A Clinical Study of Sorafenib Combined With Gefitinib for the Treatment of pNET

Neuroendocrine neoplasms (NENs) are heterogeneous tumors originating from peptidogenic neurons and neuroendocrine cells. Most commonly found in the digestive tract or lungs, it can be a benign or malignant tumor. According to their origin, neuroendocrine neoplasms are usually divided into pancreatic neuroendocrine neoplasms and non pancreatic neuroendocrine neoplasms. Approved targeted therapy drugs include sunitinib and everolimus, used to treat pancreatic neuroendocrine neoplasms or highly differentiated non functional gastrointestinal or pulmonary neuroendocrine neoplasms. The gastrointestinal tract and pancreas are home to 12 and 4 types of neuroendocrine cells, respectively, and are the most common sites of NEN occurrence, accounting for approximately 55% to 70% of all NENs. The incidence rate of neuroendocrine neoplasms from gastrointestinal tract and pancreas is about 5.25/100000, which is the second common tumor of gastrointestinal tract. In China, the ratio of incidence rate and prevalence of neuroendocrine neoplasms is estimated to be 4.4, lower than 7.4 in the United States.

In 2018, there were 19000 newly diagnosed cases of neuroendocrine neoplasms in the United States. It is noteworthy that compared with other tumors, the survival period of patients with neuroendocrine neoplasms is relatively long. Therefore, although the incidence rate of neuroendocrine neoplasms is relatively low, the patient population is relatively large. In addition, it is estimated that there were approximately 141000 neuroendocrine neoplasm patients in the United States in 2018, of which over 90%, or 132000 patients, were non pancreatic neuroendocrine neoplasm patients. In China, there were approximately 67600 newly diagnosed cases of neuroendocrine neoplasms in 2018. According to China's incidence to prevalence ratio, there may be as many as 300000 patients with neuroendocrine neoplasms in China. It is estimated that about 80% of patients with neuroendocrine neoplasms in China are non pancreatic neuroendocrine neoplasm patients. Octreotide and Lancreotide, which belong to Somatostatin Analogues SSAs, can alleviate symptoms such as flushing and diarrhea caused by carcinoid syndrome and have been widely used in clinical practice. In a phase III clinical study comparing long-acting octreotide LAR with placebo in the treatment of 85 cases of metastatic colorectal cancer NENs (PROMID), octreotide LAR significantly prolonged the time to disease progression (TTP) in patients: Octreotide LAR group at 14.3 months and placebo group at 6 months (p=0.000072). A systematic analysis report shows that after combination therapy with long-acting octreotide and other therapies (including everolimus, peptide receptor radionuclide therapy, bevacizumab, interferon, etc.), 85% of patients' diseases were controlled, with PFS ranging from 15 months to 16.4 months and OS ranging from 25 months to 61.9 months. SSAs are well tolerated drugs with few side effects, usually mild, and do not require discontinuation[5].

The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) is increasing year by year. According to the statistical results of the Surveillance, Epidemiology, and End Results (SEER) database, the incidence rate of pNENs increased from 0.27/100000 to 1/100000 from 2000 to 2016, with a median overall survival time of 68 months, and the 5-year overall survival rates (OS) of localized, locally advanced, and metastatic pNENs were 83%, 67%, and 28% respectively. pNENs are gradually attracting attention and importance from the medical community. The existing therapeutic drugs for neuroendocrine neoplasms include growth hormone inhibitors, recombinant human interferon injections, chemotherapy drugs, and molecular targeted drugs. Although these drugs can to some extent prolong patients' PFS, there is a common problem of low objective response rates. In recent years, sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine tumors, but their clinical efficacy is still limited. The study from Panzuto et al. showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 13.9 months, with an ORR of 14.9%. When imaging progression occurred and second-line treatment was adopted, the median PFS after second-line treatment was 15 months, with an ORR of only 5.5%. There is currently no effective treatment for patients with disease progression or drug resistance after existing treatments.

Therefore, there is a huge clinical demand for the treatment of pancreatic neuroendocrine neoplasm patients both domestically and globally, and effective drugs are urgently needed to benefit the vast number of patients.

Our previous research found that tumor signaling pathways are significantly affected in pancreatic neuroendocrine neoplasms and liver metastasis through KEGG pathway analysis. EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumors are unique to liver metastasis; Meanwhile, GO biological process analysis emphasizes signaling pathways closely related to tyrosine phosphorylation, DNA repair, and cell cycle regulation. Xiao et al. found that RNA seq was used to enrich epidermal growth factor receptor (EGFR) in high glycosylated pancreatic neuroendocrine neoplasms. Immunohistochemical staining revealed that 21.2% of pancreatic neuroendocrine tumors expressed EGFR, which was associated with low overall survival rate (P=0.020). Therefore, Xiao et al. believe that EGFR may be a potential therapeutic target for pancreatic neuroendocrine neoplasms. This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pancreatic neuroendocrine neoplasms with liver metastasis.

Due to the heterogeneity and complexity of tumors, the efficacy of monotherapy or blocking a single signaling pathway may be limited. The existing targeted anti-tumor drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Colony stimulating factor 1 receptor (CSF1R) is an important signaling pathway associated with the survival and function of tumor associated macrophages (TAMs). Inhibiting CSF1R can regulate the activity of macrophages , improve the immune microenvironment, promote immune response in the body, and activate immune function. Sofantinib is a novel oral tyrosine kinase inhibitor that exerts dual effects of anti angiogenesis and immune regulation by targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR1), and colony-stimulating factor 1 receptor (CSF1R) kinases, resulting in synergistic anti-tumor activity. In December 2020 and June 2021, sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic, well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms. However, in a multicenter, single blind, open label, phase Ib/II clinical trial, the objective response rate for pancreatic neuroendocrine tumor patients was only 19%, and there is no effective treatment for patients with disease progression or drug resistance after existing treatment regimens. Therefore, there is an urgent need to seek new treatment methods to improve the therapeutic effect of pancreatic neuroendocrine neoplasms.

There is a study showing that dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor pathways may delay therapeutic resistance in advanced non-small cell lung cancer (NSCLC). Bevacizumab plus erlotinib significantly improved PFS in patients with untreated metastatic EGFR-mutated NSCLC. Based on previous research results and relevant literature reports, we speculate that the combination of sorafenib and EGFR inhibitors gefitinib may improve the treatment efficacy of patients.