EGFR exon 18 mutation

As it is well-known that ALK-fusion and BRAF-mutations are described forms of acquired resistance. These two case reports contribute to the previous reports that ALK-fusion and BRAF-mutation are potential underlying mechanisms of EGFR-TKI resistance.

In this study, the four cell lines containing the L861Q mutation were constructed by CRISPR and the anti-tumour effects of CUDC-101 on them were investigated in vitro by various chemosensitivity methods, with afatinib serving as a positive control. The results demonstrated that CUDC-101 inhibited the proliferation and clonogenic capacity on the four cells through the ERK or AKT pathways, decreased the mitochondrial membrane potential of the cells, blocked the cell cycle and promoted apoptosis. Our findings suggest that CUDC-101 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation L861Q.

Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations...The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.

While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. By synthesizing these findings, we aim to guide oncologists towards more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.

EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

P2, N=100, Active, not recruiting, Vestre Viken Hospital Trust | Trial completion date: Aug 2023 --> Dec 2025 | Trial primary completion date: Aug 2023 --> Jun 2025

In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of EGFR-mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion-mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients.

This specific mutation in exon 18 seems to respond to certain EGFR TKIs such as afatinib. However, given the rarity of this mutation, determining the most effective TKI for its treatment remains unclear. We report a 70-year-old woman diagnosed with stage IV-A lung adenocarcinoma harboring EGFR delE709_T710insD mutation treated in first-line with Osimertinib using standard schedule and doses experiencing renal toxicity and disease progression after 9 weeks of treatment.

P2, N=582, Terminated, Puma Biotechnology, Inc. | Completed --> Terminated; The study was terminated to align with the sponsor's current development plans for neratinib. The decision was not based on any new efficacy or safety data for neratinib.

He received 30 mg/day of afatinib, resulting in tumour shrinkage and recovery from respiratory failure. We advocate for aggressive screening of driver oncogenes in patients with lung cancer on dialysis, including those with squamous cell lung cancer.

P2, N=117, Recruiting, Fox Chase Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2025

It is crucial to understand these distinct variants and their specific responses to active treatment options to optimize care. In this review, we discuss these uncommon mutations in depth and dissect the current literature regarding their treatment outcomes and subsequent evidence-based management guidelines.

These findings suggest that while both CDx tests are effective in detecting almost all actionable EGFR mutations, ODxTT provides slightly broader coverage. These results emphasize the importance of selecting appropriate CDx tests to inform treatment decisions for EGFR-positive NSCLC patients.

As recently evidenced by the ADAURA trial, most patients with stages IB to IIIA of resected EGFR-mutant lung adenocarcinoma benefit from osimertinib as adjuvant therapy...Our findings suggest that circRUNX1 and the presented ML-developed signature could be novel tools to predict the benefit of adjuvant EGFR tyrosine kinase inhibitors with regard to RFS in patients with EGFR-mutant NSCLC. The training and validation phases of our ML signature will be conducted including bigger independent cohorts.

P1/2, N=106, Recruiting, RemeGen Co., Ltd. | Not yet recruiting --> Recruiting

In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment..

P=N/A, N=200, Completed, Istituto Oncologico Veneto IRCCS | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> May 2023

In this review, we describe the structural, molecular characteristics, and detection strategies of EGFR ex20ins mutations and summarize the latest clinical data on approved treatments and emerging therapies for patients with NSCLC harboring EGFR ex20ins mutations. Further, we will discuss the response heterogeneity of ex20ins mutations to new drugs and acquired drug resistance mechanisms.

EGFR mutated individuals had significantly longer median overall survival compared to EGFR wild type (26 months vs. 12 months, P = 0.044). We reports the highest number of EGFR mutation analysis performed from India and mutational analysis indicated a loco-regional variation in India with regard to EGFR mutation frequency and its subtypes.

Recent trials explore drugs like bemcentinib, everolimus, talazoparib, and others for potential approaches to targeting these mutations. Therapeutically relevant gene alterations were detected in the analyzed real-world patient cohort. The loss of STK11 or KEAP1 should be interpreted in the context of KRAS mutational and could be a clinical biomarker for poor response to targeted therapy in patients with advanced NSCLC. The data highlight that in addition to established biomarkers such as PD-L1, new potential marker of resistance such as STK11 or KEAP1 should be considered in molecular analysis prior to therapy initiation.

P2, N=42, Not yet recruiting, Convalife (Shanghai) Co., Ltd.

P1, N=56, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Jul 2024 --> Aug 2023

P1, N=56, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Jul 2023 --> Jul 2024

The data indicate that STK11 or KEAP1 mutations should be interpreted in the context of KRAS mutations and could serve as a clinical biomarker for poor response to immunotherapy in patients with lung adenocarcinomas. In addition, the data highlight the benefit of panel sequencing that includes the STK11 and KEAP1.

Table: 1278P Common EGFR mutations according to tumor stage Conclusions In this series of pts operated on for NSCLC, frequency of EGFR mutation was 15%, the most frequent being exon 19 deletions and the L858R mutation, in line with data reported in Spain in advanced NSCLC. These results reinforce the importance of performing EGFRm testing in early-stage NSCLC to identify pt candidates to adjuvant osimertinib.

In summary, liquid biopsy is a valuable tool for diagnosing and monitoring EGFR-mutated advanced nonsquamous NSCLC, enabling patients to receive timely and effective treatment. This approach has the potential to improve patient outcomes and ultimately contribute to better management of this disease.

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.

The patient initially received 1st line Erlotinib with remission maintained more than 4 years, despite an early dose reduction due to skin toxicity. Despite loss of the original compound EGFR mutation, the rebiopsy revealed a new pathogenic and druggable driver (BRAF p.V600E), which gave the patient a new possibility of further treatment. Yet, replacing Osimertinib with a BRAF/MEK-Is combination resulted only in mixed response, suggesting that some lesions might have remained, at least in part, dependent on the original EGFR mutations. Indeed, re-challenge with Osimertinib in reduced dose together with continuation of Dabrafenib and Trametinib resulted in SD and reflected spatial and temporal heterogeneity of NSCLC.

Filipino patients with lung adenocarcinoma albeit small in sample size, have remarkable diversity in molecular profile while confirming reported EGFR and ALK values. CTC values were generally low despite being at advanced stages. CD133, KRT19 and MUC1 expression were detected in half of the samples and may find diagnostic and therapeutic utility.

ctDNA analysis is a critical challenge that often leads to false negative results due to biological variables such as stage of the disease, tumor volume, low DNA-shedding, and preanalytical variables. The current study demonstrates the utility of ctDNA as a non-invasive promising tool to detect targetable alterations in situations where tissue biopsy is inaccessible or tumor tissue is depleted. Real-time PCR- based platform is the most preferred option for molecular analysis of ctDNA in clinical settings over NGS, considering factors like cost, turnaround time, and availability of resources.

The Idylla EGFR testing is an accurate and simple tool useful for the early screening of EGFR mutations. The Idylla GeneFusion is a potential screening panel with short turnaround time using a minimal amount of tissue and might be considered as a relevant complementary testing to IHC in diagnostic molecular laboratories.

P2, N=93, Completed, AIO-Studien-gGmbH | Active, not recruiting --> Completed

Mutations are prevalent in those patients who are female, adenocarcinoma, and have never smoked. Moreover, advanced EGFR mutation-positive patients have better PFS and OS than those with wild type EGFR.

Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.

These findings underline the imperious need for implementing quick and efficient targeted methods for routine EGFR mutation testing among NSCLC patients, which is particularly useful in determining patients who are more likely to benefit from targeted therapy.

Patients with EGFR and ALK mutations had a longer life expectancy than those without the mutation. It was observed that testing patients diagnosed with advanced-stage NSCLC for genetic mutations of the tumor in the first step of the treatment and initiating treatment in patients with mutations provided a significant survival advantage.

Finally, we analyzed the progression-free survival (PFS) and overall survival (OS) of commutated patients vs. non-commutated treated with Osimertinib as a first line treatment and, although it was statistically non-significant due to the small sample size (11 vs 9) and the short follow-up, a very positive trend was seen (log-rank test p = 0.055 and p = 0.136 respectively). With the development of NGS, the presence of other commutations besides EGFR have implications that are still unknown, but it appears that it may cause worse OS and PFS. This should be studied in larger cohorts with longer follow-up.

NERoNE evaluates data from NGS profiling of three OU mapping key actionable molecular alterations in a large population of aNSCLC also accounting for PDL1 status. This preliminary analysis will be the starting point for further evaluations in order to improve the personalized approach to aNSCLC. >*For 15 pts PDL1 expression was not known.

Genomic alteration should be systematically evaluated using an NGS reflex testing in surgically resected NS-NSCLC, since future adjuvant therapeutic decision making may consider the presence of compound EGFR mutations as well as co-occuring mutations in other genes, especially in TP53.