EGFR E746

We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions.

Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

We also present a case demonstrating a favorable response to the dual therapy of olaparib and osimertinib in NSCLC harboring EGFR, RAD50, and ARID1A mutations that progressed on osimertinib. There were 2298 patients in the NSCLC cohort (MSKCC database). HRD aberrations are uncommon in EGFR mutated lung cancer patients. Further investigation on the role of PARP inhibitor in EGFR mutated lung cancer is warranted.

Our case indicated that the feasibility of neoadjuvant icotinib in EGFR-mutant lung adenosquamous carcinoma.

Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.

Our study revealed potential differences in TKI efficacy, resistance mechanism, and prognosis of various EGFR ex19del subtypes in NSCLC, underscoring the need for precise selection of first-line therapy.

These results suggest that specific mutations in EGFR exon 20 play a crucial role in SIP development, partially though hyper-activation of the PI3K/AKT and MAPK signaling pathways. This study presents the first in vitro model for SIP development, which could facilitate further investigations into SIP pathogenesis and preclinical studies for new therapeutic agents.

The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment...EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR-mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen.

Updated results will be presented (data cutoff, December 2021). Table: 151P Efficacy according to mutation status

Given the poor clinical outcomes observed in patients with compound EGFR mutations, it is important to detect them using NGS-based analysis.

Results from in vitro experiments suggested that the EGFR I740_K745dup mutation might be more sensitive to afatinib. Our comprehensive analysis of EGFR 19ins in lung cancer patients revealed genomic characteristics and clinical response that are distinct from 19del/delins. Our findings help better inform clinical action and might facilitate the development of more precise therapeutic options for patients with these uncommon driver mutations.

Accordingly, the patient continued Osimertinib combined with Carboplatin/Pemetrexed and with additional palliative irradiation due to a new symptomatic spinal cord compression at L3. Acquired EML4-ALK fusion represents an extremely rare (1%) acquired mechanism of Osimertinib-resistance, which enables further effective and feasible therapy by combining EGFR- and ALK-TKI. Rebiopsies, when possible, are of noteworthy value even in heavily pretreated and fragile patients.

Our study using PDX model demonstrated that epigenetic inhibitor Tazemetostat may enhance the efficacy of osimertinib, resulting in marked reduction and delayed regrowth of the DTP tumors post-drug discontinuation. However, complete elimination of persisters was not achieved, suggesting that multiple mechanisms may co-sustain DTP tumor cell survival. PDX may model in vivo studies of drug combinations to control DTP tumor cells.

MET fusions are a rare, but potentially actionable, genomic alteration. Our study provides a comprehensive characterization of MET fusions in NSCLC, revealing their diverse fusion partners and co-occurring genomic alterations. Further research is warranted to elucidate the clinical implications of MET fusions in the treatment of various types of cancer, including lung cancer.

Together, this study shows that NSCLC cell lines have heterogeneous metabolic profiles, which may be underlaid by different genetic profiles, revealing an opportunity to identify and stratify patients who can benefit from metabolism-targeted therapies.

PNA-DNA probes specific for EGFR mutations might be useful tools to detect heterogeneous mutant EGFR expression in cancer tissues and efficiently evaluate the effect of EGFR signaling inhibitors on tissues of EGFR-mutant cancer.

Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance.

Identification of actionable tumor drivers is important both for prognosis and treatment of patients with BrM. Our molecular profile database may serve as a major step in identification of BrM-specific drivers, which may lead to better understanding of BrM biology and consequently improvement in therapeutic strategies.

This is the largest preclinical/clinical report to highlight that EGFR-K745_E746insIPVAIK and other mutations with exon 19 XPVAIK amino-acid insertions are rare but sensitive to clinically available 1st, 2nd, and 3rd generation as well as EGFR exon 20 active TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q and EGFR-A763_Y764insFQEA mutations. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these EGFR mutated lung cancers.

The ex19del L747_A750>P is associated with inferior PFS compared to the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del.

In conclusion, compared with del E746-A750, indel E746 was associated with longer PFS and OS, but the non-LRE subtype was correlated with shorter survival prognosis. There were no significant differences in the acquired T790M rate and treatment effectiveness of subsequent 3 -generation EGFR-TKIs between various Del-19 subgroups.

In advanced NSCLC patients with EGFR Ex19del, the efficacy of first-line TKIs therapy was affected by the presence of pleural metastasis, Ex19del subtypes and different generation of TKIs.

Additionally 31% had STK11, KEAP1, or NFE2L2 mutations without actionable driver mutations. SRSF2 and FUBP1 mutations in NSCLC potentially serve as a target for RNA splicing inhibition in conjunction with targeted therapies or immunotherapy to enhance treatment outcomes and/or overcome resistance mechanisms.

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

This HDPCR prototype assay includes relevant research biomarkers in current National Comprehensive Cancer Network (NCCN) guidelines, including variants in EGFR, BRAF, KRAS, ERBB2, ALK, ROS1, RET, MET, and NTRK1/2/3, and has shown sensitive and specific performance. In addition, this assay leverages a proprietary bioinformatics suite, the ChromaCode Cloud, to report relevant variants with the click of a button, allowing for an easily adopted solution to testing needs.

In this study, we challenged OPA with QNS samples, and OPA successfully detected SNVs and CNVs with an at least 83% concordance rate, compared to reference methods. We demonstrated that OPA can be a valuable, rapid method for molecular testing of advanced NSCLC cases with scant tissue.

The CBFR assay provides a sensitive, specific, and simple strategy designed based on a straightforward and inexpensive process. We suggest that the CBFR assay could serve as a diagnostic approach to detect mutations, deletions, and pathogens in underequipped laboratories and promote personalized therapeutic approaches.

The success rate of ODxTT is slightly inferior to that of cobas EGFR. ODxTT shared a high concordance rate and k-coefficient with cobas EGFR in detecting EGFR mutations, but discordant results between the two tests were observed in a few cases, mainly due to the difference of detectable EGFR variants.

A large proportion of these cases harbor actionable driver alterations. The relationship between germline CHEK2 mutations and actionable driver alterations in NSCLC may be worth further investigation.

However, among the handful of small cell lung cancer samples screened, sensitizing variations (Ex18 G719S and Ex21 L858R) were seen in almost all of them. Interestingly, Ex20 T790M variation was not detected in any of the cases screened.  The results of our study indicate that EGFR variations are present in SCLCs and highly sensitive liquid biopsy techniques like ddPCR can be effectively utilized for this purpose of screening EGFR variations in such samples.

The p.L861Q localized in exon 21 of the EGFR gene was the most common mutation identified in our patients (35.3%), whereas the "classic" EGFR mutations such as Del19 and p.L858R were found in 23.5% and 11.7% of the cases, respectively. Interestingly, most of p.L861X mutation-carrying patients showed good response to TKI treatment. Altogether, our findings suggest a particular distribution of the EGFR-TKIs sensitivity mutations in Tunisian NSCLC patients.

Dacomitinib may be effective choice in afatinib-refractory carcinomatous meningitis harboring G724S mutation. This is the first case report showing that a change to dacomitinib responded to afatinib refractory cancerous meningitis.

The literature review and our report suggest that osimertinib is a promising treatment for NSCLC regardless of histology if T790M is present as an acquired mutation.

We show that in contrast to E746_A750 and E746_S752 > V, the L747_A750 > P variant forms highly active ligand-independent dimers. Enzyme kinetic analysis and TKI inhibition experiments suggest that E746_S752 > V and L747_A750 > P display reduced TKI sensitivity due to decreased adenosine 5'-triphosphate K. Through these analyses, we propose an expanded framework for interpreting ex19del variants and considerations for therapeutic intervention.

Significant pathways and biological functions potentially regulated by the deregulated 128 non-coding genes were enriched. Our work provides an important theoretical, experimental and clinical foundation for further research on more effective targets for the diagnosis, therapy and prognosis of lung cancer.

P2, N=30, Recruiting, Shanghai Chest Hospital | Trial primary completion date: Mar 2022 --> Oct 2022

NSCLC with EGFR 19Del/Delins should not be considered as a homogenous disease. NSCLC with uncommon EGFR 19Del/Delins displayed a more active adaptive immunity in tumor microenvironment, which indicated the potential vulnerability of immunotherapy.

P2, N=1, Terminated, Spectrum Pharmaceuticals, Inc | N=150 --> 1 | Trial completion date: Dec 2023 --> Mar 2022 | Recruiting --> Terminated | Trial primary completion date: Jun 2023 --> Mar 2022; Strategic business decision (unrelated to safety)