EGFR L858R + EGFR exon 19 deletion

This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

P2, N=125, Active, not recruiting, National Cancer Institute (NCI)

Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models...Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

Given that osimertinib is often the best available therapy, rechallenging with osimertinib often favors benefit over risk. Safe rechallenge with osimertinib is demonstrated in this case.

Although first-generation tyrosine kinase inhibitors have been the standard front-line treatment option for advanced EGFR mutated NSCLC, newer studies have shown improved survival outcomes with osimertinib therapy when compared to other tyrosine kinase inhibitors like gefitinib or erlotinib. While the difference in PFS between exon 19 deletion and exon 21 L858R mutation NSCLC patients was statistically insignificant, the decrease in PFS of patients with an exon 20 mutation treated with osimertinib was significant, suggesting a different treatment may benefit these patients. For the patients with a coexisting EGFR and PDL mutation, the NCCN guidelines (ref: NCCN 2023) state the treatment for PDL > 50% is pembrolizumab. This opens further prospective for research on co-existing PDL mutations with EGFR and associated treatment outcomes.

In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients with Ex19del and exon 21 L858R EGFR mutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversible EGFR TKI, in patients with Ex19del and exon 21 L858R EGFR mutation-positive advanced NSCLC in Indian settings.

False positives for exon 20 insertion may occur when using cobas EGFR, and false negatives for exon 19 deletion and L858R mutations may occur when using ODxTT.

Pharmacological Inhibition of ATM reversed the effects of CuE on autophagy-related proteins. In summary, CuE is a potential drug for the treatment of primary resistant NSCLC.

Because GSH was increased with L858R, we combined osimertinib with the GSH inhibitor buthionine sulfoximine in L858R cells and observed synergistic effects. The complexity of EGFR 19Del and L858R mutant cells was demonstrated by proteomics, transcriptomics, and metabolomics analyses. Therapeutic strategies for lung cancer with different EGFR mutations could be considered because of their different metabolic phenotypes.

No significant differences in PFS or OS were detected between the exon 19 deletion and L858R mutation groups. In early-stage lung adenocarcinoma, EGFR mutation may be considered as a treatment response predictor for tyrosine kinase inhibitors, instead of a predictor of clinical prognosis.

This is the first multi-institutional study involving a large part of the Brazilian territory, with a high assessment of miscegenation, demonstrating that the EGFR mutations are more common in women, being exon 19 deletion and L858R mutation (exon 21) the most common mutation finding, without regional differences. RT-PCR molecular platforms can be an option to use in regions where there is no access to NGS.

Characteristics and clinical outcomes of Korean patients with EGFRm+ mNSCLC in real-world practice were comparable to those observed in clinical trials. As osimertinib was not reimbursed for first-line treatment before study completion, further investigation is warranted to explore evolving treatment practice.

Background : Adding bevacizumab to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding bevacizumab to a second-generation EGFR-tyrosine kinase inhibitor. This study failed to show the efficacy of AfaBev arm for improving PFS in untreated patients with EGFR mutated non-squamous NSCLC. There was no significant difference in both EGFR exon 19 deletion and exon 21 L858R subgroups. Clinical trial information: jRCTs061180006

Compared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.

Radiomics features from the CE MRI could be used to detect the EGFR mutation, increasing the certainty of identifying exon-19 deletion and exon-21 L858R mutations based on spinal metastasis MR imaging.

Forty-eight patients received osimertinib (group O), 32 patients received gefitinib, erlotinib and afatinib plus anti-angiogenic agent (group A) as first-line treatment. Our research demonstrated that both osimertinib and first- or second-generation EGFR-TKIs plus anti-angiogenic agents as first line treatment provided good clinical outcomes in advanced and recurrence EGFR-mutant NSCLC patients.

At the 2021 ASCO annual meeting, the preliminary results of phase III AENEAS study demonstrated that aumolertinib, a novel third-generation EGFR-TKI, significantly improved PFS compared with gefitinib in the first-line treatment of patients with EGFRm advanced NSCLC(19.3 vs 9.9months, hazard ratios: 0.46). Aumolertinib in combination with bevacizumab has shown significant efficacy in patients with LM NSCLC with exon 19 deletion and exon 21 L858R mutations, even in combination with non-sensitive mutations and poor physical status. This combination regimen is characterized by a rapid onset of action, sustained remission of meningeal lesions, and a long duration of remission.

CT-based radiomic features can extract information on tumor heterogeneity in lung adenocarcinoma. In addition, we have established a radiomic model and an integrated model to non-invasively predict the EGFR mutation status and subtypes of lung adenocarcinoma, which is conducive to saving clinical costs and guiding targeted therapy.

The use of TKIs as adjuvant therapy in completely resected EGFR-mutant NSCLC significantly improves the DFS compared to chemotherapy, regardless of the mutation type, and with a better AEs profile as well, but does not affect the OS. Furthermore, The combination of TKIs and chemotherapy did not demonstrate a difference in DFS when compared to TKIs alone, however, prospective trials comparing both arms are needed to confirm this finding.

In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.

LAR is a noninvasive and effective modality in treatment of oligo-progressive diseases for patients with EGFR mutations positive NSCLC while on EGFR-TKIs.

Taking lessons from NSCLC, we also discuss potential new treatment options for ISP-associated SNSCC harbouring EGFR Ex20ins in the context of targeted therapies, drug resistance and precision cancer medicine. Moving forward, further basic and translational work is needed to delineate the biology of EGFR Ex20ins in SNSCC in order to develop more effective treatments for patients with this rare disease.

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase that plays an important role in regulating the growth and progression of cancer via signalling pathways. This review summarizes the differences in EGFR kinase structural changes, stability of active forms, and phosphorylation inhibitory effects of EGFR tyrosine kinase inhibitors between the exon 19 deletion mutation and the exon 21 L858R point mutation, which are frequently detected EGFR mutations in patients with non-small cell lung cancer.

These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

EGFR-tyrosine kinase inhibitor therapy was significantly superior to chemotherapy among EGFR mutant cases irrespective of TTF-1 status; however, no significant differences among survival outcomes were observed. Our study confirms a strong positive correlation between TTF-1 expression and common EGFR mutations (exon 19 deletion and exon 21 L858R) in advanced lung AC with significantly high negative predictive value of TTF-1 for EGFR mutations.

An exon 19 deletion mutation and an exon 21 L858R point mutation are frequently detected as EGFR mutations in patients with non‒small cell lung cancer. This review summarizes the differences in epidemiological, nonclinical, and clinical characteristics between the exon 19 deletion mutation and the exon 21 L858R point mutation.

Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases . However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.

Conclusion LAR is a safe and convenient modality in treatment of oligo-progressive disease for patients with EGFR mutations positive NSCLC. Patients with EGFR exon 19 deletion or Exon 21 L858R mutation, shorter time from diagnosis to treatment, and less prior lines of EGFR-TKI may benefit more from LAR.

Conclusion The sensitivity, specificity, and accuracy of detecting EGFR mutations in LAMP method were nearly equivalent to that in Therascreen method. This method may be a valuable alternative for the identification of EGFR mutations in pulmonary adenocarcinoma.

The combination of afatinib and bevacizumab is an effective therapy for untreated advanced EGFR-mutated lung adenocarcinoma with acceptable safety. Future prospective studies focusing on this combination for untreated advanced EGFR-mutated lung adenocarcinoma are warranted.

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.

Both ALK and ROS1 rearrangements are more common in younger lung adenocarcinoma. The young lung adenocarcinoma population is a distinct group rich in targetable genomic alterations, and more research is needed to understand the mechanism.

We generated OR cell lines in-vitro as evidenced by increased drug resistance potential, increased mesenchymal features and enhanced autophagy activity. Development of Osimertinib resistance cells may serve as in-vitro model facilitating discovery of molecular aberration present during acquired mechanism of resistance.

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.

Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

CT radiomics can sensitively identify the presence of EGFR mutation, and increase the certainty of distinguishing exon-19 deletion and exon-21 L858R mutation in lung adenocarcinoma patients. CT radiomics may become a helpful non-invasive biomarker to select EGFR mutation patients for invasive sampling.

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

EGFR mutations are more common than ALK and ROS1 rearrangements. They are more common in females. Patients less than 36 years have reduced frequency of EGFR mutations. Exon 19 deletion and L858R are most common and are more prevalent in lung adenocarcinomas. Rare EGFR mutations are seen in patients aged more than 50 years.