A Phase IIb, 4 Arm, Open-label, Randomized Trial, To assess the Safety and Efficacy of Concurrent

h-R3 (nimotuzumab) monoclonal Antibody against EGFR in combination with Chemo Radiation therapy or with

Radiotherapy alone in patients with advanced inoperable (stage III or IVA) Head and Neck Cancer

Lokesh Viswanth1. & B Krishnamurthy Reddy1, M.S. Vidyasagar2, Kamalaksha Shenoy3, Ashok shenoy1, K. Govind Babu1, T.Naveen1, B. Joseph1, R. Bonanthaya1, C.R.Tanvir Pasha1, A.S. Aravind4, A. Eswaraiah4, N.Gupta4, P.P.Bapsy1.

Kidwai Memorial Institute of Oncology1, Bangalore, Shirdi Sai Baba Cancer Hospital,Manipal2, KMC Hospital, Mangalore3, Biocon/Clinigene Bangalore4

Disclosure

No conflict of interest

Background – Treatment of SCCHN

Chemoradiotherapy and cetuximab/Radiotherapy are standard treatment modalities for patients with locally advanced SCCHN

Radiation therapy is still a standard treatment in India for patients unfit chemoradiotherapy

Independently of the treatment the prognosis of those patients are still dismal and the majority of these population will recur and/or die within 3 years

Background – Alternative Strategies

Alternatives to improve the outcome of those patients have been pursued in phase II studies:

– c225/Chemo/Radiotherapy (Pfister et al. 2006/Merlano et al. 2008)

– Encouraging results in phase II trials were shown (RR 94-100%)

– Elevated toxicity of the combination is a concern

– Phase III is ongoing and recruitment has been completed (RTOG 0522)

Nimotuzumab has shown in phase I/II studies to increase locoregional control with a benign toxicity profile

– Improved safety due to preferential target of tumor EGFR

Nimotuzumab is an IgG1, humanized EGFR-targeting monoclonal antibody1

– Affinity of ~10-8 M, lower than cetuximab 10-10 M

Competes with cetuximab and EGF for binding

Targets same/overlapping epitope as cetuximab - Domain 3

Inhibits ligand-induced EGFR activation

Inhibits cancer cell proliferation

Pro-apoptotic

ADCC, CDC

Anti-angiogenic / Anti-VEGF

1 Diaz Miqueli et al; Hybridoma, Volume 26, Number 6, 2007

Nimotuzumab is similar to cetuximab with a different biodistribution profile

Rationale

Preclinical DataEffect of nimotuzumab and cetuximab in Xenografts

SCID mice with A431 tumors

Int. J. Cancer: 101, 567–575 (2002)

EGFR +++: Inclusion Criteria

Unresectable

H&NC

N = 22

RxT

(6

0-6

6 G

y)

Nimo 50mg x 6 doses weekly

Nimo 100mg x 6 doses weekly

Nimo 200mg x 6 doses weekly

Nimo 400mg x 6 doses weekly

Crombet et al, 2004. J Clin Oncol 22:1646-1654.

Phase I/IIRD-EC 040 e RD-EC 046

Overall Survival

(50 + 100) (200 + 400)

Median(months)

8.60 44.30

3y Surv. 16.7 % 66.7 %

Survival Functions

SOBREV

50403020100

Cu

m S

urv

iva

l

1.2

1.0

.8

.6

.4

.2

0.0

-.2

Agrupacion

200+400

200+400-censored

50 +100

50 +100-censored

Crombet et al, 2004. J Clin Oncol 22:1646-1654.

Phase I/IIRD-EC 040 e RD-EC 046

Group

Phase I StudyYMB1000-004

Unresectable

H&NC

N = 31

Nimo 100mg x 6 weekly doses

+ RxT (70 Gy)

Nimo 200mg x 6 weekly doses

+ RxT (70 Gy)

Abst. #926; Proceedings ASCO 2002. Publication in preparation.

• Conducted in 6 centers in Canada

Co

ho

rts

Phase IYMB1000-004

Best ResponseBest Response 100 mg100 mg

(N=14)(N=14)

200 mg200 mg

(N=17)(N=17)

CRCR 9 (64%)9 (64%) 9 (53%)9 (53%)

PRPR 1 (7%)1 (7%) 2 (12%)2 (12%)

SDSD 2 (14%)2 (14%) 1 (6%)1 (6%)

PDPD 2 (14%)2 (14%) 1 (6%)1 (6%)

Overall Response (CR + PR) = 68%

Abst. #926; Proceedings ASCO 2002. Publication in preparation.

Study Objectives Proof of Principle: Phase II Trial - BEST Study

Primary Objectives:

– To assess the efficacy and safety of nimotuzumab with concurrent CTRT or RT alone

• Response Rate

– To assess the safety profile

• Acute toxicity

Translational Research:

– EGFR expression with IHC and its association with clinical parameters

– Will be reported in the near future

Study DesignProof of Principle: Phase II Trial - BEST Study

First Line, Unresectable,

Stage III/IV SCCHN Nimo 200mg + RT (60 – 66Gy)

+ CDDP 50mg/w

RT (60 – 66Gy)

+ CDDP 50mg/w

Nimo 200mg + RT (60 – 66Gy)

RT (60 – 66Gy)Group A

Group B

Patients were allocated at the discretion of the physician to RT alone or Chemoradiotherapy and then randomized to +/- nimotuzumab

Groups were not stratified

48 months follow up (as of August 2009)

Study DesignProof of Principle Phase II Trial: BEST Study

113 patients

Screened

92 patients

Enrolled (safety pop)

76 patients

Evaluable for Efficacy

Protocol compliant with second image evaluation

RT

18 patients

RT + h-R3

18 patients

CT + RT

20 patients

CT + RT + h-R3

20 patients

Patients that received at least one dose of nimotuzumab

R R

Radiotherapy Protocol

Same in all 4 arms

Total Dose : 6600 cGy

200 cGy/Fraction, 5fx/week

6 – 6.5 weeks

2D plan

Telecobalt

Chemotherapy & Nimotuzumab Protocols

CDDP 50mg/week (fixed dose) concurrent with start of RT

Nimotuzumab 200mg was administered 3 days before RT and then weekly

– Rationale: to differentiate & capture the mAb / CT toxicities /AEs

Demographics: Group ACharacteristic

h-R3+RT (N=23)

RT(N=23)

p-value

Age (Years)

1.0000 Mean 58.70 58.70

Standard Deviation 8.20 8.10

Sex n (%)

1.0000 Male 21 (91.3%) 20 (86.96%)

Female 2 (8.7%) 3 (13.04%)

KPS n (%)

0.6647 70 8 (34.78%) 10 (43.48%)

80 11 (47.83%) 11 (47.83%)

90 4 (17.39%) 2 (8.70%)

Site of primary tumor n (%)

0.2242

Hypopharynx 2 (8.7%) 4 (17.39%)

Oral Cavity 3(13.04%) 6 (26.09%)

Oro Pharynx 18 (78.26%) 11 (47.83%)

Larynx 0 (0%) 1 (4.35%)

Maxillary 0 (0%) 1 (4.35%)

Stage n (%)

0.4591 III 6 (26.09%) 3 (13.04%)

IV 17 (73.91%) 20 (86.96%)

Demographics: Group BCharacteristic

h-R3 + CT+RT(N=23)

CT+RT(N=23)

p-value

Age (Year)

0.1987 Mean 49.87 53.65

Standard Deviation 10.57 9.03

Sex n(%)

1.000 Male 20 (86.96%) 21 (91.3%)

Female 3 (13.04%) 2 (8.7%)

KPS n (%)

1.000 70 5 (21.74%) 6 (26.09%)

80 9 (39.13%) 9 (39.13%)

90 9 (39.13%) 8 (34.78%)

Site of primary tumor n (%)

0.8626

Hypopharynx 5 (21.74%) 5 (21.74%)

Oral Cavity 5 (21.74%) 4 (17.39%)

Oro Pharynx 10 (43.48%) 12 (52.17%)

Larynx 2 (8.70%) 2 (8.70%)

Supraglottis 1 (4.35%) 0 (0%)

Stage n (%)

0.2333 III 3 (13.04%) 0 (0%)

IV 20 (86.96%) 23 (100%)

BEST Trial - Phase IIIND 001

Overall Response Rate (CR+PR)

Treatment RegimenTreatment Regimen RR (%)RR (%)

RTRT 30-5030-50

RT + CTRT + CT 50-8050-80

RT + C 225RT + C 225 74 74 11

RT + h-R3 (nimotuzumab)RT + h-R3 (nimotuzumab) 68-7668-76

RT + CT + C 225RT + CT + C 225 94-100 94-100 2,32,3

RT + CT + h-R3 (nimotuzumab)RT + CT + h-R3 (nimotuzumab) 100100

H&NC Historical NumbersH&NC Historical Numbers

1. Bonner et al. NEJM 2006. // 2. Merlano et al.. J Clin Onco, 2007 Vol 25, No. 18S (June 20 Supplement), 2007: 6043

3. Pfister et al., JCO 2006

BEST Trial - Phase IIIND 001

CRT

CRT+ nimotuzumab

RT

RT+ nimotuzumab

Overall Survival – Evaluable Population – 30 months

0.00

0.25

0.50

0.75

1.00

Months

0 5 10 15 20 25 30

BEST Trial - Phase IIIND 001

Combined Group Analysis: Overall Survival – Nimotuzumab vs No Nimotuzumab

Unplanned post-hoc analysis

0.00

0.25

0.50

0.75

1.00

months0 5 10 15 20 25 30

HR= 0.34, p=0.0018

No nimotuzumab (n=38)nimotuzumab (n=37)

Overall Survival at 48 Months F-Up Evaluable Population

Overall Survival at 48 Months F-Up ITT Population

After End of RT  

RTn=23 (%)

RT+h-R3n=23 (%)

p-Value

1 year 12 (52.17) 11 (47.83) 0.7681

2 years 5 (21.74) 9 (39.13) 0.1999

30 mths 5 (21.74) 9 (39.13) 0.1999

48 mths 3 (13) 8 (34.7) 0.4278

After End of RT

CT+RTn =23 (%)

CT+RT+h-R3N=23 (%)

p-Value

1 year 12 (52.17) 18 (78.26) 0.0633

2 years 9 (39.13) 18 (78.26) 0.0070

30 mths 5 (21.74) 16 (69.57) 0.0011

48 mths 5 (21) 11 (47) 0.0149

Survival Data of ITT Population

RT+hR3 N RT+CT+hR3 N

Chills 1 loose stools 2

Pyrexia 4 vomiting 3

Headache 4 asthenia 1

Pruritis 2 blood in urine 3

Rash 2 dizziness 2

Urticaria 1

BP fluctuation 2

CAUSALITY CAUSALITY

Certain 3 Certain -

Possible 2 Possible 4

Probable 1 Possible 7

Nimotuzumab AEs

Treatment-Related Grade 3 & 4 AEs

Nimotuzumab: Medium Affinity Results in Targeting of Areas with EGFR Over-Expression

AACR 2008, Abstract 36,Tikhomirov et al

Bivalent Binding(Avidity = ~Affinity2)

Y

High EGFR Density (i.e. tumor)

Y

Monovalent Binding (Affinity)

Low EGFR Density (i.e. skin)P-mAb

C-mAb

N-mAb

Reliance on Avidity Results in Nimotuzumab Targeting Cancer Cells Over-Expressing EGFR

AACR 100th Annual Meeting 2009 – Abstract #2763

NimotuzumabCetuximab

Nimotuzumab FabCetuximab Fab

Human Epidermal Cells Human Renal CellsA431 Tumor Cells

AACR 2009

AACR 100th Annual Meeting 2009 – Abstract #2763

This is the first randomized study to prove that nimotuzumab is safe and efficacious in SCCHN improving the clinical parameters of those patients

Although slight imbalances between the study and control groups the benefit seen with the clinical benefit is encouraging, in line with the literature and should be considered driven by the study drug

Concurrent use of nimotuzumab with chemoradiation has enhanced long term locoregional control & survival on long term follow up

This is the first randomized study demonstrating clinical benefit from an EGFR-targeting drug in the absence of the advanced toxicities typical of the class

Nimotuzumab has shown in this pilot study a surprisingly benign toxicity profile preferentially targeting the tumor

– Attributed to mechanistic differences in its biodistribution

These data support and recommend the conduct of a Phase III trial

– Currently in planning

1 Diaz Miqueli et al; Hybridoma, Volume 26, Number 6, 2007

Conclusion