EGFR G719X

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

Finally, MAD1 and TPRN were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.

P2, N=57, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial completion date: Feb 2024 --> Dec 2024

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

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.

P2, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=52, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jun 2024

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.

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.

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

P1, N=309, Recruiting, Daiichi Sankyo | Active, not recruiting --> Recruiting | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Jan 2022 --> Mar 2026

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.

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.

P3, N=8, Terminated, EQRx International, Inc. | Phase classification: P3b --> P3

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

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.

This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.

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

P1, N=52, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

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.

P1, N=34, Completed, Zeno Pharmaceuticals, Inc. | Phase classification: P1/2 --> P1

P1/2, N=59, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P1/2, N=603, Completed, AstraZeneca | Active, not recruiting --> Completed

P1/2, N=200, Recruiting, Black Diamond Therapeutics, Inc. | Phase classification: P1 --> P1/2 | N=120 --> 200

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.

Dacomitinib may also be an option for these mutations given similar efficacy to afatinib. Superior CNS penetrance and well managed toxicity profile may also be reasons to consider osimertinib. Given that the choice of TKI may depend on the specific mutation, it is crucial that every patient diagnosed with NSCLC undergo comprehensive sequencing to identify these mutations.

P2, N=210, Completed, AstraZeneca | Active, not recruiting --> Completed

P2, N=150, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Dec 2024

P2, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=55 --> 35

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.