EGFR signaling cascade inhibition, some of these agents are able to induce T cell activation .... FcγRIIIa (CD16) on NK cells and the Fc portion of the MAb.
Author’s Accepted Manuscript
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Nimotuzumab: beyond the EGFR signaling cascade inhibition Zaima Mazorra, Lisset Chao, Anabel Lavastida, Belinda Sanchez, Mayra Ramos, Normando Iznaga, Tania Crombet www.elsevier.com/locate/bios
PII: DOI: Reference:
S0093-7754(18)30041-1 https://doi.org/10.1053/j.seminoncol.2018.04.008 YSONC52055
To appear in: Seminars in Oncology Cite this article as: Zaima Mazorra, Lisset Chao, Anabel Lavastida, Belinda Sanchez, Mayra Ramos, Normando Iznaga and Tania Crombet, Nimotuzumab: beyond the EGFR signaling cascade inhibition, Seminars in Oncology,doi:10.1053/j.seminoncol.2018.04.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nimotuzumab: beyond the EGFR signaling cascade inhibition
Authors Zaima Mazorra1*, Lisset Chao2, Anabel Lavastida1, Belinda Sanchez2, Mayra Ramos1, Normando Iznaga3 and Tania Crombet1 *Corresponding author 1
Clinical Direction, Center of Molecular Immunology, Havana, Cuba
2
Tumor Biology Direction, Center of Molecular Immunology, Havana, Cuba
3
Biocubafarma, Havana, Cuba
Key words: EGFR, monoclonal antibodies, HLA class I molecules, antibody-dependent cell mediated cytotoxicity (ADCC), natural killer cells, T cells, Abstract One of the most known oncogenes is the epidermal growth factor receptor (EGFR) family. It activates multiple signaling cascades which promote carcinogenesis and immune evasion. Therefore, these molecules have been extensively targeted in cancer immunotherapy. Beyond EGFR signaling cascade inhibition, some of these agents are able to induce T cell activation transforming a passive therapy into a vaccine-like effect. Nimotuzumab is an IgG1 humanized MAb directed against the extracellular domain of the EGFR blocking the binding to its ligands. It possesses unique pharmacodynamics properties, which allow treating patients for long–term period and with very low toxicity. Based on its clinical effect, nimotuzumab has been approved in Cuba and abroad for the treatment of different epithelial tumors. Recently, new potential mechanisms of action of nimotuzumab involving the activation of the innate and adaptive immune response have been reported. This review summarizes the main properties of nimotuzumab in comparison with others EGFR specific monoclonal antibodies highlighting its capacity to activate an effective immune response. In addition, differential clinical effect of this antibody and ongoing clinical trials to deeply characterize the biomarkers of clinical benefit are shown.
Introduction The epidermal growth factor receptor (EGFR) is one four structurally related receptor tyrosine kinases that comprise the ErbB family [1]. Specific ligands bind to this receptor causing its dimerization, which triggers a signaling cascade. EGFR is frequently overexpressed in tumor cells where it is felt to promote cell survival, proliferation, tissue invasion, and metastasis formation while inhibiting apoptosis [2]. In addition, overactivation of EGFR signaling contributes to downregulation of tumor cell immunogenicity through a decrease of HLA-I dependent antigen presentation, the upregulation of suppressive signals mediated by programmed death ligand 1 (PD-L1) and inhibitory cytokines or by reprograming metabolic pathways after aerobic glycolysis upregulation [3]. An association between EGFR overexpression and decreased patient survival has been demonstrated for different tumors [4-6]. These findings render EGFR an appealing target for tumor antigen (TA)-specific monoclonal antibody (MAb)-based immunotherapy. Two MAbs, cetuximab and panitumumab have received FDA and EMA approval for the treatment of some epithelial tumors [7, 8]. Nimotuzumab is an anti-EGFR MAb with unique and “very convenient” pharmacodynamic properties. It is a humanized IgG1 isotype MAb developed at the Center of Molecular Immunology in Cuba. It binds to the extracellular domain of EGFR, inhibiting tyrosine kinase activation [9]. Different from panitumumab and cetuximab, nimotuzumab has intermediate affinity against the EGFR [10]. This lower affinity for the target, results in preferential binding to tumor cells that overexpress the EGFR, sparing normal cells with lower levels of the EGFR target. In preclinical studies, nimotuzumab was demonstrated to have potent antitumor activity, both in vitro and in vivo, by exerting an anti-proliferative, anti-angiogenic and pro-apoptotic effects [11]. Finally, nimotuzumab has low immunogenicity, and this may constitute a potential advantage for long-term use. Since 1998, nimotuzumab has been extensively tested in many clinical trials in Cuba and abroad, demonstrating clinical efficacy in various epithelial tumors [12, 13]. Nimotuzumab is approved in Cuba for the treatment of childhood and adult glioma, advanced esophageal cancer and squamous cell carcinoma of the head and neck (SCCHN) in combination with chemoradiotherapy or radiotherapy alone. Nimotuzumab is also recommended for the treatment of unresectable pancreatic cancer in combination with gemcitabine [14]. The antibody is registered in 28 additional countries for treatment of some of the above-mentioned cancer indications. Recent data highlight the finding that TA-targeted MAbs not only block tumor cell signaling but also induce adaptive antitumor immunity [15], a property referred to as vaccine-like effect of monoclonal antibodies. The increased survival and long-term duration of response
seen in many patients after short treatment with nimotuzumab [13, 16], suggest that blocking EGFR signaling and inhibiting tumor cell proliferation might not be the only properties underlying the efficacy of this antibody. Recently, new potential mechanisms of action of nimotuzumab involving the activation of the innate and adaptive immune response have been reported [17]. These results pave the way to perform further clinical trials for exploring the immune biomarkers as surrogate of clinical benefit. This review summarizes the main characteristics of nimotuzumab and compares it with others anti-EGFR MAbs while highlighting its immunomodulatory properties.
Nimotuzumab and EGFR expression Predictive biomarkers of clinical efficacy should allow one to properly select the patient population mostly likely to benefit from a given therapy. In this sense, several pieces of evidence point toward the association between EGFR overexpression in tumor cells and clinical benefit of nimotuzumab in treated patients. In a phase II clinical trial performed in patients with SCCHN deemed unfit to receive chemo-radiotherapy, the efficacy of nimotuzumab combined with radiotherapy was compared with radiotherapy plus placebo. In a subset of patients EGFR expression was evaluated by immunohistochemistry. Patients with tumors expressing high levels of EGFR who received nimotuzumab had a significant improvement in median survival time (MST) as compared with patients in the placebo group (16,5 vs 7.2 months, p =0.0038), with no significant advantage seen for patients whose tumors were EGFR-negative [18]. Similar findings were observed in a phase IIB clinical trial in treatment-naïve patients with SCCHN that received standard therapy with or without nimotuzumab. Expression of EGFR had a significant correlation with survival in patients treated with nimotuzumab and chemoradiation (p=0.02) [19]. Data confirming expression of EGFR as a predictor of nimotuzumab efficacy was also obtained in patients with unresectable squamous cell carcinoma of the esophagus and gastric cancer. Patients with esophageal cancer received nimotuzumab in combination with radiation plus chemotherapy or either radiation or chemotherapy alone [20]. In the per protocol analysis, the objective response rate was 47.8% for the nimotuzumab cohort and 15.4% for the control group (chi square p= 0.014). Disease control rate (DCR) was 60.9% for the nimotuzumab cohort and 26.9% for the control group (Chi square p=0.017). For patients treated with nimotuzumab whose tumors had high EGFR expression, the objective response was 60% and DCR was 80%, which compares very favorably with the response and disease control rate seen in the per protocol population. Similar results were found in gastric cancer. In a phase II clinical trial [21] patients whose tumors were refractory to 5FU-based therapy, no significant PFS and overall survival
benefit was found in the intent-to-treat population. As in the previous studies, large trends toward survival benefit were observed for both PFS and overall survival in subjects with medium and high baseline EGFR expression. Finally, a randomized phase II trial comparing the efficacy and safety of nimotuzumab plus irinotecan versus irinotecan alone in patients with advanced gastric cancer also found similar results. Although there was no superiority of nimotuzumab plus irinotecan over irinotecan alone in terms of PFS, nimotuzumab treatment showed a potential benefit in the group of patients with EGFR 2+/3+ tumors in terms of response rate, PFS and OS [22]. FISH positive patients also showed a trend towards better PFS and survival. Additionally, in an uncontrolled pilot clinical study, twenty-eight advanced NSCLC patients resistant to first line chemotherapy were treated with nimotuzumab combined with gemcitabine and cisplatin as second line. EGFR gene copy number was studied by FISH and was positive in 80% of patients. Interesting, those patients with EGFR amplification showed survival and time to progression (TTP) benefit after nimotuzumab and chemotherapy [23]. Finally, in a study performed in Germany was found that GBM patients with EGFR amplification have a tendency to live longer if treated with nimotuzumab/RT and temozolomide (21.1 vs 19.9 months) [24]. Although there are more evidences towards immunohistochemistry significance over gene status evaluation, measurements of both biomarkers would help to define proper predictive biomarkers for nimotuzumab efficacy. In contrast with these results, tumor overexpression of EGFR does not seem to be a predictive biomarker of efficacy in patients treated with cetuximab or panitumumab. In a large clinical trial that enrolled patients with SCCHN, there was no association between EGFR status as determined by immunohistochemistry and cetuximab benefit [25]. In addition, in SCCHN, the EGFR gene copy number did not correlate with cetuximab response [26, 27]. In metastatic colorectal cancer, neither EGFR expression nor EGFR amplification were associated with efficacy of MAbs targeting the EGFR [28]. In patients with SCCHN, the mutational profiles of tumors have not been clearly associated with the efficacy of cetuximab or panitumumab [29]. However in metastatic colorectal cancer (CRC) numerous studies have confirmed that KRAS and NRAS mutations in exons 2, 3 and 4 found in approximately 50% of mCRCs are predictive of tumor resistance to cetuximab and panitumumab [11, 30]. This has led regulatory authorities to restrict the use of cetuximab and panitumumab to patients whose tumors do not harbor mutations in KRAS or NRAS, usually referred to as KRAS-WT tumors. However, a proportion of patients with KRAS-WT tumors do not respond to these anti-EGFR therapies, suggesting other mutations/alterations likely impact the activity of cetuximab and panitumumab. For example, the PI3K pathway is modulated in part
by KRAS activation during EGFR signaling and alterations in this pathway, such as PI3KCA mutations and loss of PTEN expression/activity, may lead to lack of response to EGFR-targeted MAbs [31, 32]. Furthermore, other studies have suggested that overexpression of EGFR ligands such as amphiregulin and epiregulin may predict response to cetuximab [33, 34]. However, these potential biomarkers need to be evaluated/validated in properly designed studies to assess their potential usefulness in clinical practice. Nimotuzumab has not been extensively evaluated in CRC patients, where KRAS mutations are well characterized as predictors of resistance. However, a recent Phase III trial in patients with unresectable pancreatic cancer showed that patients with wild type KRAS had the largest benefit. A total of 192 patients were randomly assigned to receive gemcitabine plus nimotuzumab or a placebo. The median overall survival for the experimental group was 8.6 months vs. 6.0 months for gemcitabine/placebo. Notably, patients whose tumors harbored a wild type KRAS had a significant longer survival if they received nimotuzumab as compared to the placebo (11.6 vs. 5.6 months) [35]. The survival benefit observed in patients with tumors harboring a wild type KRAS treated with nimotuzumab compares very favorably with the FOLFIRINOX regimen [36], only appropriate for younger, fit patients or with the gemcitabineabraxane regimen [37]. The fact that EGFR expression is associated with the clinical efficacy of nimotuzumab may be explained by its intermediate affinity for the receptor. Previous publications reported a KD of the order of 10-8 M [10] for the nimotuzumab Fab fragment, a 10-fold lower affinity when compared with the cetuximab Fab fragment [38]. Unlike cetuximab, nimotuzumab requires bivalent binding to maintain a stable association with the EGFR on the cell surface. Consequently, nimotuzumab preferentially binds EGFR on cells that have a medium to high surface density of EGFR molecules that allow for bivalent binding [39]. By comparison in cells with a low density of surface EGFR, nimotuzumab binding is more likely to be monovalent and transient, unlike cetuximab which keeps interacting strongly with the receptors. This intermediate affinity of nimotuzumab for the EGFR translates into reduced binding of normal cells that have lower EGFR density and may explain its low toxicity profile. This property confers a very important advantage for nimotuzumab over other anti-EGFR MAbs including cetuximab and panitumumab whose high toxicity is well-documented. Skin toxicity, often severe, hypomagnesemia and paronychia have been reported in patients treated with cetuximab and panitumumab [40]. Although paradigms for managing these toxicities have been established, treatment compliance and most importantly quality of life can be greatly affected. By comparison neither hypomagnesemia nor severe skin toxicity have been reported for nimotuzumab [12, 41].
This absence of serious adverse events has permitted the use of nimotuzumab continuously for prolonged periods of time lasting several months, or even years in many patients. Beyond the EGFR signaling cascade inhibition ADCC activity induces NK-DC crosstalk Nimotuzumab is able to disrupt the interaction of the EGFR with its ligands. The binding of this MAb with the extracellular domain of its receptor induces endocytosis and degradation of the EGFR [42]. However, the increased survival and long-term duration of response seen in many patients after a short treatment period with nimotuzumab [13, 16], suggested that blocking EGFR signaling and the resultant inhibition of tumor cell proliferation were not the only mechanisms of action underlying the efficacy of this antibody. Previous publications had provided evidenced that triggering an antibody dependent cellular cytotoxicity (ADCC) mediated by MAb-activated NK cells, had an important role in the therapeutic activity of MAbs targeting the EGFR [43]. This cytotoxic activity contributes to the vaccine-like effect of MAbs, by which these molecules induce tumor specific T cells that can in turn contribute to tumor elimination. Although cetuximab and panitumumab inhibit EGFR signaling to similar degrees, the effect on the immune system appear to be different. On one hand, cetuximab is an IgG1 chimeric MAb approved for advanced patients with SCCHN or colon carcinoma harboring wild type KRAS. Cetuximab is able to induce ADCC in EGFR expressing tumor cell lines by the interaction of FcγRIIIa (CD16) on NK cells and the Fc portion of the MAb. Published results have correlated FcγRIIIa polymorphisms with clinical benefit thus far only in patients with colon cancer [44, 45]. Furthermore, it has been reported that cetuximab can effectively trigger neutrophil-mediated ADCC against SCCHN cells. Moreover, in vitro experiments correlated this cytotoxicity with the FcγRIIa and FcγRIIIa polymorphisms of neutrophils [46]. Cetuximab-induced ADCC produces NK cell activation, DC maturation and HLA-I antigen presentation. As consequence of the NKDC cross-talk, clonal expansion of EGFR-specific T cells occurs [47]. On the other hand, panitumumab, a humanized IgG2 MAb, is approved for the treatment of colon cancer harboring wild-type KRAS, with published studies in HNSCC shown less clinical activity with panitumumab compared to cetuximab [48]. As previously reported, panitumumab with an IgG2 Fc fragment is not able to induce NK-dependent cytotoxicity with one study reporting only a modest increase in DC maturation in panitumumab-activated NK cells. Finally, while cetuximab increased EGFRpositive CTL in SCCHN cancer patients, this has not been reported in patients treated with panitumumab [47].
Like cetuximab, nimotuzumab is an IgG1 immunoglobulin with the potential to induce ADCC and has been shown to induce NK- dependent ADCC on EGFR positive tumors cells at levels comparable to cetuximab [17]. Moreover, a direct correlation between EGFR expression and ADCC activity has been reported using nimotuzumab in vitro [49]. CD16 down-modulation, reflecting the internalization of this molecule after Fc–FcɣR binding, confirms the NK-mediated lytic activity. As expected, CD16 downmodulation after ADCC has been detected with both cetuximab and nimotuzumab, while no change in CD16 expression has been observed with panitumumab. Besides NK-cytotoxicity, effective interaction between the Fc portion of antibodies and FcR, induces IFN secretion and the expression of co-stimulatory signals such as the CD137 molecule. CD137, also known as 4-1BB, is a member of the TNF receptors and is induced upon activation of NK and T cells. Its ligand, CD137L, is expressed on antigen presenting cells (APC). Endogenous ligation enhances ADCC by NK cells, CD28-dependent activation of the T cell receptor, and expansion/memory differentiation of CD8+ T cells while inhibiting the immunosuppressive function of CD4+ Tregs [50]. Previous publications, showed that cetuximab upregulated CD137 expression on human NK cells after in vitro incubation with EGFR positive tumor cells [51]. Moreover, after the administration of cetuximab to patients with head and neck cancers in the neoadjuvant setting, intratumoral NK cells upregulate CD137 levels [52]. In the case of nimotuzumab, upregulation of CD137 was induced in vitro on NK cells but at lower levels compared with cetuximab [17]. In vivo upregulation of CD137 remains to be measured in future clinical trials using nimotuzumab. Besides the activation of costimulatory molecules on NK cells, both cetuximab and nimotuzumab, increased the expression of inhibitory signals such as TIM-3. In the case of nimotuzumab this upregulation was significantly lower as compared with cetuximab. Although controversial results regarding the role of TIM-3 on NK cells have been published, it seems that TIM-3 play a suppressive role in cancer patients. TIM-3 is upregulated on NK cells from patients with a diagnosis of cancer and with a poor prognosis [53]. In the case of patients with a diagnosis of melanoma, increased upregulation of TIM-3 on NK cells with an exhausted phenotype has been reported [54]. Based on our findings, we can hypothesize that cetuximabmediated ADCC activates NK cells and increases the expression of costimulatory molecules and IFN secretion. At the same time, inhibitory molecules may be upregulated inducing NK cell exhaustion. In contrast, ADCC-induced by nimotuzumab may generate less NK cell activation, but also less exhaustion. Further experiments should be performed to confirm this hypothesis.
Cetuximab administration induces a cross-talk between NK cells and DC and this, generates DC-1 polarization and maturation dependent on IFN secretion by NK cells. These events allow for cross-presentation of tumor antigens to cytotoxic CD8+ T cells [47]. Similar results were found for nimotuzumab. Despite lower levels of IFN after nimotuzumab NK cells are activated, and autologous DC achieve full maturity as indicated by the concomitant and similar upregulation of costimulatory molecules. Additionally, comparable levels of IL-12 were detected in cell culture supernatants after incubation with nimotuzumab or cetuximab. Lastly, EGFR-specific T cells were detected in vitro, after culturing EGFR+ tumor cells in the presence of NK and dendritic cells, together with cetuximab or nimotuzumab. As expected, panitumumab was not able to induce neither NK-DC cell crosstalk nor TA specific T cell generation [17].
¨In vivo¨ T cell induction Induction of specific and effective CD8+T cells is very important in the immune response against cancer. Although detection of TA specific T cells is not common in patients treated with MAbs, EGFR-specific T cells were recently identified in patients with SCCHN treated with cetuximab alone or in combination with chemotherapy as compared to cetuximab-naïve patients. In contrast, panitumumab is not able to induce a detectable T cell response in these patients, an observation that might explain its inferior clinical effectiveness [47]. In the case of nimotuzumab, there were higher EGFR-specific cytotoxic CD8+T cells in patients with SCCHN treated at least for a year as compared with patients who did not receive nimotuzumab [17]. Although only EGFR specificity was evaluated, additonal TA specific T cells could be induced as a consequence of Ag cross-presentation by DC. In vitro experiments using cetuximab have shown non-EGFR (MAGE-3) cross-presentation to MAGE-specific cytotoxic T lymphocytes (CTLs) [47]. However, detection of these T cells in patients treated with either cetuximab or nimotuzumab remains to be studied. The main differences amongst these MAbs regarding their immunomodulatory properties and safety profile are summarized in Table 1 and 2. A prerequisite for CTL activation is human leukocyte antigen (HLA) class I dependent antigen presentation (known as signal 1) [55]. The exact mechanisms that regulate the downmodulation of these molecules in tumors are not completely understood. However, recent studies have shown that overexpression of EGFR is not only connected to oncogenic transformation, but is also involved in repression of HLA molecules as well as some of the components of the antigen presentation machinery (APM) in tumor cells [56]. For instance, overexpression of EGFR in SCCHN upregulates the level of phosphatase SHP2, which in turn reduces activation of the STAT1 transcription factor. STAT1 mediates expression of HLA class I
molecules and the components of the APM. In vitro, Inhibition of EGFR signaling by cetuximab increases the expression of HLA class I and the APM components with concomitant downregulation of SHP2 [57]. Similar to the effect obtained with cetuximab, treatment of tumor cell lines with nimotuzumab increases the expression of HLA class I molecules and the components of the APM [58]. Furthermore, a differential expression in HLA class I alleles is also seen with nimotuzumab, similar to that observed in cetuximab-treated cells. At the transcriptional level, nimotuzumab increases the expression of mRNA encoding HLA-A, HLA-B, HLA-C and β2-microglobulin (β2-m) and also induces a significant increase in the mRNA levels of components of the APM as LMP subunits, TAPs and tapasin [58]. In the case of cetuximab, the increase of HLA class I expression is linked to the class II transactivator protein (CIITA) [59]. CIITA has also been described as an IFN-responsive protein that regulates HLA class I expression [60]. For nimotuzumab further experiments are needed to study all the molecules involved in the HLA-I molecule re-expression mechanism. Upregulation of HLA class I molecules and the components of the APM adds another mechanism that helps explains how nimotuzumab can modulate the antitumor immune response. Results with cetuximab in the neoadjuvant setting demonstrated that therapy with this MAb enhances the HLA class I expression in patients who achieved a response as compared to those who did not [61]. Additional work is needed to measure changes in HLA class I expression in tumor biopsies from nimotuzumab-treated patients to study its impact on patient survival. Despite the increased frequency of TA-specific CD8+T cells in patients with SCCHN treated with cetuximab and the ability of the agent to reverse the downmodulation of HLA-I found in EGFR+ tumors, this CTL activity is insufficient to inhibit tumor growth. One possible explanation for this shortcoming is that in patients with a diagnosis of SCCHN, cetuximab induces the expansion of circulating and intratumoral Tregs [62], that are known to have strong suppressive function through IL-10, TGFβ and adenosine produced by ecto-enzymes CD39 and CD73 [63]. In the tumor microenvironment, Tregs are thought to arise from chronic exposure of T cells to self-antigens like the EGFR. In the case of cetuximab, Treg expansion is induced partially by DC maturation and T cell receptor stimulation in the presence of TGFβ. Notably, these cells were able to suppress NK-cell mediated ADCC contributing to immunosuppression in the tumor cell network. In patients treated with cetuximab, higher levels of Tregs correlate with a worse prognosis [62]. In contrast, in patients with SCCHN treated with nimotuzumab monotherapy, levels of circulating Tregs was lower when compared to the Treg levels at the end of combined chemoradiation plus nimotuzumab. Studies have shown that a combination of
cisplatin-based chemotherapy with radiation decreases the frequency of CD4+T cells but increases the percentage of highly suppressive CD4+CD39+ Tregs and that the latter remain elevated for a prolonged time [64]. Based on these findings, the high frequency of Tregs found after the combined treatment can be explained by the resistance of Tregs to chemoradiation. Interestingly, although it did not achieve statistical significance, the levels of circulating Treg was also decreased at the end of nimotuzumab maintenance period. Although these results suggests long-term use of nimotuzumab doesn’t lead to Treg expansion, at least in the circulation, the extent of infiltration of Tregs in tumors and the correlation with clinical outcome should be addressed in future clinical trials with nimotuzumab. In summary, the anti-EGFR MAb nimotuzumab induces ADCC-mediated tumor cell killing and activates adaptive immunity through TA specific T cells. At the same time, upregulation of HLA-I expression by nimotuzumab allows induced T cells to recognize and kill EGFR+ tumor cells, avoiding one of immunoescape mechanism of the tumor. Based on the findings described here, Figure 1 shows how nimotuzumab exerts its "vaccinal effect". Studies of immune-infiltration in tumors and its correlation with the clinical outcome of treated patients will need to be addressed in future clinical trials.
Differential effect between nimotuzumab and other anti-EGFR MAbs in the clinical scenario. In the clinical setting, nimotuzumab has been efficacious in the treatment of advanced head and neck cancer, in combination with radiotherapy or chemo-radiotherapy. A two-arm, randomized, placebo-controlled, multi-center Phase II/III trial evaluated the activity of nimotuzumab in patients with tumors of the head and neck, unfit to receive combined chemo and radiotherapy. The primary objective was assessment of antitumor response. Secondary objectives included safety, immunogenicity and quality of life. Patients were randomized to receive six weekly doses of placebo or nimotuzumab in combination with radiotherapy (RT). A total of 106 patients with histologically documented advanced (unresectable) SCCHN were enrolled. Amongst patients randomized to receive nimotuzumab plus irradiation 59.5% achieved a complete response while only 34.2% of the subjects treated with irradiation plus a placebo were classified as complete responders [18]. A second multicenter, open label, randomized study was conducted in India, where nimotuzumab was used in patients with advanced SCCHN, in combination with chemotherapy and radiotherapy or radiotherapy alone. Patients were randomized into one of four cohorts, comprised of nimotuzumab plus radiotherapy (RT), radiotherapy alone, nimotuzumab plus chemoradiotherapy (CRT) or chemoradiotherapy alone.
At the end of 6 months of treatment, a significantly better response rate was observed in both nimotuzumab treatment arms compared to the respective control groups. Response rate was 76% for patients treated with nimotuzumab/radiotherapy as compared to 37% in the RT arm. The difference was statistically significant between the groups (p=0.023). In the nimotuzumab plus CRT arm, 100% achieved a response as compared to 70% in the CRT alone arm (p
