d i sc l o s u re: s e b a st i a n st i ntz i n g
DESCRIPTION
R a ndo m i z e d c o m p ar i s o n o f F O LF I R I p l u s cet u x i m a b vers u s F O LF I R I p l u s b evac i z u m a b as f ir st - li n e treat m e n t o f KRA S w il d - t y p e m etasta t i c c o l o recta l ca n cer: G er m a n A I O st u d y K RK -0306 ( F I R E -3). - PowerPoint PPT PresentationTRANSCRIPT
Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line
treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3)
V. Heinemann, L. Fischer von Weikersthal, T. Decker, A.Kiani, U. Vehling-Kaiser, S. Al Batran, T. Heintges,C. Lerchenmüller, C. Kahl, G. Seipelt, F. Kullmann,
M. Stauch, W. Scheithauer, J. Hielscher, M. Scholz, S. Müller, B. Schaefer, D.P. Modest, A. Jung, S. Stintzing
Disclosure: Sebastian Stintzing
• Consultant / advisory board: Merck Serono, Hoffmann-La Roche, Amgen
• Honoraria: Merck Serono, Hoffmann-La Roche, Amgen
• Research funding: Merck Serono, German Cancer Aid
Presented by: S Stintzing
mab: 40 mg m i.v. 120min initial dose250 mg/m2 i.v. 60mi
nq 1w
Bevacizumab: 5 mg/kg i.v. 30-90min q 2w
/0i
FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2
irinotecan: 180 mg/m2
5-FU: 2,400 mg/m2 (i.v. 46h)
• Key inclusion criteria– Patients ≥18 years with histologically confirmed diagnosis of mCRC– ECOG PS 0-2
– prior adjuvant chemotherapy allowed if completed >6 month before inclusion
• Amendment in October 2008 to include only KRAS wildtype patients
• 150 active centers in Germany and Austria
Phase III study design
Cetux 2
FOLFIRI + Cetuximab
FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w
mCRC1st-line therapy KRAS wild-type
N= 592
Randomize 1:1
Cetuximab: 400 mg/m2 i.v. 120min initial dose
250 mg/m2 i.v. 60min q 1w
• Primary objective: Overall response rate (ORR)
• Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%)
• 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5%
Statistical considerations
Cetuximab: 400 mg/m2 min initial dose25 mg m2 i.v. 60mi
nq 1w
Bevac mab: 5 mg/kg i.v. 30-90min q 2wizu
/0i.v. 120
FOLFIRI + Cetuximab
FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w
mCRC1st-line therapy KRAS wild-type
N= 592
Randomize 1:1
FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2
irinotecan: 180 mg/m2
5-FU: 2,400 mg/m2 (i.v. 46h)
Cetuximab: 400 mg/m2 i.v. 120min initial dose
250 mg/m2 i.v. 60min q 1w
Primary endpoint
• ORR (mRECIST 1.0, investigators‘ read)
Secondary endpoints
• Progression-free survival (PFS)
• Overall survival (OS)
• Time to failure of strategy (time to failure of 1st-line therapy) (TFS)
• Deepness of response (percent of tumor shrinkage compared to baseline)
• Secondary resections of liver metastases with potentially curative intention
• Safety and tolerability according to NCI-CTCAE criteria
analyses were performed in the ITT and assessable for response population
Endpoints
evacizumab
255FOLF
bamRI +
CetuxiI
N=
LF RI B+IOF172=N
bamuximab
N= 295FOLFIRI + Be cizavuCet
FIR +ILOF7
Consort Diagram
24
N= 752
N= 592KRAS wild-type ITT populationN= 29N= 297
FOLFIRI +Cetuximab
N= 295FOLFIRI + Bevacizumab
N= 526Assessable for response*
N= 271FOLFIRI + Bevacizumab
N= 255FOLFIRI +Cetuximab
160 KRAS mutant :100 KRAS unknown: 43No treatment: 17
Early death: 4Other reasons: 20
* predefined per protocol: 3 cycles of chemotherapy and one CT scan following baseline
Early death: 1Allergic reaction: 13Other reasons: 28
42
Follow-up time
FOLFIRI +Cetuximab
N= 297
FOLFIRI +Bevacizumab
N= 295P
Median follow-up time (months)
(95% CI, months)
33.0 39.00.540
29.0 – 39.5 31.7 – 41.2
p = two-sided log-rank test
Patient Demographics
Characteristic FOLFIRI + Cetuximab N= 297
FOLFIRI + Bevacizumab N= 295
Sex, male, %
Age, median, years
72.1
64.0
66.4
65.0
Age < 65, %Age ≥ 65, % Age > 70, %
ECOG Performance Status, %
012
Leukocyte count
≥ 8,000/µl, %
Alkaline Phosphatase
53.246.830.3
54.245.823.4
51.945.82.4
53.645.11.4
43.4 40.0
≥ 300 U/L, % 13.5 13.2
Tumor related patient characterists
CharacteristicFOLFIRI + Cetuximab
N= 297FOLFIRI + Bevacizumab
N= 295
Site of primary tumor, %Colon RectumColon + Rectum
Liver metastasis only, %
Yes
Number of metastatic sites, %
1 site≥ 2 sites
Prior treatment, %
Surgery
Adjuvant chemotherapy
Radiotherapy pretreatment
56.638.73.0
60.035.94.1
31.3 31.9
40.159.9
41.758.3
83.822.113.1
85.418.913.4
Treatment duration
FOLFIRI + Cetuximab N= 297
Median, months
Cycles, n
FOLFIRI + Bevacizumab N= 295
p
4.80.0 – 31.3
5.30.0 – 33.0
0.112
101 – 63
121 – 72
0.014
treatment with all 3 substances; two-sided Wilcoxon test
Evaluation of ORR
FOLFIRI + Cetuximab FOLFIRI + BevacizumabOdds ratio
p
Assessable for response
(N= 526)72.2 66.2 – 77.6 63.1 57.1 – 68.9
1.521.05-2.19 0.017
1.180.85-1.64 0.183
p = Fisher´s exact test (one-sided)
ORR % 95%-CI % 95%-CI
ITTpopulation
62.0 56.2 – 67.5 58.0 52.1 – 63.7
(N= 592)
Evaluation of response
RECIST, n (%)FOLFIRI + Cetuximab
N= 297FOLFIRI + Bevacizumab
N= 295
Complete response 13 (4.4)* 4 (1.4)*
Partial response 171 (57.6) 167 (56.6)
Stable disease 53 (17.5)* 85 (28.8)*
Progressive disease 21 (7.1) 16 (5.4)
Not evaluable 39 (13.1) 23 (7.8)
*significant differences in response; p = two-sided Fisher´exact test
Progression-free survival
0.75
1.0
0.50
0.25
Pro
ba
bil
ity
of
su
rviv
al
Eventsn/N (%)
Median (months)
10.0
95% CI
― FOLFIRI + Cetuximab
250/297(84.2%)
8.8 – 10.8
― FOLFIRI + Bevacizumab
242/295(82.0%)
HR 1.06 (95% CI 0.88 – 1.26)
10.3 9.8 – 11.3
Log-rank p= 0.547
0.012 24 36 48 60 72
months since start of treatment
numbers 297 10099
1915
106
54
3
at risk 295
Overall survival
Events n/N (%)
Median (months)
28.7
95% CI
― FOLFIRI + Cetuximab
158/297(53.2%)
24.0 – 36.6
― FOLFIRI + Bevacizumab
185/295(62.7%)
HR 0.77 (95% CI: 0.62 – 0.96)
25.0 22.7 – 27.6
Log-rank p= 0.017
0.75
1.0
0.50
0.25
Pro
ba
bil
ity
of
su
rviv
al
0.012 24 36 48 60 72
months since start of treatment
numbers 297 218214
111111
6047
2918
92at risk 295
Subsequent anticancer therapy
FOLFIRI + Cetuximab N= 297
Any 2nd-line therapy, %
2nd-line bevacizumab, %
2nd-line anti- EGFR, %
FOLFIRI + Bevacizumab N= 295
p
65.7 61.7 0.347
48.2 17.6
42.914.4
p = two-sided Fisher´s exact test p
Exploratory subgroup analysis for OS
Gender: malefemale
1>1
Number of metastaticsites:
≤ 65> 65
Age:
colonrectum
Localization:
noyes
Liver limited disease:
yesno
Synchronous mets:
< 8/nl≥ 8/nl
Leukocytes:
0.73 (0.56 – 0.94)0.88 (0.61 – 1.29)
0.75 (0.56 – 1.01)0.80 (0.58 – 1.09)
0.88 (0.67 – 1.16)0.62 (0.43 – 0.89)
0.78 (0.56 – 1.09)0.77 (0.58 – 1.02)
0.79 (0.61 – 1.02)0.74 (0.50 – 1.10)
0.75 (0.59 – 0.97)0.83 (0.54 – 1.25)
0.68 (0.51 – 0.90)0.92 (0.66 – 1.28)
HR (95% CI)
0.1
FOLFIRI + cetuximab10
FOLFIRI + bevacizumabfavors:1
Hematological toxicity
FOLFIRI + Cetuximab N= 297
FOLFIRI + Bevacizumab N= 295 p
p = Fisher´s exact test
%
any grade
grade ≥3 any grade gradegrade ≥3≥3
Leucopenia 66.7 12.8 66.8 11.2 0.613
Anemia 87.9 2.4 90.9 1.4 0.545
Thrombocytopenia 25.6 0.3 23.4 0.3 >0.999
Neutropenia 61.3 24.2 60.3 22.8 0.699
Febrile neutropenia
1.7 1.7 3.0 1.0 0.725
Non-hematological toxicity
FOLFIRI + Cetuximab N= 297
FOLFIRI + Bevacizumab N= 295
p grade ≥3
0.414
0.473
0.458
0.835
0.449
0.401
0.037
0.030
0.066
significant differences in any grade toxicity: *p=0.0005; **p= 0.03, ***p= 0.0002, p = Fisher´s exact test p
Toxicity, % any grade grade ≥3 any grade grade ≥3
Pts. with any event 100.0 71.0 100.0 63.7
Nausea 48.2* 3.4 62.4* 4.8
Vomiting 24.6** 2.4 32.9** 3.4
Diarrhea 57.2 11.5 62.7 13.6
Mucositis/Stomatitis 42.1 3.7 44.8 4.1
Fatigue 50.2 0.7 54.9 1.4
Pain 50.2 5.4 58.0 7.1
Hand-foot-syndrome 26.6*** 3.4 14.2*** 0.7
Fatal adverse events na 0.0 na 1.7
Non-hematological toxicity
FOLFIRI + Cetuximab N= 297
FOLFIRI + Bevacizumab N= 295
p grade ≥3
0.414
0.473
0.458
0.835
0.449
0.401
0.037
0.030
0.066
significant differences in any grade toxicity: *p=0.0005; **p= 0.03, ***p= 0.0002, p = Fisher´s exact test p
Toxicity, % any grade grade ≥3 any grade grade ≥3
Pts. with any event 100.0 71.0 100.0 63.7
Nausea 48.2* 3.4 62.4* 4.8
Vomiting 24.6** 2.4 32.9** 3.4
Diarrhea 57.2 11.5 62.7 13.6
Mucositis/Stomatitis 42.1 3.7 44.8 4.1
Fatigue 50.2 0.7 54.9 1.4
Pain 50.2 5.4 58.0 7.1
Hand-foot-syndrome 26.6*** 3.4 14.2*** 0.7
Fatal adverse events na 0.0 na 1.7
Non-hematological toxicity
FOLFIRI + Cetuximab N= 297
FOLFIRI + Bevacizumab N= 295
p grade ≥3
0.414
0.473
0.458
0.835
0.449
0.401
0.037
0.030
0.066
significant differences in any grade toxicity: *p=0.0005; **p= 0.03, ***p= 0.0002, p = Fisher´s exact test p
Toxicity, % any grade grade ≥3 any grade grade ≥3
Pts. with any event 100.0 71.0 100.0 63.7
Nausea 48.2* 3.4 62.4* 4.8
Vomiting 24.6** 2.4 32.9** 3.4
Diarrhea 57.2 11.5 62.7 13.6
Mucositis/Stomatitis 42.1 3.7 44.8 4.1
Fatigue 50.2 0.7 54.9 1.4
Pain 50.2 5.4 58.0 7.1
Hand-foot-syndrome 26.6*** 3.4 14.2*** 0.7
Fatal adverse events na 0.0 na 1.7
Adverse events of special interest to cetuximab
FOLFIRI + Cetuximab N= 297
any grade grade ≥3
FOLFIRI + Bevacizumab N= 295
any grade grade ≥3p
grade ≥3Toxicity, %
significant differences in any grade toxicity: *p<0.0001 **p=0.0003, p = Fisher´s exact test p
Acneiform exanthema
77.4* 16.8 7.8* 0.0 < 0.0001
Desquamation 35.4* 6.7 11.5* 0.7 0.0001
Paronychia 37.4* 5.7 9.2* 0.0 < 0.0001
Infusion related allergic reaction
7.7* 4.0 0.0* 0.0 0.0004
Hypocalcaemia 27.6** 4.0 15.3** 2.4 0.351
Hypomagnesaemia 63.3* 4.4 39.7* 0.7 0.007
Adverse events of special interest to bevacizumab
FOLFIRI + Cetuximab N= 297
any grade grade ≥3
FOLFIRI + Bevacizumab N= 295
any grade grade ≥3p
grade ≥3Toxicity, %
significant differences in any grade toxicity: *p<0.001; **p=0.046, #p=0.006, p = Fisher´s exact test p
Hypertension 21.2* 6.4 38.3* 6.8 0.870
Proteinuria 2.7 0 2.0 0.3 0.498
Bleeding/hemorrhage 21.2** 0.7 28.5** 0.3 > 0.999
Abscesses/fistulae 1.4# 0.3 5.4# 1.0 0.372
GI-perforation 0.3 0.3 0.7 0.7 0.623
Thrombosis (any) 9.4 6.1 11.5 6.1 >0.999
Thromboembolic event
7.4 5.1 7.1 5.8 0.720
Wound healing complications
2.0 0.3 2.7 1.4 0.216
Adverse events of special interest to bevacizumab
FOLFIRI + Cetuximab N= 297
any grade grade ≥3
FOLFIRI + Bevacizumab N= 295
any grade grade ≥3p
grade ≥3Toxicity, %
significant differences in any grade toxicity: *p<0.001; **p=0.046, #p=0.006, p = Fisher´s exact test p
Hypertension 21.2* 6.4 38.3* 6.8 0.870
Proteinuria 2.7 0 2.0 0.3 0.498
Bleeding/hemorrhage 21.2** 0.7 28.5** 0.3 > 0.999
Abscesses/fistulae 1.4# 0.3 5.4# 1.0 0.372
GI-perforation 0.3 0.3 0.7 0.7 0.623
Thrombosis (any) 9.4 6.1 11.5 6.1 >0.999
Thromboembolic event
7.4 5.1 7.1 5.8 0.720
Wound healing complications
2.0 0.3 2.7 1.4 0.216
Efficacy Summary
• ORR favored FOLFIRI plus cetuximab (62% vs 58%, p= 0.183), but did not reach the level of significance within the ITT population
• ORR was significantly higher in patients receiving FOLFIRI plus cetuximab (72.2% vs 63.1%, p= 0.017) in patients assessable for response
• No difference in PFS between both arms could be observed (HR 1.06, p= 0.547)
• OS was significantly longer (HR 0.77, p= 0.017) in patients treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab
Deepness of response correlates with post-progression survival
• Data from the CRYSTAL trial indicate that tumor size reduction is more predictive for OS than PFS
Mansmann et al,ASCO 2013 abstract #3630
• Central, independent review of FIRE-3 CT scans is ongoing to analyze tumor volume changes (secondary endpoint of FIRE-3 study)
Cetuximab+ FOLFIRI
(n=315)
FOLFIRI (n=348)
p
Median DpR (95% CI)
Median OS (95% CI)
50.9(18.4 - 78.6)
33.3(8.0 - 58.0)
p<0.0001
23.5(21.2 - 26.3)
20.0(17.4 - 21.7) p<0.0093 adopted from Mansmann et al, ASCO GI 2013 abstract
#427
Conclusions
• FIRE-3 is the first head-to-head comparison of FOLFIRI plus
cetuximab versus FOLFIRI plus bevacizumab in KRAS wild-type
mCRC patients
• First-line treatment with FOLFIRI plus cetuximab resulted in a
clinically meaningful difference in median OS of 3.7 months
(HR 0.77) when compared to FOLFIRI plus bevacizumab
• Toxicity profiles were as expected and manageable for both
combinations
Acknowledgement
Patients and their families
FIRE-3 study investigatorsGermany: Fischer von Weikersthal, Decker, Jäger, Al-Batran, Vehling-Kaiser, Heintges, Kiani, Lerchenmüller, Kahl, Kullmann, Seipelt, Stauch, Müller (Ansbach), Hielscher, Scholz, Niederle, Schäfer, Lindig, Möhler, Höffkes, Rost, Reeb, Geißler, Denzlinger, Kubin, Maschmeyer, Burckhard, Knorrenschild, Ketzler, Schmits, Siebler, Schepp, Schneider, Harich, Bohle, Mergenthaler, Eggers, Puchtler, Uhlig, Römmele, Schmidt (München), Raßmann, Engel, Zimber, Link, Gehbauer, Lerch, Hebart, Königsmann, Kiehl, Kempf, Wolff, Fleck, Meiler, Schwittay, Herrmann, Schlimock, Spes, Bair, Pihusch, Stötzer/Salat, Lambertz, Müller (Osnabrück), Schwella, Michl, Breunig, Schlag, Behringer, Demandt, Gassmann, Schneider-Kappus, Quitzsch, Weiß, Siveke, Respondek, Sölling, Prügl, Haberl, Schulze, Feder, Schmidt (Bochum), Peuser, Schulz-Abelius, Walther, Fauth, Dürk, Hagen, Truckenbrodt, Constantin, Slawik, Hitz, von Wichert, Koch, Abele, Horndasch, Schanz, Hoffmann (Ludwigshafen), Holtmann, Hoffmann (Weimar), Fries, Erhardt, Luhn, Pfeiffer, Porschen, Rummel, Perker, Mittermüller, Matzdorff, Kappauf, Greif, Pohl, Post, Pistorius, Buschmann, Holtkamp, Zöller, Hartnack, Kreibich, Winkelmann, Jakobs, Müller (Leer), Cordes, Weber, Fischinger, von Schilling, Losem, Kindler, Hegewisch-Becker, Abendhardt
Austria: Scheithauer, Samonig, Dittrich, Ziebermayr, Andel, Thaler, Ludwig, Ulrich-Pur