A phase IIb 4-arm open-label randomized study to assess the safety and efficacy of h-R3 monoclonal antibody against EGFR in combination with chemoradiation therapy or radiation therapy in patients with advanced (stage III or IVA) inoperable head and neck cancer

Abstract

6041 Background: Patients (pt) with advanced inoperable squamous cell carcinoma of the head and neck (SCCHN) have poor radiotherapy alone (RT) outcome. EGFR is over-expressed in >90% SCCHN. h-R3mAb (BIOMAb/nimotuzumab/TheraCIM) is a humanized monoclonal antibody, a validated oncotherapeutic-targeting EGFR. Objective: To investigate the safety and efficacy of concurrent h-R3mAb in combination with chemoradiotherapy of SCCHN. Methods: September 2004–2005, pt 18–70 yrs, SCCHN stageIII-IVA, 113 screened, 92 enrolled and randomly asssigned to, Group A: radical radiotherapy (pt) and Group B: chemoradiotherapy (pt). Randomization within Group A: [RT]v/s[RT+h-R3mAb] and within Group B: [RT+CT]v/s[RT+CT+ h-R3mAb] (n = 23 in each arm). Protocol: Radiotherapy: TD: 66 Gy,2Gy/Fr,5Fr/w,6.5wks. Radiation sensitizer (chemotherapy): CDDP-50mg/wk x 6wks. Study Drug (h-R3mAb): 200 mg/wk I.V.60min x 6weeks. Results: Evaluable (n = 76) in Group A-36 and Group B-40. F/u Analysis at 30 months after end of RT. Survival rate ITT: Group B: CT+RT+hR3- 69.5% v/s CT+RT-21.7% (p - 0.0011), Group A: RT alone - 21.7% v/s RT+ hR3–39.1% (ns). Progression-free survival: RT alone - 3(13.04 %) v/s RT+hR3mAb-8 (34.78 %), RT+CT-5 (21.74 %) v/s RT+CT+hR3mAb-13 (56.52%). Median overall survival (OS): CT+RT+hR3 - NR* v/s CT+RT- 21.96 months (hazard ratio [HR]-0.337, p - 0.0018) and RT alone - 25.02 v/s RT+hR3 - NR*(HR-0.678, p - 0.39). Disease-free survival: CT+RT+hR3- NR*v/sCT+RT-21.30 mths (HR-0.344, p - 0.0052) and RT alone-25.02 v/s RT+hR3- NA* (HR-0.599, p - 0.32). (NR*- median OS is yet to be reached). Safety: few grade - 1/2AE, no HAMA observed. OS per protocol - adding h-R3mAb to chemoradiation resulted in a reduction in risk of death (rrd) by 85% (HR 0.15, p - 0.0006) and to RT a 36 % rrd (HR0.64, p - 0.33). Conclusions: Concurrent use of h-R3mAb with RT or RT+CT is safe and efficacious. It enhances radiation and chemotherapy responses. Concurrent use of h-R3mAb with chemoradiotherapy enhances long-term loco-regional control and survival. Adding biological agents to physically targeted modality improves long-term therapeutic outcome of SCCHN. No significant financial relationships to disclose.

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

“…A retrospective study of 835 patients with advanced carcinomas of diverse tissue types suggested that nimotuzumab was well tolerated in combination with CRT, without potentiating the toxicities of concurrent therapy [42]. Randomized phase II data demonstrated that nimotuzumab plus CRT improved median OS compared with RT alone [25,28]. Similarly, sequential lapatinib and RT yielded improvements in ORR compared with placebo/ RT (70% vs. 53%) in the definitive setting [26].…”

“…Analyses of outcomes among patients with HPV-and non-HPV-associated disease The Oncologist ® treated with RT/platinum/EGFRI have been mixed [17,27]. Of interest, the addition of nimotuzumab to conventional RT/ cisplatin appears to improve the CR rate (96% vs. 72%) [29] and 30-month OS (70% vs. 22%) [25] but does not appear to potentiate the toxicity of CRT compared with RT/cisplatin alone [25,29,32,35,38].…”