

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946 randomized patients

473 at 400mg/day

473 at 800mg/day

30 (6.3%) were 10-y prog-free26 censored prior to 10 years

415 progressed before 10 years

29 (6.1%) were 10-y prog-free41 censored prior to 10 years

403 progressed before 10 years

10-y progression-free survivors (59 pts)

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Surgery of residual disease

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Surgery of residual disease

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Dose intensity

3 6 9 12 15 18 21 24 27 30 33 36 39 42 450%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

800600500400300200100

Time (months)

3 6 9 12 15 18 21 24 27 30 33 36 39 42 450%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

800600500400300200100

Time (Months)

400 mg 800 mg

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10-y survivors

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10-y progression-free survivors

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Univariate and multivariate analyses were done using: Cox regression for PFS and OS Logistic regression for RR

For prognostic factor analysis a full model was built and reduced using backward selection method at a 5% significance level

Factors included in the full model were: age PS sex time delay between diagnosis and registration prior surgery prior chemotherapy prior radiotherapy primary site of disease KIT mutation initial tumor load and diameter of longest lesion

Prognostic factor analysis

    Reduced  model  after  backward selection

 

Factor HR 95% CI HR p-valueAge        40-50 vs. <40 yrs. 1.48 1.04 2.09 <.00150-60 vs. <40 yrs. 1.27 0.92 1.77  60-70 vs. <40 yrs. 1.44 1.04 1.99  >70 vs. <40 yrs. 2.66 1.70 4.16  Prior chemotherapy        yes vs. no 1.30 1.07 1.60 0.007

Multivariate model

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Reduced model  

Factor OR95% Confidence 

Limits

P value

Diameter of longest lesion 0.81 0.78        0.84 <0.0001Initial tumor load 1.08 1.06         1.09   <0.0001KIT mutation

Exon 9 vs. exon11  0.29 0.15          0.57   <0.0001Wild type vs. exon 11 0.38 0.26           0.53Other vs. exon 11 0.40 0.15          1.09

Objective response

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CovariatesReduced model

Hazard Ratio (95% CI) P-Value

Diameter  of longest lesion Per 10mm increase                         

1.08(1.06,1.09) <.0001 

 Initial tumor load Per 10mm increase                             

0.99(0.98,0.99) 0.0005 

Prior chemo yes vs. No                          

1.19(1.02,1.39)    0.028 (df=1)

Performance status 1    vs. 0                         1.12(0.96, 1.31) 0.048(df=3)

  2    vs. 0                       1.29(1.00, 1.67)

  3    vs. 0                        1.54(1.05, 2.26)

Kit mutation exon 9 vs. exon11 1.45 (1.06, 1.99) <.0001(df=3) 

Wild type vs. exon 11 1.08(0.91, 1.27)

Other vs. exon 11 2.63(1.65, 4.19)

Progression-free survival

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CovariatesReduced model

Hazard Ration(95% CI)

P-Value

Age

40-50 vs. <40 yrs.                 

1.18(0.82,1.70)    <.0001  (df=4)   

50-60  vs. <40 yrs.                     

1.41(0.99, 2.01)   

  60-70 vs. <40 yrs.                   

1.26 (0.89, 1.78)   

  >70 vs. <40 yrs.                       

1.97 (1.38, 2.83)   

Performance status 1    vs. 0                         1.48(1.25, 1.76)    <.0001 (df=3)  

  2    vs. 0                       1.68 (1.28, 2.20)   

  3    vs. 0                        2.27 (1.52, 3.39)   

Gender female vs. male                     

0.83 (0.71, 0.97)    0.023 (df=1) 

Prior chemotherapy yes vs. No                       1.31 (1.10, 1.55)    0.002 (df=1) 

Diameter of largest lesion Per 10mm increase 1.05(1.04, 1.06) <.0001 

Kit mutation Exon 9 vs. exon11 1.46 (1.04, 2.06) 0.0002 (df=3)Wild type vs. exon 11 1.18(0.98, 1.41)Other vs. exon 11 2.61 (1.62, 4.22)

Overall survival

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A large trial in a rare cancer, carried out on a wide inter-group basis at the beginning of the imatinib learning curve

At a median FU of 10 yrs, less than 10% and 15% of pts, respectively, were long-term progression-free and overall survivors

No difference between 400 and 800 mg /d, though the subgroup of exon 9 mutated pts was already shown separately to benefit from the higher dose

Mutational status and initial tumor burden were prognostic factors also on a long follow-up

An even longer follow-up and «high-resolution» assessments needed to characterize long-term progression-free survivors either as a specific subset biologically, or just the expression of stochastic processes leading to secondary resistance

Conclusions

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Participating institutionsInstitution Country

Fondazione IRCCS Istituto Nazionale dei Tumori IT

Institut. Gustave Roussy FR

Charite Universitaetmedizin Berlin - Buch DE

Centre Leon Berard FR

Ludwig Maximilians Universitaet Muenchen Klinikum Grosshadern DE

Royal Marsden Hospital UK

Universitair.Ziekenhuis. Gasthuisberg BE

Centre Hospitalier Universitaire Vaudois CH

Institut Bergonie FR

Medizinische.Hochschule.Hannover DE

Hospital De La Santa Creu ES

Ashford Cancer Center AU

Instituto Europeo Di Oncologia Milano IT

Universitair.Ziekenhuis.Rotterdam NL

Netherlands Cancer Institute – Antoni Van Leeuwenhoekziekenhuis Amsterdam NL

Maria Sklodowska Curie Memorial Cancer Centre Warsaw PL

Fondazione del Piemonte per l’Oncologia-Institue for Cancer Research and Treatment Candiolo

IT

Assistance Publique – Hôpitaux de Marseille La Timone FR

Christie Manchester UK

Wellington Hospital NZ

Centre Claudius Regaud FR

Prince Of Wales Hospital AU

University College hospital UK

Hospital Universitario 12 Octubre ES

St James'S Leeds UK

Universitaets.Krankenhaus.Eppendorf DE

Peter Maccallum Cancer Institute AU

Centro Di.Riferimento Oncologico Aviano IT

Institution Country

Centre Oscar Lambret FR

Herlev Hospital University Copenhagen DN

Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Napoli IT

National Cancer Center SG

Sir Charles Gairdner Hospital AU

Western Infirmary Glasgow UK

Ospedale Gradenigo Torino IT

St George Hospital. AU

University Medical Center Groningen NL

Wesley Clinic AU

Weston Park Hospital Sheffield UK

Royal Prince Alfred Hospital. AU

Royal Brisbane Hospital. AU

University Medical Center Leiden NL

Aarhus University.Hospital. DK

Bankstown-Lidcombe Hospital AU

Universitair.Ziekenhuis. Antwerpen BE

Hospital Uno,versotarop Central De Asturias ES

Instituto Valenciano De Oncologia ES

Royal Melbourne Hospital AU

The Geelong Hospital AU

Westmead Hospital AU

Flinders Medical Center AU

Launceston Hospital AU

Nottingham University Hospitals UK

Royal Perth Hospital AU

Princess Alexandra Hospital – University of Queensland AU

Royal North Shore Hospital AU