Long term results of Concurrent Nimotuzumab with chemoradiation Inoperable Head & Neck Cancer

Role of Nimotuzumab in Head & Neck Cancer

Dr. Lokesh Viswanath M.DPrincipal Investigator : Clinical Trial hR3 SCCHN/IND

Professor & Head of Unit IIDepartment of Radiation Oncology

Kidwai Memorial Institute of Oncology1, Bangalore

Epidemiology Globally the burden of New Cancer Cases

~ 10 million PA 53% - Developing nations India:

Incident Cases : ~ 9 Lakhs PA (IR- 86/Lakhs >106 next 5yrs)

Prevalence Cases : ~24 Lakhs (PR- 260/Lakhs>320 next 5yrs)

Head & Neck Cancer: ~ 1.23 Lakh PA (M-92K,F-31K) Next 5yrs >>~ 1.89 Lakh PA (M-1.4L ,F-

49.5K)

Introduction Radiation therapy is the primary modality of

treatment for loco-regionally advanced inoperable Head & Neck / Oral cancers.

Radiation therapy alone : treatment failure is high > lower cure rate and survival.

Use of concurrent chemotherapeutic drugs as radiation sensitizers has perhaps had the strongest impact on radiation therapy practice. Concurrent CRT - Survival benefit of 6.5% at 5yrs. CRT is the current Standard of Care

New strategies : Currently Biological response modifiers which

enhance radiation and chemotherapy responses have been shown to further improve the therapeutic outcome of radiation therapy with acceptable morbidity.

Recent Advances Recent discoveries in molecular biology have

identified a number of receptors, enzymes, or growth factors that may be responsible for resistance of cancer cells to radiation or other cytotoxic agents, and as such may serve as targets for augmentation of radioresponse or chemoresponse.

One of the newer therapeutic approach being investigated extensively is to use antibodies that have specific ability to recognize and bind to cancer cell surface receptors.

One attractive target for such investigation is the epidermal growth factor receptor (EGFR), a transmembrane glycoprotein with tyrosine kinase activity that plays a critical role in the regulation of tumor cell growth and survival.

EGFR ligand binding stimulates multiple cellular functions essential to tumor growth including invasiveness, cell damage repair, and angiogenesis.

EGFR is highly expressed by the majority of SCCHN cell lines and primary tumors, and this expression is correlated in clinical models with poor prognosis including decreased survival and increased metastatic potential

EGFR EGFR is an Receptor Tyrosine Kinases protein. It was the

first receptor that was linked directly to cancer. Overexpression:

EGFR Ligands

o EGFo TGF α

Overexpression + ↑mRNA of TGF αo Poor response to RTo Strong predictor of ↓ DFSRationale for development of EGFR targeted therapies –

intention to interrupt the EGFR mediated pathway

The ErbB family EGFR belongs to the ErbB family which contains four

RTKs:

1) EGFR2) ErbB23) ErbB34) ErbB4

EGFR Receptor : Potential target

Targeting Oncoproteins - Monoclonal antibodies

Theoretically : Eliminate cancer cell directly

Most often: disable > Oncogene driven intracellular signaling

prevention receptor dimerization facilitate the apoptotic effects of RT &

chemotherapy tumor cell growth arrest G1 arrest & decrease in S-Phase

Targeting EGFR - mitigates the advantages cancer cell has from EGFR over expression

h-R3 mAb/Nimotuzumab/Biomab

humanized monoclonal Antibody (mAb) against the EGF-R extracellular ligand binding domain

Ig G subtype 1, similar to C225 (Cetuximab)

in order to decrease immuno-reactivity and HAMA response the mAb is Genetically engineered Human immunoglobulin framework cloning hyper variable region of m-R3

(murine Ab, ior egf/r3), CDR grafting

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

Expression

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

A Phase IIb, 4 Arm, Open-label, Randomized Trial, to assess the Safety and Efficacy of Concurrent Nimotuzumab (h-R3 Monoclonal Antibody) in combination with Chemo-Radiation therapy or with Radiotherapy alone in patients with advanced inoperable (stage III or IVA) Head and Neck Cancer

,

Medical Research / Clinical Trail Conducted as per ICH GCP Guidelines

Governmental Agencies Approval – yes Institutional Ethical & Scientific Committee

Approval – Yes Periodic Monitoring & audit by CRO – yes Disclosure - none

Investigating TeamPrincipal Investigators1. Dr. B. Krishnamurthy Reddy M.D. (PI active phase) &

Dr. V. Lokesh M.D(Current PI for Follow-up Phase, charges of PI handed over consequent to retirement of 1st PI)

Kidwai Memorial Institute of Oncology, Bangalore.

2. Dr. M. S. Vidyasagar M.D Shirdi Sai Baba Cancer Hospital,Manipal.

3. Dr. Kamalaksha Shenoy M.D KMC Hospital, Mangalore.

Investigating team: Co-investigators1. Kidwai Memorial Institute Of Oncology

Dept of Radiation OncologyDr. T. Naveen M.DDr. Bindu Joseph M.DDr. B. Ravikiran M.DDr. K.P.R.Pramod M.DDr. Siddanna Pallade M.DDr. C.R. Tanvir Pasha M.DDr. Vijay Bhaskar M.DDr. G. Bhanumathy M.DDr. Kumaraswamy M.D

Dept of Head and Neck OncologyDr. Ashok M Shenoy M.S Co-PIDr.NanjundappaM.S

Dept of Medical OncologyDr. K. Govind Babu DM Co-PIDr. P.P.Bapsy DMDr. Lokanath DM

Study Co-Ordinator Dr.Tazeen Aamena MBBSDr.Sathya M . M.D

2. Shirdi Sai Baba Cancer Hospital, Manipal.

3. KMC Hospital, Mangalore

Trial Design by: Dr. B.K.M. ReddyDr. V. LokeshDr. Ashok M. ShenoyDr. M. Vijaykumar

Rationale for the study Nimotuzumab is known to sensitize

radiation effects Chemo-radiation therapy being the

standard of care for inoperable H&N Cancer.

The safety & efficacy of concurrent h-R3 mAb with Chemo-radiation therapy needs to be established for further study and usage

Objective of the Study This study was designed to

investigate the safety and efficacy of concurrent h-R3mAb (Nimotuzumab) along with Radiation therapy or with Chemo-radiation therapy of advanced inoperable Head & Neck Cancer

Material & Methods Advanced inoperable Head & neck Cancer

SC, Stage III or IVA (T1-T4a/ N0-N2) 18 – 70 yrs KPS > 60% Informed Consent - Screening Primary & Nodal assessment / Staging :

Clinical & MRI Assessments Criteria

Tumor Evaluation : RECIST Toxicity Assessments : CTC Radiation Toxicity Assessments : RTOG

Random Allocation to:

Group A : planned for Radical Radiation therapy (n=46)

Group B: planned for Chemo-Radiation therapy (n=46)

Computer Randomization within the Group:

[RT alone arm] (n=23) Group A : v/s

[RT + h-R3 mAb] (n=23)

[RT + CT] (n=23) Group B : v/s

[RT+CT+ h-R3 mAb] (n=23) [BRM + Any RT] v/s [Any RT]

(n=46) (n=46)

Sample Size The hypothesis tested is one sided and the

null hypothesis - there is no difference in safety or efficacy by using h-R3 as an adjuvant with standard therapy (CRT/RT)

Applying the methodology of George W Snedecar and William G.Cochrane the sample size was estimated to be 17 patients per arm.

In this study, the numbers of patients considered are 23 patients in each arm. The sample size calculation was arrived at by assuming p <0.05 (5%) < 0.2 (20%) power =0.80 (80%) and confidence level of 95%.

Radiotherapy: Protocol

Same in all 4 arms TD : 6600cGy 200cGy/Fraction, 5fx/week 6 – 6.5 weeks 2D plan Clinac/Telecobalt

Radiation sensitizer: Chemotherapy protocol

Same in chemo-radiation arm CT drug : CDDP / Cisplatin Dose: 50mg IV / week For 6 weeks

Study Drug (Nimotuzumab): Protocol

h-R3 monoclonal antibody 200mg (4vials) in 250 ml

N.Saline, 60 min infusion Every week For 6 weeks * tissue EGFR status was not

required for infusion

Sequencing In chemoradiation arm

Weekly CDDP was given on the day of start of RT - 6hrs before RT

h-R3 mAb was given 3 days before RT Rationale: to differentiate & capture the

Adverse events of hR3 mAb / CDDP toxicities seperately

In RT alone + mAb arm : hR3mAb was started on the day of start of RT

Results Study initiation date: 17/09/2004 – July

2005 Number of subjects:

Screened: 113 Enrolled & Randomized : 92 Safety analysis : 92 Efficacy analysis : 76

Patient Characteristics

Efficacy – Response assessment

6mths after end of RTRT arm Chemo radiation arm

RT alone (n=19)

RT + Nimotuzumab (n=17)

CT +RT(n=20)

CT + RT + Nimotuzumab(n=20)

CR 31.5% (6) 70.59% (12)

70% (14) 90% (18)

ITT (n=23 in each arm) CR rate

26% 52% 60.8% 78%

CR + PR 37% (7) 76% (13) 70% (14) 100% (20)

5 year Overall Survival rate (ITT):

Median follow-up time - 65.7 months Study subjects observed for a minimum of

60 months

CRT+Nimotuzumab - 57% (95% CI, 34.49, 76.81)

CRT arm - 26%  (95% CI, 10.23, 48.41) (p = 0.03)

RT+Nimotuzumab - 39% (95% CI, 19.71, 61.46)

RT arm - 26% (95% CI, 10.23, 48.41)  (NS).

Median overall survival at 60mths

CRT+h-R3 arm - is yet to be reached CRT - 21.94 months

(p=0.007). The hazard ratio for death in the CRT+h-

R3 arm compared to CRT arm was 0.36 (95% CI, 0.16 to 0.79) with 64% reduction in the risk of death

RT+h-R3 - 14.36 months RT arm - 12.78 months

(p=0.451) hazard ratio 0.76 (95% CI, 0.37 to 1.56),

24% reduction in the risk of death in the Nimotuzumab+RT arm

Progression Free Survival

at 60 Months– ITT Population

Statistics CT+RT CT+RT+h-R3 RT RT+h-R3 p-Value

n 23 23 23 23

0.1093

Mean (SE) (in months) 22.53 (4.48) 40.30 (4.77) 16.53 (3.10) 22.50 (4.26)

Median (in months) 14.95 54.24 9.76 14.29

95% CI for Median (6.44, 25.82) (24.01 , NA) (5.91, 22.27) (4.70 , NA)

Note: p-Value calculated using log-rank test to compare survival distributions of two groups.

RT v/s RT+Nimo OS ITT - 60mo

CRT v/s CRT+Nimo OS ITT - 60mo

Any RT with Nimotuzumab v/s

non Nimotuzuamb Group .n=46 in each arm Median 5yr overall survival

Any RT + h-R3 arms - 49.38 months

Any RT non h-R3 arms - 16.36 months

(p=0.012, HR= 0.52 (95% CI, 0.30 to 0.89) 48% reduction in the risk of death in the

subjects in h-R3 compared to non h-R3 arms

Progression Free Survival at 60 Months

h-R3mAb v/s non h-R3mAb Group ITT Population

Statistics h-R3 Group Non h-R3 Group p-Value

N 46 46

0.0286

Mean (SE) (in months) 33.71 (3.68) 20.86 (3.04)

Median (in months) 44.97 12.78

95% CI for Median (11.99 , NA) (6.90 , 25.00)

Hazard Ratio (Relative to Non – nimotuzumab

Group)0.566

Note: p-Value calculated using log-rank test to compare survival distributions of two groups.

Discussion

Discussion: RT alone : 5yr Data

TMH n~1400: 5yr OS: Ph Ca– 8-25%, Oral 20-43%

Intergroup n=293, RT 70Gy: 5yr OS – 55%, DFS- 27.3%

GORTEC: n=226, 5yr OS – 15.8%, DFS-14.6%

Budach et al, n=384, AFRT, 5yr OS-23.7%, PFS-26.6%

Our Study : n=23, 5yr OS-26%, PFS-26.09%

Discussion RT+CT Intergroup: 5yrs: OS - 55%, DFS -

39% GORTEC: 5yr OS - 22.4%, DFS-

26.6% Budach et al, n=384, AFRT+CT

:5yr OS-28.6%, PFS-29.3%

Our Study: :5yr OS – 26%, PFS-26.09%

Discussion: RT + BRM Bonners et al, C225 +RT, Phase

III, 5yr -OS 46%, PFS- Our Study: Nimotuzumab+RT,

5yr - OS 39% , PFS- 39.13%

Discussion : Chemo Radiation + BRM

H.Quon Univ Pennsylvania ASRO 2009

Phase II Data : n=60 RT – 70Gy, 35# +

C 225 (Load-400mg/m2 + weekly 250mg/m2)

CT – CDDP – 75mg/m2

Dec 2004-Jul 2006 ,

33.8 mo, 2yr

OS – 66% Median OS – 34.2 mo

PFS – 44%

Our StudyASTRO 2009 Phase IIb, n=23 CRT+Nimotuzu

mab RT – 66Gy, 333#

+ weekly 200mg) CT – CDDP –

50mg Sept 2004-Ju2005

, n=23 30 mo 2 ½ yr

OS – 69.5%% Median OS – not reached

PFS – 56.5% 5yrs

OS - 57% PFS- 47.83%

Pfister et al (2006)

Phase II, n = 20 RT – 70Gy CB C225

400 mg m-2 LD + 250 mg m-2 weekly

Cisplatin 100 mg m-2 w1+4

3yrs OS (3y)

76% PFS (3y)

56%

Discussion: CRT+BRM: 5yrs Data

SCCHN – Comparison of Overall Survival

69.5% (hR3mAb)  2 ½ yrs

57% (hR3mAb)39% (74% Stg-IV)

26%(100% Stg-IV)

26%(87% Stg-IV)

OUR STUDY (hR3mAb Trial)60mths

37-68%23-34%Kyle E

46%36%60mths

76% (C225)(86% Stg-IV)

55% (74% Stage- IV)45%Bonners, C225 Phase III 25mths

37% RTOG 99-14 n=84(76 eval) III/IV 

C-Boost

31%Univ Vienna : VCHART41%24%Univ Vienna : 40%25%GORTEC 94-0138%20%FNLCC-GORTEC49%24%Wendt et al

* Biological Response Modifiers 

Chemoradiation

20%Gleich L L (n=86)RT+CT+BRMRT+BRM*RT+CTRT alone  Advanced Inoperable SCCHN

(87% Stg-IV)Pfister D (n=22)

5 yrs

Any RT+hR3 Group

Any RT

ITT: 5yr OS

ITT - 60mo n=23

Pfister et alN=23

RT+CT+BRMRT+CT+BRM

CRT+BRM

Grade - 3 ToxicityTOXICITYRTOG (%)

RT ALONE

RT+hR3 RT+CT RT+CT+hR3

Mucositis 59.26 55.56 29.41 55

RT Skin Reaction

6.67 - 5 -

Grade 1 -2RT Skin reaction

65.22 73.91 86.96 86.96

hR3 AEsRT+hR3 RT+CT+hR3

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

CAUSALTYCERTAIN 3 CERTAIN -possible 2 POSSIBLE 4probable : 1 PROBABLE 7

 Hypersensitivity 1st

doseacneform

reaction Rash

Bonner4 (after test dose) &

discontinued 9 (grade 3 - ) 4

   5% dose

reduction  

P fister  (1) 5%  (2)10%   

Our study

1~ 40minutes into infusion –

patient experienced aggravation of pre-

existing cardiac condition, hence infusion of mAb

was discontinued    

2 Patchy skin rash was seen during infusion of

hR3mAb & BRM infusion was continued

- no HAMA reaction)

Hypersensitivity

Conclusion This study demonstrates that hR3

mAb/Nimotuzumab is safe and efficaious for administration along with radiation therapy or with chemo-radiation therapy

Concurrent use of hR3 mAb as a 2nd Radiation Sensitizer along with Chemoradiation has enhanced long term loco-regional control & survival.

Even low dose CDDP seems to augment the efficacy of Nimotuzumab

The data generated adds to the currently available proof to the principle that adding biological agents (BRM) to physically targeted modality improves long-term therapeutic outcome in advanced inoperable SCCHN.

hR3 mAb is a newer humanized BRM, with lower skin and hypersensitivity toxicity and is found safe for usage along with Chemoradiation.

Further studies with more aggressive

Radiotherapy & Chemotherapy schedules are indicated.

Acknowledgments Special Thanks to

Director, KMIO Bangalore Dept of Radiation Oncology: HOD, All the

Doctors, PG Students, staff nurse, RT Technologist and other co-worker, supportive staff involved in the study

H&N Oncology Team, KMIO Dept of Medical Oncology, KMIO Dept of Surgical Oncology, KMIO

*** Due acknowledgement & credit to other Doctors and Teams members & supportive staff not officially registered but who contribute to the study

Acknowledgments BIOCON , Bangalore: (Clinical Trial Sponsor)

Mrs. Kiran Majumdar Shaw, Chairman BIOCON Mr.Sukrit Chimote, GM, Head Marketing Mr. Praveen Bose Mr. Amith Kumar

Cuba Patricia Tania combert Perez

CLINIGENE : Clinical Trial : CRO : Dr. A. S. Aravind (COO) Dr.Anand Eswaraiah Denzil Gerorge Mala srivatsava Dr. S.Kumaresan Sarbjit Kaur Manoj V.Y B.Geetalakshmi

Thank You