D i sc l o s u re: S e b a st i a n St i ntz i n g

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= 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= 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


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= 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


Any 2nd-line therapy, %

2nd-line bevacizumab, %

2nd-line anti- EGFR, %


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 + 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



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


any grade grade ≥3


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


any grade grade ≥3


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

D i sc l o s u re: S e b a st i a n St i ntz i n g

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