EGFR G719A

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.

The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard-of-care treatments. (ClinicalTrials.gov identifier: NCT04790409).

The other driver oncogenes detected using CGP assays were 23 (7.0%) patients of KRAS G12C, 40 (12.1%) patients of KRAS non-G12C, 20 (6.1%) patients of HER2 mutation, 14 (4.2%) patients of MET exon 14 skipping, and 4 (1.2%) patients of RET. Conclusions CGP assays are useful for identifying driver oncogenes in patients with advanced NSCLC, especially for patients whose driver oncogenes were not identified at initial diagnosis.

Updated results will be presented (data cutoff, December 2021). Table: 151P Efficacy according to mutation status

Furmonertinib 160mg orally once daily has shown encouraging efficacy as first-line therapy in EGFR-mutated advanced NSCLC patients with CNS metastases. Patients were well tolerated and the AEs were consistent with previous studies.

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.

P1, N=51, Recruiting, Mayo Clinic | N=77 --> 51

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

He received 2 cycles of carboplatin and paclitaxel followed by ipilimumab and nivolumab. However, our case has shown a durable complete response in CNS disease in a patient with an atypical EGFR mutated NSCLC with LMD that progressed on osimertinib. Further studies are warranted to explore the clinical utility of amivantamab monotherapy in treating patients with CNS metastases or other rare EGFR mutations who progressed on conventional TKIs.

The Idylla EGFR assay demonstrated high specificity and sensitivity for identifying exon 18 and 21 SNVs, and exon 19 deletions. However, the platform has not detected any of the exon 20 insertions seen in our cohort, leading to erroneous results and potentially compromising patient care if this is the only platform used. These insertion mutations are not included in the Idylla EGFR assay design, which is a significant limitation of this assay.

Patients with NSCLC who had LM without BM had better survival outcomes (11.6 months) compared with those who had LM after BM or concurrent LM and BM. Aggressive shunt implantation may be favored for LM.

Conclusions Furmonertinib showed good efficacy as adjuvant therapy in EGFR-muteted NSCLC patients who underwent radical lung cancer surgery, along with an acceptable safety profile without new signals. Furmonertinib also had potential therapeutic efficacy in patients with mGGO lesions.

Together with afatinib, 1G-TKIs combined with chemotherapy might be another effective option for NSCLC patients harboring EGFR uncommon alterations. Based on computational findings, afatinib, dacomitinib, and osimertinib might confer favorable activity to G719A, S768I, and L861Q, whereas almonertinib and furmonertinib revealed less activity to G719A.

Key endpoints were: objective response rate (confirmed ORR, RECIST 1.1); duration of response (DOR); clinical benefit rate (CBR); progression-free survival (PFS); safety; and biomarkers. 29 patients were included (23 with any prior TKI, 16 with prior osimertinib, 6 with no prior TKI). Neratinib monotherapy had meaningful activity in patients with EGFR exon 18-mutant NSCLC in SUMMIT; 31% of patients had a PR and most patients had prior TKIs. Rates of diarrhea were lower than seen in patients with HER2+ breast cancer and compared favorably with rates reported for other TKIs commonly used in lung cancer. Given the lack of effective treatments for patients with NSCLC and difficult-to-treat uncommon mutations after failure of EGFR TKIs, further examination of neratinib in this setting is warranted.

The p.L861Q localized in exon 21 of the EGFR gene was the most common mutation identified in our patients (35.3%), whereas the "classic" EGFR mutations such as Del19 and p.L858R were found in 23.5% and 11.7% of the cases, respectively. Interestingly, most of p.L861X mutation-carrying patients showed good response to TKI treatment. Altogether, our findings suggest a particular distribution of the EGFR-TKIs sensitivity mutations in Tunisian NSCLC patients.

This is the first report of the icotinib treatment achieving long-lasting and stable disease control in an NSCLC patient with EGFR G719A/L833V mutation. Icotinib could be a first-line treatment option in NSCLC patients harboring EGFR G719A/L833V mutation.

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

Combination of sintilimab and anlotinib demonstrated durable efficacy and good tolerability in NSCLC patients with uncommon EGFR mutations. And further investigate is warranted to confirm this new chemo-free strategy.

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.

EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD.

This case first identified a patient with lung squamous cell carcinoma harboring uncommon compound EGFR mutation (G719A and R776C) benefited from afatinib and achieved 11 months of progression-free survival (PFS). Then, new MYC amplification was detected after disease progression, indicating that MYC amplification may be one of the reasons for afatinib resistance.

However, caution is warranted when NGS detects no aberration from any of the multiple sequenced nodules. Examination of the mutational landscape found that altered proto-oncogene KRAS was associated with smaller tumors whereas altered tumor suppressors TP53 and CDKN2A associated with smaller ones, suggesting different roles in these molecules play in tumor growth.

Two cycles of chemotherapy were delivered followed by immunotherapy with ipilimumab and nivolumab. This supports current trial evaluating the efficacy of amivantamab for NSCLC with rare EGFR mutations such as G719X, and ones progressed on 3rd Gen TKI treatment. Additional studies evaluating the efficacy of amivantamab on CNS metastasis are warranted.

Conclusions Combination of sintilimab and anlotinib demonstrated durable efficacy and good tolerability in NSCLC patients with uncommon EGFR mutations. And further investigate is warranted to confirm this new chemo-free strategy.

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

Lung adenocarcinoma with synchronous EGFR G719A and BRAF V600E mutations is rare and has not been previously reported. This case highlights the importance of an adequate response to afatinib and provides an optimal therapeutic option for such patients.

One patient harboring germline T790M mutation and somatic L861Q and G719A mutations received icotinib and the DOT was 15 months...One patient with germline P848L mutation did not respond to either ecotinib or afatinib. Another patient with germline R831H mutation received gefitinib treatment and the progression-free survival was 14 months. Conclusion This study identified more EGFR germline variants other than the previously reported T790M mutation. Patients with EGFR germline variants may benefit from TKIs treatment.

In conclusion, Idylla EGFR assay offers rapid (<2.5 hours) and reliable EGFR testing in routine and challenging specimens with limited material. Automated calling and inclusion of manual review in the process will help to reduce the false negatives in samples with small tissue.

In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.

Presence of EGFR R776H mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that Osimertinib could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients with EGFR R776H.

Funding: Foundation Medicine Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance... Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition . EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.

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)

P3, N=200, Terminated, Sichuan Provincial People's Hospital | Trial completion date: Dec 2023 --> Aug 2020 | Recruiting --> Terminated | Trial primary completion date: Dec 2021 --> Aug 2020; After interim analysis, IRB recommend termination.

Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations but also one ROS1 fusion. The germline-TP53 variants and lung cancer carcinogenesis driven by oncogenic processes needs further evaluation.