EGFR Gene Mutation

This is a Phase 3, randomized, positive-controlled, open-label clinical study. The primary objective is to evaluate the efficacy of JMT101 in combination with osimertinib versus osimertinib alone in patients with newly diagnosed locally advanced or metastatic non-squamous NSCLC harboring EGFR-sensitive mutations.

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.

This study will be a multi-center observational study and will enroll patients with advanced EGFR exon 20 insertion mutated NSCLC. The study will include patients recruited from countries across Asia, including sites in, but not limited to - Hong Kong, Korea, Singapore, Taiwan and Thailand. There will be approximately 20-30 sites recruiting for the study. In Singapore, sites may include National Cancer Centre Singapore (NCCS), National University Hospital (NUH) and Tan Tock Seng Hospital (TTSH). Approximately 600 patients will be enrolled retrospectively.

\<Part A: Dose Escalation Study\> This part of the study evaluates MTD using the BOIN design in advanced or metastatic NSCLC subjects with EGFR mutant C797S or T790M. The target DLT rate for determination of MTD in this study is 30%. The administration cycle is defined as 28 days and JIN-A02 is administered QD. The DLT period for each subject is 21 days. When a subject receives at least 75% of his or her assigned daily dose during the DLT period or shows DLT during the DLT period, the subject is considered evaluable for DLT. The first cohort starts with 12.5 mg QD, and at least 3 subjects will be recruited per cohort. Dose escalation between cohorts is made at up to twice the prior dose level. At any dose level, if DLT occurs to 1 subject or if 2 subjects experience a grade 2 or higher AE considered related to JIN-A02 during the first Cycle after administration, subsequent dose escalation shall be made at no more than 50%. Before proceeding with a subsequent cohort, the SRC will convene and conducts a review meeting at a time point when subject DLT evaluation is available and then determines a subsequent dose level. In the Part A dose escalation study, the estimated sample size is 30 subjects, and if an additional dose cohort is added, the maximum sample size can be increased by 6 subjects per dose level. If there is no DLT or disease progression in subjects after Cycle 1 (28 days), the dose level can be maintained or escalated as determined by the investigator though it must not exceed the MTD determined, or the level reviewed by SRC at that time. If there is a subject who withdraws from the study before completion of Cycle 1 due to reasons other than DLT, the subject can be replaced for MTD determination. The total number of subjects for a given dose level must not exceed 12. If 12 subjects are evaluable for DLT at a given dose level, it is considered that the dose escalation has been completed. Additionally, if a dose level has not exceeded the level approved by SRC and a subject has completed administration for 8 weeks or longer without experiencing a grade 3/4 AE or DLT, dose escalation is permitted for these subjects who were enrolled to the earlier lower dose levels. \<Part B: Dose Exploration Study\> This part of the study is to determine the optimal RP2D by further investigating safety, tolerability, PK and efficacy of JIN-A02. SRC will select 2 preliminary effective dose levels based on the results of Part A and additionally enrolls 3 to 6 subjects to each of the 2 dose levels. Up to 12 evaluable subjects are expected per dose level, including those previously enrolled in Part A of the study. If data for the 12 subjects have been collected at a dose level during the dose escalation phase, an exploratory cohort may not be required at the same dose level. SRC will determines the RP2D based on the dose escalation phase and dose exploration phase of this study. \<Part C: Dose Expansion Study\> This part of the study will utilize the RP2D. A total of 5 cohorts will be selected based on the type of EGFR mutation identified in the tumor tissue or through plasma ctDNA test. Cohort 1 with both EGFR C797S and T790M mutations and Cohort 2 with EGFR-C797S but not T790M, will enroll around 36 subjects each according to the single-stage design in order to evaluate the feasibility for further studies of the anti-tumor activity of JIN-A02. Cohort 3 will enroll subjects with EGFR T790M but not C797S, Cohort 4 subjects with any EGFR mutation and stable brain metastasis and Cohort 5 with any EGFR dependent mutation other than C797S or T790M, will enroll 12 subjects each in order to explore the anti-tumor activity of JIN-A02 in these settings. Data will be collected regularly and will be evaluated by SRC for safety and benefit/risk assessment.

This is a Phase II, open-label, multicentre study of ABSK043 administered orally in combination with Firmonertinib to patients with EGFRm+ advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule whilst ensuring the safety of patients with intensive safety monitoring. There are two main parts to this study; Part A, dose escalation and Parts B Dose expansion. The expansion part will evaluate the efficacy of ABSK043 in combination with Firmonertinib as first-line treatment for locally advanced or metastatic NSCLC patients with EGFR-mutated at the one or more recommended dose. Dose escalation: • Post-line: Patients with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with systemic treatment Dose Expansion: • First-Line: Patients with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation, and without prior systemic therapy for advanced or metastatic disease.

Phase Ib: Classic "3+3" design used for Phase 1b to select the putative RDEs. Four dose groups are preset in phase Ib of this study, which including QD groups and BIW groups. Subjects will be enrolled in parallel cross into the group. Phase IIa: Two cohorts are preset in this stage, Cohort 1: GH21 RDE1 QD + Osimertinib 80 mg QD, Cohort 2: GH21 RDE2 D1D2-BIW + Osimertinib 80 mg QD, Cohort 1 and Cohort 2 are enrolled in parallel. Phase IIb: Phase IIb preset 1 cohort. The investigator and sponsor will comprehensively evaluate safety, efficacy, and PK data from Phases Ib and IIa to determine the dose level for Phase IIb.

This study is a patient-centered, two-group, three-cohort, multi-center, prospective study to further evaluate the survival benefits and safety of zorifertinib as a first-line treatment in EGFRm+ advanced NSCLC patients with CNS metastases, and to compare the clinical value of zorifertinib with other epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

IFCT-2202 ROSIE study aims to incorporate a broad-panel centralized NGS testing at baseline in all patients with completely resected NSCLC with common EGFR mutation after confirmation of an optimal preoperative extension assessment and with a centralized review of the quality of the surgical excision. Furthermore, the IFCT-2202 ROSIE study also aims to study the molecular events associated with relapse on, or after osimertinib exposure, that should result in the opportunity to accede to optimal treatment in case of metastatic relapse.

The primary objective of this study was to evaluate PFS of laseratinib and bevacizumab combination therapy as the primary treatment for advanced lung cancer with EGFR mutation. For laseratinib monotherapy, the expected median PFS is 15 months. On the other hand, assuming the expected median PFS 27 months of laseratinib and bevacizumab combination therapy, the one-sided test alpha level is 0.05, the power 0.8) dropout rate should be approximately 120 (60 people per group) enrolled in this study. Patients would be enrolled in this study for 18 months and followed up to at least 24 months from the last patient enrollment date. This study is a phase 2 clinical trial, and the primary goal is PFS, and based on the log rank test, the laseratinib bevacizumab combination therapy group significantly increases PFS when one side p value \<0.05. Fisher's Fisher exact test or chi-square test will be used in consideration of laboratory data and laboratory test abnormalities or clinical adverse reactions.

The ADME-associated SNPs included are CYP3A4,CYP3A4,CYP1A1,CYP2D6, ABCB1,ABCG2 and so on .The somatic mutations included are EGFR ,K-RAS ,ALK and so on