EGFR L747P

EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001)...Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.

However, NGS had a 12-day longer TAT compared to EGFR PCR. Gene fusion-panel PCR and NGS identified an additional 11.6% of patients harboring actionable alterations who may benefit from FDA-approved targeted therapies.

Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.

Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Droplet digital polymerase chain reaction analysis of uncommon pathogenic EGFR variants can yield unique and reproducible results. Recognition of atypical patterns in EGFR ddPCR testing can prompt confirmatory molecular testing and aid appropriate targeted therapy selection for patients with non-small cell lung cancer.

In patients with advanced NSCLC harboring uncommon EGFR mutations, high-dose aumolertinib demonstrated a tolerable safety profile and encouraging antitumor activity in NSCLC pts harboring uncommon EGFR mutations. High-dose aumolertinib is also currently being evaluated in a phase 3 clinical trial for patients with uncommon EGFR mutations (NCT04951648).

Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.

The up to date data suggested CK Increase was positively associated with the efficacy of Aumolertinib. On the other hand, Aumolertinib in G719X&L861Q&S768I genotypes showed better outcome compared to other genotypes.

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

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.

To date, there are no ongoing clinical trials on the use of osimertinib in NSCLC with EGFR L747P mutation. Further investigations are warranted to confirm the efficacy of osimertinib in this type of mutation.

The uncommon p.L747P mutation in EGFR exon 19 resulted in a poor response to first-generation EGFR TKIs. Afatinib revealed a better clinical response and binding affinity compared with osimertinib for this specific alteration.

Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.

We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool which can assist clinical decision making and accelerate development of therapeutic strategies.

Their therapies were changed to cetuximab combined with TKI of afatinib or osimertinib, and local treatment including local radiation, intraventricular pemetrexed administration, or with intrathoracic drain . Cetuximab-based systemic therapy combined with local treatment demonstrated preliminary clinical activity in the rare EGFR-mutant lung cancer with LM who have already undergone heavily previous therapy, warranting further investigation.

This study demonstrates that ctDNA monitoring is a useful method for molecular genotyping of advanced lung cancer patients. Genomic profiling of liquid biopsy may help to identify gene signatures for biomarkers predictive of response to treatment. The gene mutations identified in the individual patient of this study may help access the clinical benefit of therapy with ICIs or other drugs.

P2, N=30, Recruiting, Shanghai Chest Hospital | Not yet recruiting --> Recruiting

Our study contributes an incremental step in understanding the clinical responses of patients with rare EGFR mutations located in exon 18 and 19. Understanding the treatment responses and survival outcomes are critical in the optimal treatment management and improving the survival outcomes of patients with rare EGFR mutations.

As for patients treated with EGFR TKIs, three EGFR L747P patients achieved partial response through afatinib treatment, and two EGFR L747S patient achieved progressive disease to icotinib treatment. Figure 1. Chest computed tomography images before (at baseline) and after treatment with afatinib in patients 2.

Hence, we reported a patient with advanced lung adenocarcinoma harboring an EGFR L747 P who benefited from first-line treatment with gefitinib. After disease progression, this patient was subsequently administered osimertinib and responded, as evidenced by a significant reduction in nodular lesions. This case revealed that EGFR L747 P rendered both gefitinib and osimertinib therapeutically efficacious.

P2, N=30, Not yet recruiting, Shanghai Chest Hospital