4. Discussion
tumor, neutropenia, neuropathy, toxicity, thrombocytopenia, rash, pancreatic cancer, unresectable pancreatic cancer, tumors, pancreatic adenocarcinoma
ADVERSE REACTIONS, TUMOR, NEUTROPENIA, FOLLICULITIS, METASTATIC PANCREATIC CANCER, ADVERSE EVENTS, NEUROPATHY, THROMBOCYTOPENIA, DISEASE, METASTATIC DISEASE, PANCREATIC CANCER, INFILTRATING, TUMORS, PANCREATIC ADENOCARCINOMA, INFILTRATED
In the present study, with a mean follow-up time of 11.4 months, the very low toxicity profile of nimotuzumab was confirmed when administered in combination with gemcitabine in conditions of real-world practice.The fundamental problem in terms of toxicity of the therapies that target the EGFR is the appearance of severe rash, infiltrated lymphocytes, folliculitis, and other adverse reactions that can cause in kidney cells and gastrointestinal mucosa. These reactions are caused by the interaction of these therapies with receptors found in other tissues of the body than the tumor [
In the phase III randomized clinical trial comparing the anti-EGFR monoclonal antibody cetuximab+gemcitabine versus gemcitabine as monotherapy, toxicity was significant to detriment of the monoclonal antibody. There was no significant difference between the groups when assessing overall survival, and the combination was less effective than gemcitabine alone; therefore, its use was not approved for the treatment of these patients [Ko et al. studied patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma that were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/mThe anti-EGFR tyrosine kinase inhibitor erlotinib was the first to show a slight increase in survival in combination with gemcitabine in the Phase III NCIC CTG PA.3 clinical trial that included 569 patients with advanced or metastatic pancreatic cancer, randomized to receive erlotinib+gemcitabine, or gemcitabine alone. A statistically significant benefit was obtained in favor of patients treated with the combination: in terms of global OS (HR, 0.82; The OSAG Phase III study that compared the combination of nimotuzumab and gemcitabine versus gemcitabine in patients with locally advanced or metastatic pancreatic cancer obtained a statistically significant clinical improvement in global OS and PFS with the combination of nimotuzumab and gemcitabine. In this study, data from 186 patients were analyzed: 93 in the nimotuzumab+gemcitabine group and 93 in the placebo+gemcitabine group. In patients treated with nimotuzumab, a 2-month advantage in overall survival was achieved, with a median overall survival of 8.6 months; survival rates at 12 and 18 months of 34% and 17%, respectively, in this group; and a statistically significant difference when compared with the control group (In another phase III clinical trial, a total of 92 Chinese patients were randomly assigned to the nimotuzumab-gemcitabine (The safety and survival results for the nimotuzumab+gemcitabine combination also reflected in the abovementioned German and Chinese studies could be considered together with other clinical-demographic variables such as ECOG and age when thinking about a personalized therapy in a real-world condition.Lima et al. evaluated the response to treatment and overall survival of 118 patients with advanced pancreatic adenocarcinoma in an observational and retrospective Cuban study. Patients were treated with nimotuzumab but combined with a GEMOX (gemcitabine+oxaliplatin) chemotherapy regimen. The median survival was 13.8 months (95% CI: 11.7-15.8). The second line of chemotherapy was administered to 42 patients, obtaining a median survival of 17.4 months (95% CI: 13.5-21.4). 51 grade 3-4 adverse events were reported, presented in 27 patients (22.9%). The most frequent adverse events were neuropathy (14.4%), neutropenia (10.2%), and thrombocytopenia (9.3%) [The combination of leucovorin, gemcitabine, cisplatin, and 5FU (LGCF) combined with bevacizumab and cetuximab versus LGCF was compared in a phase III study in patients with locally advanced or metastatic pancreatic adenocarcinoma. The benefit was achieved to the detriment of immunotherapy, in mPFS (3.0 versus 9.0 months) and mOS (7.0 vs. 10.0 months) [The phase III clinical trial of Imaoka et al. compared the combination of gemcitabine and S-1 (tegafur/gimeracil/oteracil), versus S-1 alone, and in a third group, gemcitabine alone, in patients older than 70 years with unresectable pancreatic cancer. It was found that there was no statistically significant benefit for the combination, superior to that of gemcitabine monotherapy. Median OS values of 10.2 months, 8.0 months, and 8.5 months, respectively, were reached [When analyzing specifically survival results in locally advanced disease, the mOS of 16.4 months and the 1-year survival rate (72.2%) obtained in our study in this patients were higher than the value obtained by the patients in the Phase III OSAG study with the same disease status and treatment [In a 2016 randomized study that again compared gemcitabine alone versus gemcitabine and erlotinib, but only in patients with locally advanced disease, the median OS in the combination group was lower than that achieved in those treated with gemcitabine alone (11.9 versus 13.6 months, respectively) [The mOS obtained in patients with metastatic disease in the present study was five months lower than the value obtained by the FOLFIRINOX subgroup in the PRODIGE study and two months lower than the result obtained in the nab-paclitaxel+gemcitabine subgroup in the MPACT study. Also, the mOS obtained in the present study is one month higher than that achieved by the subgroup of 69 patients with metastatic disease treated with nimotuzumab in the OSAG study (17.2%) [The Phase III study “MPACT” compared nab-paclitaxel+gemcitabine (431 patients) versus gemcitabine (430 patients) in metastatic patients. It obtained a median OS of 8.7 months in the group treated with the combination, OS rate of 35% at 12 months, and a median PFS of 5.5 months. An increase of 1.8 months in OS was obtained in the combination group compared to monotherapy [In the Phase II-III trial “PRODIGE 4,” which compared gemcitabine with FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic cancer and good performance status, an increase of 4.3 months in median survival was obtained in favor of the combination (11.1 vs. 6.8 months; In our study, the overall objective response was lower than that achieved in other published studies. The overall disease control rate obtained in the present study was lower than that achieved in the group of patients treated with the same treatment scheme in the OSAG Phase III study [The primary limitation of this study is that the number of subjects required to estimate the proportion of patients with serious adverse events related to the use of the product was not reached, and the sample size was small. Another limitation deals with the impossibility to perform any biomarker determination to identify subgroups of patients that could receive greater survival benefits. Nevertheless, there are evidence that pancreatic cancer cells with EGFR high expression were sensitive to nimotuzumab treatment in vivo [Immunotherapy and targeted therapy did not yield significative changes in pancreatic cancer, due to PDAC tumor immune microenvironment with lack of infiltrating T cells and low tumor mutational burden. Also, the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC [With the exception of erlotinib and nimotuzumab, all EGFR inhibitors failed in clinical trials in PDAC, indicating the presence of underlying molecular mechanisms that bestow intrinsic and acquired resistance to this group [