EGFR S768I

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.

The side effects were mild to moderate hand-foot-syndrome, hypertension, and proteinuria. Afatinib in combination with bevacizumab are effective and safe in the management of patients with NSCLC harboring EGFR G719X, S768I, L861Q/P single or compound mutations.

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

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

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

P2, N=51, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

The ctDNA-based 101-test is a highly sensitive and specific tool for detecting targetable variants in metastatic NSCLC, particularly in cases with insufficient tissue samples. The findings support the use of ctDNA testing as a reliable and complementary method to traditional tissue-based molecular analysis, enhancing the precision of treatment strategies for NSCLC patients.

Conclusions Comprehensive ctDNA NGS can identify driver EGFR mts and other informative co-alts for patients with LUAD. Frequency and types of such co-alts are mostly similar in AME and other regions.

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.

P3, N=354, Active, not recruiting, Takeda | Trial completion date: Jun 2026 --> Dec 2024 | Trial primary completion date: Feb 2026 --> Dec 2024

Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.

P2, N=23, Not yet recruiting, Taipei Veterans General Hospital, Taiwan | Trial completion date: May 2025 --> Jun 2027 | Trial primary completion date: May 2025 --> Jun 2026

P2, N=95, Active, not recruiting, ETOP IBCSG Partners Foundation | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=100, Recruiting, The University of Sydney | Not yet recruiting --> Recruiting

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 case report is a compelling testimony to the evolving therapeutic landscape of non-small cell lung cancers, providing valuable insight into the potential therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in the realm of rare and complex epidermal growth factor receptor mutations.

This systematic review supports the use of 2nd generation TKI afatinib for G719X, S768I, E709X and L747X mutations, as well as for compound uncommon mutations. For other uncommon mutations such as L861Q, 3rd generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.

MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

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.

P2, N=95, Active, not recruiting, ETOP IBCSG Partners Foundation | Trial primary completion date: Dec 2023 --> Mar 2024

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.

Timely screening of patients with NSCLC for CSF ctDNA, especially for patients with positive plasma ctDNA, may facilitate the early detection of LM. Furthermore, patients with the EGFR 19del may have a higher risk of developing BPM.

P1, N=170, Recruiting, ArriVent BioPharma, Inc.

P1, N=18, Recruiting, Ohio State University Comprehensive Cancer Center | Trial primary completion date: Dec 2023 --> Dec 2024

This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.

The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.

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

P1, N=170, Recruiting, ArriVent BioPharma, Inc. | Phase classification: P1b --> P1

Exon20 insertion mutation was correlated with favorable DFS and lower incidence of bone metastasis in radiological solid lung adenocarcinoma harboring atypical EGFR mutation.

The results support the use of osimertinib as a treatment option for this patient population. Japan Registry of Clinical Trials Identifier: jRCTs071200002.

Exploratory endpoints include: tissue/plasma concordance; analysis of circulating molecules in plasma samples using different profiling approaches to detect minimal residual disease; incidence and change over time of incidental pulmonary nodules. TARGET is currently recruiting, and completion is expected in 2029.

P2, N=95, Active, not recruiting, ETOP IBCSG Partners Foundation | Trial primary completion date: Sep 2023 --> Dec 2023

P1/2, N=334, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

P=N/A, N=70, Recruiting, Pusan National University Hospital | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Dec 2023

Conclusions The result is consistent with FLAURA study for patients with EGFR-activating mutation. Osimeritinib showed clinical activity in patients with EGFR uncommon mutations as first-line treatment.

P1, N=36, Not yet recruiting, Jonathan Riess

P2, N=21, Completed, Zhejiang Cancer Hospital | Active, not recruiting --> Completed

P2, N=100, Not yet recruiting, The University of Sydney

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.

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

The efficacy of second- and third-generation TKIs for NSCLC with uncommon EGFR mutations does not differ, and so can be used to treat NSCLC patients with these mutations.