EGFR mutation + EGFR T790M

Further exploration of the osimertinib plus savolitinib combination is underway in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. Table

The L858R mutation-associated lung adenocarcinoma acquired de novo T790 mutation without previous therapy. The results of this study suggest that lung tumors may spontaneously acquire T790M mutations without any drug-related selective pressure.

The results of CF-LAMP assay were consistent with those obtained in ddPCR assay, indicating the robustness of the method. CF-LAMP may serve as a valuable and cost-effective alternative for liquid biopsy techniques used in molecular diagnosis of non-small cell lung cancer.

The Cobas and UltraSEEK™ tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.

Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

To promote open-source drug discovery, a tool has been developed, which incorporates the best performing models and allows users to predict the potential of chemical molecules as anti-TMLR inhibitor. It is expected that the machine learning classification models developed in this study will pave way for identifying novel inhibitors against the resistant EGFR double mutants.

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

Conclusion These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFRm brain metastasis. This work also demonstrates the link between low in-vitro transporter efflux ratios and increased brain penetrance in-vivo supporting the use of in-vitro transporter assays as an early screen in drug discovery.

These real-world results support the overall study results and demonstrate prolonged time on treatment with sequential afatinib and osimertinib. The results suggest that sequential afatinib and osimertinib is a feasible therapeutic strategy for patients who acquire the T790M mutation, particularly those with Del19-positive disease or Asian patients.

Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.

The longitudinal analysis of BW-derived EVs showed excellent correlation with the disease progression measured by CT images. The EGFR mutations can be readily detected in BW-derived EVs, which demonstrates their clinical potential as a liquid-biopsy sample that may aid precise management, including assessment of the treatment response and drug resistance in patients with lung cancer.

OSI-loaded liposomes composed of l-α-phosphatidylcholine (egg-PC) demonstrated a higher toxicity in non-small lung cancer cells with EGFR T790M resistance mutation (H-1975) when compared with free OSI. Developed OSI formulations did not show antiproliferative activity in vitro in healthy lung epithelial cells (MRC-5) without the EGFR mutation.

Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce "detection overlook" among such patients.

Recently, osimertinib improved progression-free survival first-line, but no overall survival, versus first-generation TKIs (erlotinib and gefitinib) in Asian patients. The model was most sensitive to variance in the parametric survival inputs and percentage of patients eligible for subsequent treatment. CONCLUSIONS : First-line treatment with afatinib increase patient benefit and reduce cost compared with first-line osimertinib for patients with EGFR mutation-positive NSCLC in China.

Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%).

Compound 27 also exhibited good microsomes stabilities in human, rat and mouse liver species, but low bioavailability. This work would be very useful for discovering new quinazoline derivatives as tyrosine kinase inhibitors targeting triple mutant L858R/T790M/C797S.

Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns. Heterogeneous PD-L1 expression in higher level usually occurred in solid component both in EGFR mutated and EGFR wild-typed LACs. EGFR mutated LACs heterogeneously had sensitizing and resistant mutation and was accompanied with PD-L1 expression, but discordant among histological constituents. Immune checkpoint inhibitor combined with third generation EGFR tyrosine kinase inhibitor should be more effective to these LACs.

Concomitant mutations were widespread in 19Del and L858R and were associated with poorer OR to EGFR-TKIs. However, 19Del and L858R had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.

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Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations, unaffected by ethnicity. Asian pts appeared to have a high proportion of major uncommon mutations, known to be highly sensitive to afatinib.

One patient discontinued the drug because of drug-related interstitial pneumonitis. Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, non-covalent inhibition of C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small cell lung cancer.

Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Approximately one fifth of EGFR-mutant patients harbor uncommon and compound mutations. Unlike those with exon19del/L858R, these patients-particularly those with baseline T790M mutations-show significantly inferior response rates to treatment (EGFR TKI or chemotherapy) and early disease progression.

Five of the synthesized compounds, 11a, 11b, 12b, 15b and 16a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib...Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFRWT and EGFRT790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.

EGFR T790M testing is the standard of care for activating EGFR mutation (EGFRm) non-small cell lung cancer (NSCLC) progressing on 1st/2nd generation TKIs to select patients for osimertinib...Patients with liver or bone progression and 3-5 progressing sites are more likely to have informative EGFR ctDNA testing. Detection of EGFR ctDNA is a negative prognostic indicator in the absence of a T790M resistance mutation, potentially reflecting the disease burden in the absence of targeted therapy options.

This meta-analysis confirmed that in treatment-naive advanced NSCLC CNS metastases harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity.

We report osimertinib inhibits signalling pathways and cellular growth in G719X mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of PDX harboring the G719X mutation alone or in combination with L861Q and S768I. Together this data supports clinical testing of osimertinib in patients with uncommon EGFR NSCLC.

Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib treated patients after disease progression.

Among the four drugs evaluated (dasatinib, KPT-185, trametinib, and pluripotin), all except trametinib demonstrated strong inhibitory effects on the resistant PC9GR cells, among which KPT185 was the most potent. Acquired TKI-resistant lung cancer cells (PC9GR) have dramatically changed transcription and pathway regulation, which expose new treatment targets. Existing drugs may be repurposed to treat those patients with developed resistance to TKIs.

Moreover, both the AO/EB and DAPI staining assays also demonstrated the inhibitory efficacy of 7b against the resistant H1975 cells. This contribution provides a new scaffold 2(1H)-pyrimidinone as potential EGFR T790M inhibitor against drug-resistant NSCLC.

Almonertinib is safe, tolerable and effective for patients with locally advanced/metastatic NSCLC harboring the EGFR T790M mutation who were pre-treated with EGFR-TKIs.

The patients with baseline co-mutations and ctDNA non-clearance at first visit might require combined therapy due to limited survival benefit of EGFR-TKI monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

PD-L1 TPS ≥ 50% was an independent predictor of a lower frequency of this mutation (HR = 0.63, p = 0.043). High PD-L1 expression was associated with unfavorable clinical outcome and less development of secondary T790M mutation, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach.

Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.

In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC.

Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in two of six individuals. Thus, three additional patients will be enrolled in a third cohort at the same dose level. Efficacy data are premature and needs further evaluation.

Recently, osimertinib demonstrated superior median overall survival (OS) over erlotinib/gefitinib in the first-line (1L) setting. Outcome of this real-world population (median OS 46.5m) compares favorably with the FLAURA study cohort (median OS 38.6m). Pts qualifying for SEQ fare exceptionally well with a median OS of more than 5 years.

Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in two of six individuals. Thus, three additional patients will be enrolled in a third cohort at the same dose level. Efficacy data are premature and needs further evaluation.