EGFR L858R

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance. These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.

Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC50 = 56.9 nM. The deuterated analogue of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.

The compounds 7b, 7 h, and 7i produced more potent cytotoxicity than doxorubicin with IC50 values of 1.83 ± 0.1, 2.54 ± 0.14, 2.75 ± 0.15, and 3.63 ± 0.2 μM, respectively...In addition, compound 7b produced a promising multi-kinase inhibition against EGFR (WT) while being very selective toward the mutant forms (L858R and T790M) with IC50 values of 0.099 ± 0.006, 0.064 ± 0.006, and 0.026 ± 0.007 μM, respectively, in comparison to gefitinib and osimertinib...Compound 7b was predicted to have promising oral absorption, good drug-likeness, and low toxicity risks in humans. Moreover, MD simulations confirmed the stable complexes of 7b with EGFRWT, EGFRL858R, and EGFRT790M (with RMSD 0.12-0.35 nm, RMSF 0.2-0.55 nm, SASA 140-150, and Rg 1.80-2.00 nm).

The CRISPR corona nanomachine was successfully employed to detect various CTNAs, including circulating tumor (ct)DNA/RNA (EGFR L858R) and microRNA-21, achieving a limit of detection of 0.14 pM for ctDNA and 1.0 pM for RNA. This CRISPR corona nanomachine enables simultaneous detection of both DNA and RNA in complex biological samples, offering a promising tool for early diagnosis.

The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

This large-scale, cross-sectional study reveals a complex interplay between genetic mutations, immunological features and pre-existing conditions in NSCLC patients, offering insights that could inform personalised treatment strategies.

In contrast, related Type I1/2 inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as "Type V" bivalent inhibitors.

In RELAY, OS was not significantly improved with similar long OS durations in both treatment arms.

Both deep learning models and radiomic signature-based models offer reasonably accurate non-invasive predictions of EGFR status and its subtypes. Fusion models hold the potential to enhance noninvasive methods for predicting EGFR mutations and subtypes, presenting a more reliable prediction approach.

P3, N=354, Active, not recruiting, Takeda | Trial completion date: Dec 2024 --> Jul 2025

This case demonstrates the efficacy of osimertinib for rare EGFR mutations, aligning with literature suggesting its potential for managing such variants. Although large-scale trials are impractical due to the rarity of these mutations, this report adds valuable evidence supporting osimertinib's use, highlighting the need for comprehensive genomic profiling in NSCLC.

P1/2, N=10, Terminated, Astellas Pharma Global Development, Inc. | Phase classification: P1b/2 --> P1/2

Transformation to PC following osimertinib administration is rare, and we report this unique case. This study was approved by the Jichi Medical University Saitama Medical Center Ethics Committee (S24-073), and written informed consent was obtained from the patient.

EGFR mutations are robust biomarkers for RFS estimation in stage I invasive LUAD. Combining EGFR mutations with other actionable mutations enhances individualized RFS estimation.

P=N/A, N=923, Completed, AstraZeneca | Recruiting --> Completed

P3, N=624, Active, not recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2024 --> Jun 2024

The sensing system was able to effectively differentiate between wild-type and other mutation types, and its detection results were consistent with qPCR. The excellent performance of the sensor suggests its promising application in the diagnosis and precision treatment of NSCLC.

Osimertinib demonstrated robust response in NSCLC harboring uncommon EGFR mutations, without unanticipated safety concerns.

In summary, there are limited prospective data to guide therapy in patients with rare EGFR mutations. Prospective studies are required to evaluate the response to endothelial growth factor receptor-tyrosine kinase inhibitors in patients with rare EGFR mutations in order to ensure patient safety and response to treatment in this patient population.

P2, N=30, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Feb 2025 --> Feb 2026

The Agena iPlex HS Lung Panel on the MassARRAY System is highly tolerant of poor quantity and quality DNA, recovering and delivering accurate results on samples that would otherwise fail NGS-based analysis.

P=N/A, N=40, Not yet recruiting, The Second Affiliated Hospital of Army Medical University; The Second Affiliated Hospital of Army Medical University

P2, N=30, Not yet recruiting, Jining Medical University Affiliated Hospital; Jining Medical University Affiliated Hospital

P2, N=180, Recruiting, Sun Yat-sen University Cancer Center; Sun Yat-sen University Cancer Center

P2, N=25, Recruiting, Cancer Hospital Affiliated of Shandong First Medical University; Cancer Hospital Affiliated of Shandong First Medical University

P3, N=192, Active, not recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd. | Trial primary completion date: Jan 2026 --> Jul 2024

P2, N=187, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.

Under the premise of not exacerbating adverse effects, neoadjuvant immunochemotherapy achieved superior rates of MPR and pCR, with long-term survival comparable to targeted therapy.

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P=N/A, N=187, Enrolling by invitation, Pfizer | N=1200 --> 187

P3, N=586, Active, not recruiting, Daiichi Sankyo | Trial primary completion date: Aug 2024 --> May 2024

The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations.

These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation. In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR.

P2, N=40, Active, not recruiting, British Columbia Cancer Agency | Recruiting --> Active, not recruiting | N=76 --> 40

P2, N=160, Active, not recruiting, Xiuning Le | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

Interestingly, "common mutations" were found seldom in our study population, while the uncommon variants constitute 83% of all mutations, which we assume is due to diverse Indian genetics and ethnicity and co-existing signature mutations that involve the tyrosine kinase domain of EXON20. We suggest future genome-wide association studies to identify plausible genetic polymorphisms responsible for interethnic differences in EGFR mutation, which will contribute to better treatment and prevention of NSCLCs.

P2, N=150, Active, not recruiting, Myung-Ju Ahn | Recruiting --> Active, not recruiting

This case underscores the transient efficacy of targeted therapy in SMARCA4-deficient NSCLC with concurrent EGFR mutations. It highlights the need for continuous therapeutic adjustments and emphasizes the importance of further research into effective strategies for treating this complex and challenging subset of NSCLC, as current modalities have limitations in sustained efficacy.

Among them, 16 patients received systemic chemotherapy based on etoposide, of which 13 cases could be evaluated for efficacy, 11 cases could be calculated for PFS...After SCLC transformation, the standard chemotherapy regimen for SCLC is generally used for treatment. The OS after SCLC transformation is related to the stage, and the prognosis is better in the limited stage.

P2, N=200, Recruiting, Janssen Research & Development, LLC | N=300 --> 200