nimotuzumab chemoradiation in head & neck cancer
DESCRIPTION
TRANSCRIPT
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