EGFR G719S

In a real-world cohort of patients with NSCLC, we identified race-associated differences in therapeutic outcomes and described molecular characteristics in NHB and NHW patients with NSCLC. To proactively identify patients most likely to respond to systemic therapies, a more comprehensive approach is needed to help guide therapy selection in individualized patient populations.

Although wet lab experiments are required to unravel the mechanistic details of mEGFR inhibition, MD results provide structural basis for those events that are difficult to address experimentally. The outputs of the current study may assist to design small molecules with high potency to mEGFRs.

Conclusions LM biopsy is safe and feasible for driver mutation-positive NSCLC-LM patients. Importantly, LM biopsy can be used to diagnose otherwise difficult cases and identify actionable genomic alterations for targeted therapy.

ctDNA monitoring during Osimertinib treatment helps identify a subgroup of patients with poor prognosis. A lack of cfDNA negativization could identify a subgroup of patients requiring adaptive therapy

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.

P3, N=200, Active, not recruiting, National Cancer Institute, Naples | Trial completion date: Jul 2022 --> Jul 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

Subsequently, structure activity relationship (SAR) and scaffold similarity inquiry were used to rationally propose a few erlotinib analogues...For this purpose, MD-based conformational sampling of ligand-enzyme complexes and ligand-water associations were used to acquire thermodynamic energy averages. Though mechanistic details are to be explored, results of the current study identify synthetically accessible quinazoline small molecules with potential affinity toward frequent EGFR-TK mutants.Communicated by Ramaswamy H. Sarma.

Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies.

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 work done for inhibitor dissociation suggests that IRE exhibits a stronger binding affinity to EGFR mutant. Together, these findings provide a deeper understanding of minor mutations, which is essential for drug development targeting EGFR with less common mutations.

While two EGFR ex20ins-targeting drugs were recently approved by the US Food and Drug Administration (amivantamab and mobocertinib), neither have established CNS activity. Phase 2 will enroll patients in 3 cohorts (n=18 each): patients treated with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients treated with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases treated with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned to enroll at approximately 40 centers in North America, the Asia-Pacific region, and/or Europe.

This real-world study indicates that dacomitinib is potent and well-tolerated in NSCLC patients harboring uncommon EGFR mutations in multi-line settings, and has favourable activity for brain metastases.Data are n (%). AEs, adverse events. There were no grade 4-5 treatment-emergent AEs.

In this cohort, very few of ALK fusion patients coexisted with other driver mutations. Among the co-existence samples, ALK fusion were mainly coexisting with the site mutations of EGFR and KRAS, amplifications of MET and ERBB2, fusions of ROS1 and RET. These samples maybe obtain more effective outcomes by combined or sequential therapies.

The ex19del activating mutation of the EGFR gene frequency in adenocarcinoma samples was 9.7%. A more frequent EGFR alteration was detected when assessing the locus copy number in the tumor relative to the non-tumor tissue: changes were recorded for 30% of adenocarcinoma cases and 69.1% of squamous cell lung cancer.

AFA+BEV after OSI resistance demonstrated moderate efficacy and favorable safety. A small portion of C797S pts exhibited the sensitivity. Higher potency was suggested in T790M/BRAF/KRAS/PIK3 mutation-negative and uncommon EGFR/HER2 mutation-positive pts.

While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe.

While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 potently suppressed EGFR phosphorylation in tumor tissue (e.g. 99%, 3 h post 50 mg/kg dose) but had minimal-to modest suppression of phospho-EGFR in large intestine tissue (e.g. 4.2%, 3h post 50 mg/kg dose) and skin tissue (e.g 1.9%, 3h post 50 mg/kg dose). Taken together, LNG-451 is a wild-type EGFR-sparing, CNS-penetrant EGFR Ex20ins inhibitor that is expected to provide strong anti‑tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR-driven toxicities.

P2/3, N=90, Not yet recruiting, The First Affiliated Hospital of Henan University of Science and Technology

P3, N=200, Ongoing, ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE

After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript's submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patient with LM carrying EGFR G719S and L861Q.

The Idylla system was able to detect the exon 19 deletion from 6 copies/mL and up to 91 copies/mL for the G719S mutation. These results support that the Idylla ctEGFR mutation assay is a rapid option for the detection of EGFR hotspots mutations in plasma samples, however a particular attention is needed for its interpretation.

Two cases showed the presence of G719S and T790M mutations respectively and another had compound mutations (T790M and L858R). The detection of EGFR mutations in non-malignant pulmonary conditions opens up a new area of research.

P2, N=170, Recruiting, Fondazione Ricerca Traslazionale

Our cases provide evidence for utility of NGS in facilitating diagnosis and treatment decisions.

The current study represents the first epidemiological study in Iraq to find EGFR mutations frequency among NSCLC patients that reveals the incidence rate of 27.53%, which is between the higher prevalence rate in Asian populations and lower rates in western countries. These results explain the genetic differences of NSCLC in the world due to ethnic differences of the population, more studies are needed in Arab countries to study the EGFR mutations, find the effect of ethnicity and environmental factors for lung cancer, and the subsequent therapy.

P2, N=189, Ongoing, FONDAZIONE RICERCA TRASLAZIONALE (FORT)

For six patients, longitudinal data were analyzed and it was found that the ddPCR results reflected well the course of the disease and radiologic response. This study confirms that ddPCR on cfDNA supports the diagnosis and therapy selection, and shows that ddPCR multiplex assays on cfDNA could be a valuable additional diagnostic tool for therapy monitoring of NSCLC patients.

We provide point-by-point discussion, reviewing multiple laboratory mistakes and clinical misinterpretations occurred with this patient. This case report exemplifies the need to involve rigorous clinical expertise in the daily practice of medical laboratory facilities.

No abstract available

Conclusion More and more uncommon EGFR mutations are identified owing to the development of NGS. This is the largest NGS-based cohort of Chinese lung cancers for investigating uncommon EGFR mutations, and 5.48% patients that with EGFR-TKI-sensitive uncommon mutations alone were found, which should be informative for the clinical therapies.

Of them, 6 patients received EGFR TKI treatment (4 gefitinib and 2 erlotinib). Conclusion Kras-G12C mutation was associated with shorter TTR in early-stage NSCLC patients, while Kras-G12V mutation was associated with shorter OS in advanced-stage patients. Kras-G12C was also associated with favorable ICIs treatment effectiveness.

Although tissue biopsies cannot be replaced due to the large amount of information they provide regarding tumor type and structure, liquid biopsy and ddPCR represents a new promising strategy for genetic analysis of tumors from plasma samples. In the present study, G719S mutation was detected in a highly sensitive manner, allowing its monitorization with a non-invasive technique.

Overall TAT for the ultra-rapid workflow was reduced by ~50% compared to PCR/CE, and in most cases, results are delivered on the same day as tumor sampling. The lack of nucleic acid extraction and single-slide sample input enables targeted profiling of even scant tumor samples. Although both PCR/CE and the ultra-rapid workflow provide drastic improvement of TAT compared to NGS-based profiling, more comprehensive coverage of actionable EGFR mutations in the ultrarapid workflow allows for faster and more definitive treatment of NSCLC

Despite low sensitivity, combined DS, RFLP, and PCR-HRM was able to detect EGFR mutations in plasma cfDNA with high specificity. Moreover, TKI resistance exon 20 insertions mutation was detected as early as 3 months post TKI treatment.

The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.

The median time to developing T790M mutation was 22 m. In group 1, 8 patients received first-line osimertinib, while other 37 received erlotinib (23), gefitinib (4) and afatinib (10). Patients who developed the T790M mutation appeared to have a longer PFS than those who did not and the mean duration to detection of T790M was 22 m. The development of T790M may confer a slower growth pattern and longer PFS. This question should be further explored in larger studies. Research Funding: None

TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in NSCLC patients with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates anti-tumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.

P2, N=37, Recruiting, SCRI Development Innovations, LLC