EGFR exon 21 mutation

Our experience confirms the need to develop standards-based guidelines for the routine performance and evaluation of EGFR testing to improve clinical care for this subset of lung cancer. On the other hand, our study demonstrated that tumors with exon 19 deletions and L858R harbor specific clinicopathological features in NSCLC.

This suggests that ctDNA shedding might be associated with some underlying tumor biology, reflective of a more aggressive phenotype. Given the small sample size, validation using a larger cohort should be performed.

P2, N=41, Active, not recruiting, University of Texas Southwestern Medical Center | Trial primary completion date: Apr 2024 --> Sep 2024

Besides, there is also a subtype of EGFR mutations, known as EGFR 20 exon insertion (EGFR 20ins) mutation. The authors summarized the treatment of a lung adenocarcinoma patient with EGFR 20ins mutation accepting Furmonertinib mesylate, in order to provide effective references for clinical diagnosis and treatment..

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

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.

The status of EGFR mutations serves as a predictive factor for PFS, DCR, and ORR in lung cancer patients undergoing EGFR-TKI first-line therapy. This status can be a valuable predictive indicator of lung cancer treatment efficacy, with potential applications in clinical practice.

First-line treatment with upfront brain RT plus EGFR-TKIs is likely to be more effective than EGFR-TKIs alone. The benefits of combination therapy did not appear to be significantly affected by BM-related symptoms, EGFR mutation subtype, number of BMs, or sex.

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.

These cases suggest that osimertinib is a promising treatment option for patients with EGFR 19 deletion-mutated lung adenocarcinoma and bone metastases, although further clinical studies are needed to confirm its efficacy.

In our cohort, poor outcomes among pts with EGFR and TP53 co- mutation were driven primarily by the Ex21mt-TP53mt co-mutated population. This data suggests that previously described inferior disease response of TP53mt cancers to first- and second-generation EGFR TKIs may extend to osimertinib use in the 1L setting, with this difference more pronounced in Ex21mt-TP53mt NSCLC.

Osimertinib is an effective first-line treatment in Asian patients with advanced EGFRm+ NSCLC with durable OS, PFS and TTF, comparable with reported data. Positive smoking history, poor ECOG and EGFR exon 21+ are negative prognostic factors. Common post-osimertinib resistance mechanisms in this cohort were cMET amplification, C797S mutation and histologic transformation.

EGFR-independent alterations are common among patients with primary resistance to osimertinib and significantly impact PFS and OS. Our results suggest that among Hispanic patients, other variables associated with intrinsic resistance include the number of commutations, high levels AXL mRNA, and low levels of BIM mRNA, T790M de novo, EGFR p.L858R presence, and a high tumoral mutational burden.

The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

P3, N=60, Recruiting, Qingdao Central Hospital | Trial primary completion date: Dec 2022 --> Dec 2023

Neoadjuvant osimertinib therapy is feasible in stage III patients, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks prior to definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumour size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

P2, N=117, Recruiting, Fox Chase Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2023 --> Jan 2024

EGFR-independent alterations are common among patients with primary resistance to osimertinib and significantly impact PFS and OS. Our results validate the execution of broad NGS panels that allow the identification of the main co-mutations and calculates TMB to define the best approach for patients with EGFR mutations and complex genotypes. A greater understanding of the role of early cfDNA tracing and BIM/AXL mRNA expression is required to consider its use in regular clinical practice.

Hybrid therapy in NSCLC resulted in 95% local control at 2 years after surgery. EGFR treatment-naïve patients initiating therapy after hybrid therapy had significantly improved survival advantage. EGFR-targeted therapy initiated before hybrid therapy did not confer survival benefit.

Increased age, smoking, distant metastases, brain metastases, and exon 21 mutations were not associated with PFS. NLR significantly affected PFS.

Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

Patients with EGFRm + NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.

Gender and Osimertinib affected OS...This is the only study who reported a better PFS in EGFR exon 21 mutation. Additional research are needed to further investigate whether a difference in the tumor biology between exon 19 deletion and exon 21 mutation exists especially in Asian population.

Surprisingly, the incidence of PD in the brain was 29%, indicating the importance of regular brain imaging. The role of LAT needs to be explored in future studies.

Pathological biomarkers of primary cancer should be considered to predict clinical outcomes after SRS in patients with lung ADC. Use of such biomarkers may help to provide personalized treatment to each patient, improving clinical outcomes after SRS.

Clinical trial identification Editorial acknowledgement Legal entity responsible for the study N. Peled Funding AstraZeneca Background The treatment of unresectable, locally advanced stage III NSCLC is concurrent chemoradiation therapy (CRT), followed by consolidation durvalumab. No particular SAEs were reported during the osimertinib or the radiation phases. Conclusions This chemotherapy-free approach is a potentially good option for downstaging locally advanced, inoperable, EGFR-mut NSCLC, allowing reduction of the radiation field, preservation of lung tissue, and reduced radiation-induced toxicity.

Gefitinib was used in 59.1% of patients and erlotinib in the remaining 40.9%, resulting in an objective response of 56.0%. PFS and OS were numerically longer when EGFR TKIs were used in combination with nicotinamide than when patients were treated with EGFR TKIs alone. (ClinicalTrials.gov Identifier: NCT02416739)

The KEAP1/NFE2L2 transcriptomic signature outperforms mutational status in identifying patients with a bad prognosis. Our analysis confirms the poor prognosis of this NSCLC-subgroup in the real-world setting, even when favorable subgroups are excluded for comparison.

70% of patients with actionable alterations were matched to targeted therapies: 100% of patients with an EGFR exon 19/21 mutation (Erlotinib or Gefitinib), ALK fusion (Crizotinib or Alectinib) or ERBB2 exon 20 insertion mutation (Poziotinib, clinical trial); 50% of patients RET fusion (Alectinib, clinical trial), 50% of patients with MET exon 14 skipping mutation (Tepotinib or Capmatinib, clinical trial) and 0% of patients with BRAF V600E mutation or EGFR exon 20 insertion mutation. With the increasing number of targeted therapies developed for molecularly-driven NSCLC, genomic profiling of all patients with advanced adenocarcinoma is crucial. When there is not enough tissue for molecular testing, plasma-based NGS can guide first-line treatment decisions in metastatic NSCLC and increase access to targeted therapy, which may lead to prolonged survival.

Background : The treatment of EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) has been modified over the last years with the advent of osimertinib...TKI sequencing in the setting of EGFR-mutant NSCLC is thus highly feasible in a real-world setting. With new therapeutic options still emerging, TKI sequencing remains clinically relevant.

In this cohort study, driver variations in patients with unresectable locally advanced NSCLC were associated with significantly shorter PFS time after definitive chemoradiation and consolidative durvalumab. These findings suggest the need to consider additional or alternative treatment options to the PACIFIC regimen for patients with driver variations.

P2, N=41, Active, not recruiting, University of Texas Southwestern Medical Center | Recruiting --> Active, not recruiting | Trial completion date: Apr 2022 --> Apr 2025 | Trial primary completion date: Apr 2022 --> Apr 2024

In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR-TKI. The benefit was especially pronounced in patients with the exon 21 mutation.

EGFR overexpression in range of 61% to 80% was an independent survival predictor in patients with HCC, implying that these patients could benefit from EGFR inhibition. However, the absence of EGFR mutations in exons 18-21 in any of the cases of this study suggest that single drug EGFR targeted therapy in patients with HCC may be insufficient.

Analysis included 16 stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers which started treatment in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP) between October 2018 and January 2022...9 patients received a TKI therapy in first line (4x Afatinib; 5x Osimertinib) with an ORR of 66.7% (CR = 1; PR = 5; SD = 1; PD = 2) and a median time-to-next-treatment of 6.7 months (range: 2.1-39.1 months)... In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations, comparable to results for common EGFR mutations in IMpower150 (ORR 71%, mPFS: 9.7 months, mOS 29.4 months). This in contrast to immunotherapy alone which shows poor ORR and PFS. Together with new targeted treatment options for Exon 20 insertions like amivantamab (ORR 40%, mPFS 8.3 months) or mobocertinib (ORR 28%, mPFS 7.3 months), ABCP is a valuable option in the early course of treatment for this patient cohort.

This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.

P2, N=26, Active, not recruiting, National Cancer Center, Korea | Recruiting --> Active, not recruiting

An analysis of resected and non-resected lung ADC specimens in 150 Moroccan Northeast patients, revealed that acinar and papillary patterns may predict the presence of a mutation in the EGFR gene. While the solid major pattern may indicate a low mutation rate of the EGFR gene.

Mixed tumor histology and baseline bone metastases were also noted in our patients, and 3 patients had EGFR, KRAS, and BRAF amplifications. A larger systematic analysis of genetic and clinical predictors of poor response to 1L osimertinib is ongoing.

P2, N=117, Recruiting, Fox Chase Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2022 --> Jan 2023

Presence of EGFR T854A mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that osimertinib may be an effective treatment to improve survival outcomes in patients with EGFR T854A.

A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.