Cetuximab in scchn how far we go?

CETUXIMAB IN LA

SCCHN:

HOW FAR WE GO?

MOHAMED ABDULLA M.D.

PROF. OF CLINICAL ONCOLOGY

NEMROCK

CAIRO UNIVERSITY

NEMROCK – 08/02/2015

LASCCHN: The Outcome:

SurgeryRadiation

TherapyKey

Components

L.R. Distant

Metastases

Systemic

Therapy

83%

59%

36%

0%

50%

100%

Localized Regional Metastatic

5-

ye

ar

Su

rviv

al

SEER. Stat fact sheets: oral cavity and pharynx cancer. 2003-2009.

MACH-NC: 2009 Update:

93 Trials – 17346 Patients:

J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14
















CISPLATIN 100 mg/m2 (D1+22+43) +

RTH

Impact of low adherence to treatment of CT on

efficacy

LA HNSCC: Theme of

Management:

RTH No impact.

CRT The most accepted standard, < 70 years.

Cisplatin: 100 mg/m2 D1+22+43.

IC NPX Ca. & Organ Preservation Trial, TPF.

Sequential:

Healthy (PS 0 – 1).

Young.

N2-3 (Tany).

T4 not destroying the organ.

Physician – Patient preference.

www.uptodate.com 09/12/2014


Can we go better?

PI3-K

STAT

AKT

Grb2

SOS RAS

RAF1

MEKMPA

K

Gene Transcription & Cell Cycle

Progression

1. Angiogenesis

2. Survival

3. Proliferation

4. Progression

Molecular Key Players:

Carter P. Nat Rev. Cancer 2001.

Heinemann V et al. Cancer Treat Rev. 2009.

NK

CELLS

Erbitux + RT

Erbitux initial dose (400 mg/m2)

Erbitux (250 mg/m2) + RT (wks 2–8)Stage III and IV

non-metastatic

SCCHN

RT

Bonner JA, et al. N Engl J Med 2006;354:567–578

Curran D, et al. J Clin Oncol 2007;25:2191–2197

R

Primary endpoint: Duration of locoregional control

Secondary endpoints: OS, PFS, RR, QoL, and safety

Cetuximab in LA SCCHN:

Bonner Phase III study: Study

Design:

N=424


Months

Lo

co

reg

ion

al

co

ntr

ol

(%)

100

80

60

40

20

0

0 10 20 30 40 50 60

14.9 months

24.4 months

HR=0.68 [95% CI: 0.52–0.89]

p=0.005

3-year control rate

47%

34%

RT

Erbitux + RT


Bonner Phase III study: Local

Control:

Bonner JA, et al. Lancet Oncol 2010;11:21–28

HR=0.73 [95% CI: 0.56–0.95]

p=0.018

0 10 20 30 40 50 60 70

Overa

ll s

urv

iva

l (%

) 5-year survival rate

36%

Months

46%

36%

49.0 months

29.3 months

RT

Erbitux + RT 100

80

60

40

20

0

10

30

50

70

90


Bonner Phase III study: 5-Year

Survival:

Bonner et al. Lancet Oncol 2010; 11:21-28

Time (months)

Pro

bab

ilit

y o

f su

rviv

al

(%)

1.00

0.80

0.60

0.40

0.20

0

0 10 20 30 40 50 60 70

0.10

0.30

0.50

0.70

0.90

Prominent rash group (n=127): Grade 2–4

Mild rash group (n=81): Grade 0/1

51% reduction in the

risk of death (p=0.002)

>68.8 months

p=0.002, HR=0.49 (0.34–0.72)

25.6

months


Bonner Phase III study: 5-Year Survival & Severity

of Rash:


Change of QoL Over Time:

Curran et al. J Clin Oncol 2007; 25:2191-2197

Glo

bal

hea

lth

sta

tus/Q

oL

sco

re 100

80

60

40

20

0

Visit

RT

RT + Erbitux

Baseline Week 4 Month 4 Month 8 Month 12

QoL assessment of Bonner study

QoL: Post-baseline scores for the EORTC QLQ-C30

*Listed for its relationship to Erbitux


p<0.001

p=0.01

Patients (%)

0 10 20 30 40 50 60

Mucositis

Dysphagia

Radiation dermatitis

Xerostomia

Fatigue/malaise

Acne-like rash

*Infusion reactions

RT (n=212)

Erbitux + RT (n=208)

90%

10%

COMPLIANCE

Full dose Not Full dose


Bonner Phase III study: Complications &

Compliance:

CRT: Compliance and adherence to treatment:

CRT arms of studies comparing CRT vs RT alone

Cisplatin/5-FU/FA 46%

51%

71%

0 20 40 60 80 100

Carboplatin/5-FU

Cisplatin

Patients receiving all planned doses (%)

10 705030 90

2 cycles at weeks 1 and 5

3 cycles at weeks 1, 4, and 7

3 cycles at weeks 1, 3, and 6

2nd cycle

3rd cycle

3rd cycle

1 Huguenin et al. J Clin Oncol 2004; 22:4665-4673; 2 Calais et al. J Natl Cancer Inst 1999;

91:2081-2086;

3Wendt et al. J Clin Oncol 1998; 16:1318-1324

1

2

3

CRT versus Bio-Radiotherapy:

TREMPLIN Study: Safety Data:

• RT: 70 Gy

• Erbitux: initial dose 400 mg/m2 prior to RT

then 250 mg/m2 weekly for 7 weeks

• Cisplatin: 100 mg/m2 on days 1, 22 and 43

1. Lefebvre JL et al. J Clin Oncol 2009. 2. Lefebvre JL et al. J Clin Oncol 2011.


Projected Efficacy:

2) Bonner J.A, et al. ASTRO 2008

1) Pignon JP, et al. Lancet 2000;355:949–955

Prominent rash group *

Most of the randomised trials have used

a dose of cisplatin of 100 mg/m2, three

times throughout the course of

radiotherapy (cumulative dose of 300

mg/m2).


Survival Advantages:

Huguenin, Karl 2004two cycles of concomitant

cisplatin (20 mg/m2 on 5

days of weeks 1 and 5).

P= NS

CRT versus Bio-Chemo-

Radiotherapy:

CRT

Bio-Radiotherapy

Bio-Chemo-Radiotherapy

RTOG 0522: Progression-Free

Survival and Overall Survival

Pts at Risk, n

448 316 217 78447 302 197 80

Pts at Risk, n

448 385 266 96447 378 251 94

Ang KK, et al. ASCO 2011. Abstract 5500.

PF

S (

%)

0

25

50

75

100

Yrs After Randomization0 1 2 3

HR: 1.05 (95% CI: 0.84-1.29;

log-rank, 1-sided P = .66)

2-Yr Rate, % (95% CI)

64.3 (59.7-68.8)Cisplatin

63.4 (58.7-68.0)Cisplatin + cet

Primary Endpoint

OS

(%

)

0

25

50

75

100

Yrs After Randomization0 1 2 3

HR: 0.87 (95% CI: 0.66-1.15;

log-rank, 1-sided P = .17)

2-Yr Rate, % (95% CI)

79.7 (75.9-83.6)Cisplatin

82.6 (78.9-86.3)Cisplatin + cet

Radiation Therapy Oncology Group

RTOG-0234:

Stage III/IV

SCCHN High

Risk Su

rgery

Cetuximab +

Cisplatin 30 mg/m2

+ RTH 60 Gy

Cetuximab +

Docetaxel 15

mg/m2

+ RTH 60 Gy

J Clin Oncol 32:2486-2495. © 2014 by American Society of Clinical Oncology

DFS OAS

57%

66%

69%

79%

This is where all footnotes and references go.

• At present, induction chemotherapy is not

considered standard treatment in advanced disease.

• ICT followed by RT-CT (so-called sequential CT-RT) is

still under evaluation.

• The overall toxicity of this approach can be

substantial thus compromising the final result.

•Radiotherapy given concomitantly with cetuximab has

demonstrated a higher response rate, longer disease-

free progression and longer overall survival versus

radiotherapy alone [II, B].

•The magnitude in effect was similar or even better than

that achieved by concomitant chemoradiation, it proved

to be less toxic

Take Home Message:

Cetuximab is an approved key component

plus radiation therapy of LA HNSCC.

Significant lower toxicity profile than platinum

based CRT more adherence to treatment

schedule.

Cisplatin + RTH: 300 mg/m2.

Cetuximab + Docetaxel + RTH = Ideal

Partners.

Cetuximab + RTH = Level 1 Evidence in

Guidelines.

Thank You

Health & Medicine

Cetuximab in scchn how far we go?