HS Hochster

Safety and efficacy of oxaliplatin–fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC):

Final analysis of the TREE study

HS Hochster

H. S. Hochster, L. L. Hart, R. K. Ramanathan, J. D. Hainsworth, S. Griffing, R. D. Mass, Y. Nagarwala, G.

Jirau-Lucca,A. Shpilsky, B. H. Childs

Background

Oxaliplatin–fluoropyrimidine regimens: standard combination chemotherapy for stage III and IV CRC

TREE-1 trial: comparison of three different oxaliplatin–fluoropyrimidine regimens (mFOLFOX, bFOL, CapeOx) for toxicity

Bevacizumab: promising results in mCRC when added to first-line chemotherapy (bIFL or 5-FU–LV)1,2

TREE-2 trial: TREE-1 trial modified to include bevacizumab

1. Hurwitz H, et al. N Engl J Med 2004; 2. Kabbinavar F, et al. J Clin Oncol 2003

Study design

mFOLFOX

CapeOx

RRbFOL

(n=50)

(n=50)

(n=50)

Nov 2002 – Oct 2003

mFOLFOX +bevacizumab

bFOL + bevacizumab

CapeOx(reduced dose)

+ bevacizumab

(n=75)

(n=74)

(n=74)

Nov 2003 – Apr 2004

RR

TREE-1 TREE-2

n=150 n=223

mFOLFOX6: 14-day cycle

bFOL: 28-day cycle

LV (350 mg IV, 2 h)

OX (85 mg/m2 IV, 2 h)

5-FU (400 mg/m2, IV bolus)

5-FU (2400 mg/m2 IV, 46 h)

Day 1

CapeOx: 21-day cycle

OX (130 mg/m2 IV, 2 h)

Day 1 Days 1–15CAPE (1000 mg/m2 orally bida)

a28 doses in total

Day 1 Day 8

OX (85 mg/m2 IV, 2 h)


LV (20 mg/m2, IV bolus)

Day 15

Day 2

OX (85 mg/m2 IV, 2 h)

Treatment regimens: TREE-1

mFOLFOX6 + bev: 14-day cycle

bFOL + bev: 28-day cycle

LV (350 mg IV, 2 h)

OX (85 mg/m2 IV, 2 h)


5-FU (2400 mg/m2 IV, 46 h)

Day 1

CapeOx + bev: 21-day cycle

OX (130 mg/m2 IV, 2 h)

Day 1 Days 1–15CAPE (850 mg/m2 orally bida)

a28 doses in total; 650 mg/m2 bid for patients with creatinine clearance 30–50 mL/min

Day 1 Day 8

OX (85 mg/m2 IV, 2 h)


LV (20 mg/m2, IV bolus)

Day 15

Day 2

OX (85 mg/m2 IV, 2 h)

Treatment regimens: TREE-2

BEV (5 mg/kg IV, 30–90 min)



BEV (7.5 mg/kg IV, 30–90 min)

Inclusion criteria

Histologically documented adenocarcinoma of the colon or rectum

Inoperable metastatic disease

No prior chemotherapy for metastatic/recurrent disease

Age ≥18 years; ECOG performance status 0–1

At least 1 unidimensional measurable lesion

Exclusion criteria

Prior treatment with oxaliplatin or bevacizumab

Myocardial infarction within 6 months, current clinical evidence of congestive heart failure, or non-stable coronary artery disease

Blood pressure >160/110 mmHg on medication; symptomatic peripheral vascular diseasea

Peripheral neuropathy

aTREE-2 cohort only

Objectives

Primary: Incidence of grade 3/4 toxicity during initial 12

weeksof therapy

Secondary: Response rate (RECIST) TTP (censored for second-line treatment) TTF (treatment discontinuation, progression, or

death) Survival

Demographic and baseline characteristicsa

TREE-1 TREE-2mFOLFO

X(n=49)

bFOL(n=50

)

CapeOx

(n=48)

mFOLFOX + bev(n=71)

bFOL + bev(n=70)

CapeOx + bev(n=72)

Median age (years) [range]

62[35–79]

62[31–84]

62[32–84]

64[31–83]

57[30–85]

62[32–82]

Male (%) 57 62 65 61 49 58

ECOG PS 0 (%) 61 58 52 61 54 65

Prior adjuvant chemotherapy (%)

45 16 27 24 31 31

aWith the exception of tumor response, all data are presented for the as-treated population, defined as all patients who received at least one dose of treatment

Grade 3/4 adverse events during first 12 weeks

Patients (%)

TREE-1 TREE-2(primary endpoint)

mFOLFOX(n=49)

bFOL(n=50)

CapeOx(n=48)

mFOLFOX + bev

(n=71)

bFOL+ bev(n=70)

CapeOX+ bev(n=72)

Related eventa

[95% CI]

59[44–73]

36[23–51]

67[52–80]

59[47–71]

51[39–64]

56[43–67]

All events [95% CI]

76[61–87]

44[30–59]

73[58–85]

65[53–76]

60[48–72]

58[46–70]

aDetermined by the investigator to be related (possibly or probably) to study drug

Grade 3/4 adverse events occurring in ≥5% of patients

Patients (%)

TREE-1 TREE-2

mFOLFOX

(n=49)

bFOL(n=50)

CapeOx(n=48)

mFOLFOX + bev (n=71)

bFOL+ bev (n=70)

CapeOX+ bev (n=72)

Neutropenia 53 18 15 49 19 10

Dehydrationa 8 12 27 6 14 8

Diarrheaa 33 26 31 13 26 19

Hypertension 0 0 2 7 13 15

TE, arterial TE, other

210

04

02

010

010

34

Nausea 16 14 19 6 11 11

Vomiting 14 10 19 1 13 10

Neurotoxicity 18 10 23 14 11 15

Hand–foot 8 2 19 0 0 10

Any grade 3/4 96 76 85 85 74 76aThe high incidence of dehydration and diarrhea in the CapeOx arm in TREE-1 was effectively reducedby capecitabine dose reduction in TREE-2. TE, Thromboembolic events

Adverse events of special interest

Adverse event (all grades), n (%) of patients

TREE-1 TREE-2mFOLFO

X(n=49)

bFOL(n=50)

CapeOx(n=48)

mFOLFOX + bev(n=71)

bFOL+ bev(n=70)

CapeOX+ bev(n=72)

Sepsis 0 (0) 0 (0) 2 (4.2) 3 (4.2) 3 (4.3) 1 (1.4)

Bowel perforation

0 (0) 0 (0) 0 3 (4.2) 2 (2.9) 2 (2.8)

Impaired wound healing

0 (0) 0 (0) 1 (2.1) 4 (5.6) 1 (1.4) 4 (5.6)

Treatment- related death

0 (0) 1 (2.0) 3 (6.3) 0 (0) 3 (4.3) 3 (4.2)

Best confirmed tumor response (per-protocol population)a

Tumor response (RECIST)(% patients)

TREE-1 TREE-2mFOLFO

X(n=46)

bFOL(n=45)

CapeOx(n=37)

mFOLFOX + bev(n=70)

bFOL+ bev(n=63)

CapeOX+ bev(n=69)

CR 0 0 3 6 5 3

PR 43 22 32 47 37 45

SD 26 47 51 39 41 32

PD 28 29 14 6 13 9

NE 2 2 0 3 5 12

ORR (CR+PR) [95% CI]

43[29–59]

22[11–37]

35[20–53]

53[41–65]

41[29–54]

48[36–60]

aAll patients who received at least 1 treatment with oxaliplatinfluoropyrimidine ± bevacizumab andwho have sufficient data to allow assessment of response

Time to treatment failure1.0

0.8

0.6

0.4

0.2

0

Pro

ba

bil

ity

0 5 10Time to treatment failure (months)

15 20 25

1.0

0.8

0.6

0.4

0.2

0

Pro

ba

bil

ity

0 5 10Time to treatment failure (months)

15 20 25

TREE-1 TREE-2

mFOLFOX

bFOL

CapeOx

mFOLFOX + bevacizumab

bFOL + bevacizumab

CapeOx + bevacizumab

CapeOx(n=48)

bFOL(n=50)

mFOLFOX(n=49)

4.44.96.5Median (months)

3.0–5.83.5–6.15.4–8.395% CI

mFOLFOX+ bev(n=71)

4.9–6.7

5.8

bFOL+ bev(n=70)

4.0–6.6

5.5

CapeOx+ bev(n=72)

4.7–6.5

5.5

Median (months)

95% CI

Time to tumor progressiona

aWith censoring for second-line treatment

CapeOx+ bev(n=72)

bFOL+ bev(n=70)

mFOLFOX+ bev(n=71)

8.6–12.56.6–9.97.9–11.795% CI


CapeOx(n=48)

bFOL(n=50)

mFOLFOX(n=49)

5.1–7.44.2–8.06.5–9.895% CI


1.0

0.8

0.6

0.4

0.2

0 5 10Time to tumor progression (months)

15 20 250

Pro

ba

bil

ity

1.0

0.8

0.6

0.4

0.2

0 5 10Time to tumor progression (months)

15 20 250

Pro

ba

bil

ity

TREE-1 TREE-2

mFOLFOX

bFOL

CapeOx


bFOL + bevacizumab


Survival: TREE-1

CapeOx

mFOLFOX

bFOL

1.0

0.8

0.6

0.4

0.2

0.1

0.3

0.5

0.7

0.9

0 5 10

Survival time (months)

15 20 25 30 35 40

0

Pro

ba

bil

ity

CapeOx

(n=48)bFOL

(n=50)

mFOLFOX

(n=49)

12.5–22.311.5–24.614.2–24.295% CI


Survival: TREE-2



bFOL + bevacizumab

1.0

0.8

0.6

0.4

0.2

0.1

0.3

0.5

0.7

0.9

0 5 10


15 20 25 30 35 40

0

Pro

ba

bil

ity

CapeOx+ bev

(n=72)

bFOL+ bev

(n=70)

mFOLFOX+ bev

(n=71)

21.8–NE18.8–25.318.0–NE95% CI


NE, not evaluable

Survival: chemotherapy regimens combined

TREE-1(n=147)

TREE-2(n=213)

Patients who have died, n (%) 101 (69) 111 (52)

Patients alive at last follow-up, n (%)

46 (31) 102 (48)

Median survival time, months [95% CI]

18.2[14.5–21.6]

24.4[21.4–26.8]

Survival probability, % [95% CI] 12 months 18 months 24 months

67.3 [58.9–74.3]50.1 [41.5–58.1]35.8 [27.6–44.1]

79.1 [73.0–84.0]

64.7 [57.8–70.8]

50.7 [43.6–57.4]

Survival: oxaliplatin-based regimens combineda

21.4–26.814.5–21.695% CI

24.418.2Median survival(months)

TREE-2

(n=213)

TREE-1

(n=147)

1.0

0.8

0.7

0.5

0.3

0.1

0.9

0.6

0.4

0.2

0 5 10 15 20 25 30


35 40

0

Pro

ba

bil

ity

TREE-1

TREE-2

aSequential cohorts without (TREE-1) and with bevacizumab (TREE-2)

Efficacy summary

TREE-1 TREE-2

ORRa (% patients) 22–43 41–53

TTPb (months) 6.1–8.7 8.3–10.3

TTF (months) 4.4–6.5 5.5–5.8

Median survival time (months)c

18.2 24.4

aPer-protocol population. bCensored for second-line therapy.

cAll three treatment arms combined

Conclusions (1)

Oxaliplatin, in combination with bolus, infusional, or oral fluoropyrimidine regimens, is active and well tolerated in previously untreated mCRC

No major differences in activity were observed between the three fluoropyrimidine regimen, but bFOL may be the least efficacious (response and TTP in both cohorts)

With dose reductiona of capecitabine, CapeOx with bevacizumab was tolerated much better (compared with CapeOX in TREE-1)

equivalent activity to FOLFOX with bevacizumab

aFrom 1000 mg/m2 (TREE-1) to 850 mg/m2 orally bid (TREE-2),

Conclusions (2)Bevacizumab, when added to oxaliplatin–fluoropyrimidine regimens results in increased efficacy with the expected toxicity profile Addition of bevacizumab did not change TTF but

improved TTP

Overall survival was improved with the addition of bevacizumab (sequential historical cohorts) Median survival time was: 18.2 months in TREE-1a (95% CI:14.5–21.6 months) 24.4 months in TREE-2a (95% CI: 21.4–26.8

months)

aAll three treatment arms combined

AcknowledgmentInvestigators

Lowell Hart, Florida Cancer SpecialistsR. Ramanathan, Univ PittsburghJohn Hainsworth, Sarah Cannon Cancer CenterLouis Fehrenbacher, Kaiser PermanenteYusif Abubakr, Florida OncologyLee Schwartzberg, West Cancer ClinicPeter Eisenberg, California Cancer CareJames Atkins, Southeastern Medical OncologyMaunuel Modiano, Arizona Clinical Research CenterMarshall Levine, Greater Baltimore Medical CenterJoaquina Veranda, Kansas City VA HospitalGladys Rodriguez, South Texas Oncology Michael Wertheim, Treasure CoastGeorge Geils, Charleston Hematology OncologyMargaret Deutsch, Raleigh Hematology Oncology Renato LaRocca, Kentuckiana Cancer InstituteDavid Mintzer, Pennsylvania Hematology Oncology

Other investigators

sanofi aventisGilbert Jirau-Lucca, MSArkady Shpilsky, PhDYasir NagarwalaLauri Wells, MDBarry Childs, MD

GenentechRobert Mass, MDEric Hedrick, MDDavid Emanuel, MD

OTHERSNursing personnelData PersonnelResearch StaffPATIENTS

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