We presented these numbers last ASCO and what we are showing in this study is a response rate for the nimotuzumab + radiotherapy arm that is inline with the previous studies studies done with nimotuzumab and quite similar to those responses presented by cetuximab in combination with radiotherapy. The radiotherapy alone arm is in bottom range of the historical numbers and we believe that this is due to the radiohterapy protocol that had been used as well as the advanced population. Chemoradiotherapy arm has responses in line with the expected historical numbers and the evaluable population of chemoradiotherapy in association with nimtuzumab arm had a response rate of 100% that is also in line with the initial proof of concept phase II studies presented with cetuximab in association with chemoradiotherapy. Dr. Pfister and colaborators presented a 94% response rate in a similar population and Dr. Merlano and colleagues at ASCO 2007 presented 100% response rate.
The toxicity of the drug was unremarkable. Most of the cases were non-serious and we only observed the typical rash of anti-EGFR drugs grade 1 and 2 in only 2 patients. No hypomagnesimia were noted.
Long term results of Concurrent Nimotuzumab with chemoradiation Inoperable Head & Neck Cancer
Role of Nimotuzumab in Head & Neck Cancer Dr. Lokesh Viswanath M.D Principal Investigator : Clinical Trial hR3 SCCHN/IND Professor & Head of Unit II Department 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 CareNew 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 EGF o TGF α Overexpression + ↑mRNA of TGF α o Poor response to RT o Strong predictor of ↓ DFS Rationale 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) EGFR 2) ErbB2 3) ErbB3 4) 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 P-mAbLow EGFR Density (i.e. skin) C-mAb Monovalent Binding N-mAb (Affinity) Y High EGFR Density (i.e. tumor) Bivalent Binding (Avidity = ~Affinity2)
A Phase IIb, 4 Arm, Open-label, Randomized Trial,to assess the Safety and Efficacy of ConcurrentNimotuzumab (h-R3 Monoclonal Antibody) incombination with Chemo-Radiation therapy or withRadiotherapy alone in patients with advancedinoperable (stage III or IVA) Head and NeckCancer ,
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 OncologyDept of Radiation OncologyDr. T. Naveen M.D 2. Shirdi Sai Baba Cancer Hospital,Dr. Bindu Joseph M.D Manipal.Dr. B. Ravikiran M.DDr. K.P.R.Pramod M.D 3. KMC Hospital, MangaloreDr. Siddanna Pallade M.DDr. C.R. Tanvir Pasha M.DDr. Vijay Bhaskar M.DDr. G. Bhanumathy M.DDr. Kumaraswamy M.DDept of Head and Neck OncologyDr. Ashok M Shenoy M.S Co-PIDr.NanjundappaM.S Trial Design by:Dept of Medical Oncology Dr. B.K.M. ReddyDr. K. Govind Babu DM Co-PI Dr. V. LokeshDr. P.P.Bapsy DM Dr. Ashok M. ShenoyDr. Lokanath DM Dr. M. VijaykumarStudy Co-OrdinatorDr.Tazeen Aamena MBBSDr.Sathya M . M.D
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
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: ProtocolSame 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
Efficacy – Response assessment 6mths after end of RT RT arm Chemo radiation arm RT alone RT + CT +RT CT + RT + (n=19) Nimotuzumab (n=20) Nimotuzumab (n=17) (n=20)CR 31.5% (6) 70.59% (12) 70% (14) 90% (18)ITT (n=23 in 26% 52% 60.8% 78%each arm)CR rateCR + 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 23Mean (SE) (in months) 22.53 (4.48) 40.30 (4.77) 16.53 (3.10) 22.50 (4.26) 0.1093 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.
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 Mean (SE) (in months) 33.71 (3.68) 20.86 (3.04) Median (in months) 44.97 12.78 0.0286 95% CI for Median (11.99 , NA) (6.90 , 25.00)Hazard Ratio (Relative to Non – nimotuzumab 0.566 Group)Note: p-Value calculated using log-rank test to compare survival distributions of two groups.
Hypersensitivity Hypersensitivity 1st acneform dose reaction Rash 4 (after test dose) &Bonner discontinued 9 (grade 3 - ) 4 5% dose reductionP fister (1) 5% (2)10% 1 ~ 40minutes into infusion – patient experienced 2 Patchy skin rash wasOur aggravation of pre-existing seen during infusion of cardiac condition, hence hR3mAb & BRM study infusion of mAb was infusion was continued discontinued - no HAMA reaction)
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