EGFR Mutation Type Research Articles

EGFR mutation based on lung laterality in adenocarcinoma type of non-small cell lung cancer

Targeted therapies have shown promise in improving survival rates for lung adenocarcinoma, a common and deadly malignancy. EGFR-targeting tyrosine kinase inhibitors (TKIs) are particularly effective among these therapies in cases with EGFR mutations. Detecting these mutations before TKI treatment is essential. Various radiological features have been linked to EGFR mutations. However, the relationship between tumor location and mutation types in Indonesian lung adenocarcinoma patients remains unexplored. This study aimed to identify the frequency of EGFR mutation in local lung adenocarcinoma cases based on the tumor location. Clinical data of lung adenocarcinoma patients (n = 272) diagnosed between 2018 and 2022 were retrospectively taken from the Department of Anatomical Pathology, Dr. Sardjito General Hospital, Yogyakarta. The qRT-PCR data of EGFR mutation status was obtained from the Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta. Descriptive analysis was performed using STATA version 14.0. EGFR mutations were found in 60.7% of patients, with 58.2% having exon 19 mutations and 21.2% exhibiting exon 21 L858R mutations. Mutation status was found to be significantly different based on the patient's gender (p = 0.022) and age (p = 0.029) but not with lung laterality (p = 0.093). The proportion of exon 19, exon 21 L858R, and uncommon mutations in the right and left lung adenocarcinoma was similar across all samples. This study found no difference between specific EGFR mutation types and tumor location in lung adenocarcinoma.

Correlation analysis between driver gene mutation and clinicopathological features in lung adenocarcinoma based on real-world cumulative clinical data.

Driver genes are essential predictors of targeted therapeutic efficacy. Detecting driver gene mutations in lung adenocarcinoma (LUAD) patients can help to screen for targeted drugs and improve patient survival benefits. This study aims to investigate the mutation characterization of driver genes and their correlation with clinicopathological features in LUAD. A total of 440 LUAD patients were selected from Sir Run Run Shaw Hospital between July 2019 and September 2022. Postoperative tissue specimens were analyzed for gene mutations using next-generation sequencing technology, focusing, including epidermal growth factor receptor EGFR, ALK, ROS1, RET, KRAS, MET, BRAF, HER2, PIK3CA and NRAS. At the same time, clinicopathological data were collected and organized for multidimensional correlation analysis. Of 440 LUAD patients, driver gene mutations were not detected in 48 patients. The proportion of patients with driver gene mutations was as high as 89.09%. The top three driver genetic mutations were EGFR, KRAS, and MET. Sixty-nine types of EGFR mutations were detected and distributed in the protein tyrosine kinase catalytic domain (56, 81.16%), Furin-like cysteine-rich region (9, 13.04%), receptor binding domain (3, 4.35%), and EGFR transmembrane domain (1, 1.45%). Single gene locus mutation occurred in 343 LUAD patients, but the mutation gene types covered all tested genes. Our findings showed that EGFR mutations were more commonly observed in non-smoking and female patients (P<0.01), KRAS mutations were more prevalent in male patients and smokers (P<0.01), ROS1 mutations had larger tumor diameters (P<0.01) and RET mutations were more prevalent in smokers (P<0.05). LUAD patients exhibit diverse genetic mutations, which may co-occur simultaneously. Integrated analysis of multiple mutations is essential for accurate diagnosis and effective treatment of the disease. The use of NGS can significantly expand our understanding of gene mutations and facilitate integrated analysis of multiple gene mutations, providing critical evidence for targeted treatment methods.

CD155 Expression in Early-Stage Lung Adenocarcinoma

BackgroundCluster of differentiation (CD) 155 is a transmembrane protein that belongs to the nectin-like molecule family, which is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathologic stage I lung adenocarcinoma remains poorly understood. MethodsWe analyzed 320 patients diagnosed with pathologic stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinical and pathologic characteristics and clinical outcomes between these groups. ResultsMutation status of the epidermal growth factor receptor gene (EGFR) was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, and 131 patients (40.9%) had EGFR mutant-type. CD155 expression was classified as high in 77 patients (24.1%) and as low in 243 (75.9%) as low. Multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. Multivariate analysis showed high CD155 expression was an independent poor prognostic factor for recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type. ConclusionsOur findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathologic stage I lung adenocarcinoma, particularly in cases without EGFR mutation.

OSIRAM-1/TORG1833: Overall survival results of a randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer.

8613 Background: Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). We have previously shown the result of progression free survival (PFS) as a primary endpoint, the median PFS was 20.0 months for Osi+Ram and 24.0 months for Osi, hazard ratio of 1.054 (95% CI 0.674-1.648). In further analyses, we aimed to examine the effects of this combination therapy on overall survival (OS). Methods: Previously untreated EGFR mutation-positive advanced non-squamous NSCLC patients with a performance status of 0 or 1 were eligible. Asymptomatic and/or treated brain metastases were included. Eligible patients were randomized at a 1:1 ratio to receive Osi (80mg) every day either without or with Ram (10mg/kg) every 2 weeks until disease progression or unacceptable toxicity, stratified according to gender and the type of EGFR mutation (exon 19 deletion, L858R). The primary endpoint was PFS assessed by the independent blinded radiologic reviewer. Secondary endpoints included PFS assessed locally, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), OS and safety. Results: Between November 2018 and April 2020, 122 patients (Osi+Ram: 59, Osi: 63) were enrolled. The patients' characteristics were well balanced. 59% were females, and 61% had an exon 19 deletion. Median age was 70 years old (range, 29-86). With a median follow up of 36.0 months, the median OS was 43.4 months (95% CI 36.5-N.R.) for Osi+Ram and N.R. (95% CI 41.3-N.R.) for Osi, resulting in a hazard ratio of 1.159 (95% CI 0.645-2.083, p = 0.62). Median treatment duration for Ram was 140 (14-1239) days. Ram was discontinued in 45 patients (76%) by the treatment related adverse effects. Common reasons for Ram discontinuation were platelet count decreased (n=14), proteinuria (n=12), neutrophil count decreased (n=11), pneumonitis (n=3), bleeding (n=3) and infection (n=3). Pneumonitis was observed in 16% in Osi, 9% in Osi+Ram, with grade 3 observed in 2% of both arms. Conclusions: Both treatment arms demonstrated sustained OS over 43 months. However, this study did not show an advantage of biweekly Ram administration with Osi in terms of PFS and OS. Notably, there was surpassed increase of early discontinuation of Ram due to higher adverse events. Clinical trial information: 2080224085 .

Validation of article analysis by ChatGPT: Using a cohort of patients with EGFR mutation-positive non-small cell lung cancer treated with first-line osimertinib.

e20542 Background: The rapid advancement of large language models like ChatGPT has shown potential in various fields, including medicine. However, their applicability in clinical practice, especially in complex medical knowledge interpretation, remains unclear. This study developed a framework for article analysis, retrieval of additional information, and knowledge updating using ChatGPT and tested its clinical validity by comparing it to clinical data. Methods: To simplify the prompt to ChatGPT by selecting monotherapy, patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) who had received 1st -line treatment with Osimertinib, were included in this study. ChatGPT analyzed published FLAURA trial data and developed a scoring system for predicting treatment efficacies for comparison with clinical data. Treatment efficacies were evaluated by using progression-free survival (PFS) and overall survival (OS). ChatGPT searched for papers needed to update the scoring system and extracted 5 papers. To reduce the bias of the search, the extraction of papers by ChatGPT was repeated 10 times and the top 5 papers were selected. The revised scoring system, incorporating insights from these 5 papers, was applied to data from Shizuoka Cancer Center (1st-line osimertinib initiated during 2018-2022.3). The clinical validity of analyses by ChatGPT was evaluated in terms of whether the scoring system reflects clinical practice. Analysis with ChatGPT was performed using GPT4 and natural language prompts. Results: Based on the FLAURA study, ChatGPT created a scoring system consisting of the following items: EGFR mutation type, presence of CNS metastasis, smoking history, sex, and performance status (PS). ChatGPT extracted two prospective studies and three retrospective studies. The scoring system, updated by ChatGPT included EGFR mutation type: exon 19 del /L858R (3/1point), sex: female/male (2/1), smoking history: never-smoker/smoker (2/1), CNS metastases: without/with (2/1), PS 0/1/2/3/4 (2/1/0/-1/-2), age: &lt; 75/≥ 75 years (2/1) PD-L1 expression &lt; 50%/≥ 50% (2/0); liver metastasis, without/with (2/0). Group A showing better efficacies to treatment was defined as patients with a cutoff value of 11 or higher. The scoring system was fitted to validate cohort (140 patients without missing scoring system items). Group A (n = 98, ≥11points) outperformed Group B (n = 42, &lt; 11) in both PFS and OS (medianPFS 22.6 months vs. 9.7 months HR 0.32, 95% CI 0.20-0.50, p &lt; 0.0001, medianOS 54.4 months vs. 21.7 months HR 0.28, 95%CI 0.16-0.49, p &lt; 0.0001). Conclusions: The scoring system created by using ChatGPT reflected the efficacies in a cohort of EGFR-positive NSCLC patients treated with 1st-line osimertinib. The framework for article analysis, retrieval of additional information, and knowledge update using ChatGPT is potentially applicable to other cohorts.

A randomized phase II trial of 8 months of afatinib switching to osimertinib (A) versus osimertinib alone (B) as first-line treatment in advanced NSCLC patients with common EGFR mutation: YAMATO study (TORG1939/WJOG12919L).

8574 Background: NSCLC with common EGFR mutation (L858R or exon 19 deletion (Del19)) is known to originally comprise small portion of uncommon and compound EGFR variant cells including T790M-mutant ones albeit treatment-naïve. To overcome concomitant heterogeneous EGFR mutations, we planned a randomized phase II trial to assess the strategy of switching to osimertinib following 8 months of afatinib compared with osimertinib alone. Methods: YAMATO study is an open-label, multi-center, randomized phase II study. Patients with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (L858R or Del19) were randomized in a 1:1 ratio to receive up-front 8 months of afatinib (30 mg or 40 mg QD) followed by osimertinib (80 mg QD) (arm A) or osimertinib (80mg QD) alone (arm B) until disease progression or intolerable toxicity. The primary endpoint is 2-year progression free survival (PFS) rate with threshold rate of 22% and expected rate of 40% (one-tailed alpha of 0.1, beta of 0.2). Secondary endpoints are objective response rate (ORR), PFS, time to treatment failure, overall survival and adverse events. Results: Between May 2020 and Apr 2021, 113 patients were enrolled from 27 institutions (A/B 56/57). Patient characteristics were as follows: median ages, 73.5/71 years (range 41-85/41-92 years); proportion of males, 42.9/35.1%; EGFR mutation types, L858R/Del19 59/41% in A, 58/42% in B. The difference of two-year PFS rate was not observed statistically significant between groups (37.3% [80% CI, 29.0 to 45.5] in arm A vs 47.4% [80% CI, 38.5 to 55.7] in arm B; p=0.44; HR:1.28 [80% CI, 0.95-1.73]). The ORR was 82% in arm A and 87% in arm B. With the median follow-up of 27.5 months, median PFS was 16.8 months in arm A, and 22.2 months in arm B (HR: 1.280, p = 0.29). Severe pneumonitis occurred in 7% in arm A, most of which developed after switching to osimertinib, and 1.8% in arm B. Conclusions: YAMATO study failed to demonstrate the superiority of EGFR-TKI switching therapy of 8 months afatinib to osimertinib over osimertinib alone in terms of 2-year PFS rate in untreated advanced NSCLC patients with common EGFR mutations. Clinical trial information: 031200021 .

Real-world data analysis of first-line targeted therapy for patients with non-small cell lung cancer with different EGFR mutation status in a tertiary care hospital.

e20586 Background: Lung cancer is still the malignant tumor with the highest incidence and mortality rate in the world, of which non-small cell lung cancer (NSCLC) accounts for about 85%. The EGFR mutation rate in Asians is 30%-60%, with exon 19 deletion mutations and exon 21 L858R point mutations accounting for about 90% of EGFR mutations, which are the classic EGFR mutation types. The two have significant differences in clinical characteristics, and some clinical trials have shown differences in efficacy between different subgroups, but whether they exist in the real world needs to be further confirmed. Meanwhile, the efficacy of first-line targeted therapy in patients with coexisting mutant NSCLC harboring different EGFR classical mutations and whether there is a difference in different subgroups has not been conclusively determined. Methods: To collect general clinical data and their genetic test reports of NSCLC patients diagnosed with gene mutations who attended the Affiliated Hospital of North Sichuan Medical College from January 2019 to December 2021 for follow-up, with a follow-up date of June 30,2023, as the end date. Kaplan-Meier survival analysis and log-rank test were applied to compare:1)the median PFS in different subgroups of patients with no co-mutation classic EGFR mutation;2)the median PFS in patients with co-mutation classic EGRR mutation and no co-mutation classic EGFR mutation;3)the median PFS in different subgroups of patients with no co-mutation 19-Del/L858R and with co-mutation 19-Del/L858Rpatients;4)median PFS of patients between co-mutated 19-Del and L858R subgroups. Results: The median PFS of 19Del was significantly better than that of L858R in different subgroups of EGFR classical mutations (14.0 months vs. 8.1 months, p = 0.004 &lt; 0.05). The median PFS of EGFR classical mutation was significantly better than that of EGFR classical mutation with co-mutation,11.1months vs. 5.8 months, respectively, p &lt; 0.001. In different subgroups,19Del median PFS was superior to 19Del co-mutation (14.0 months vs. 6.1 months, p = 0.001 &lt; 0.05),and L858R median PFS was superior to L858R co-mutation (8.1 months vs. 5.8 months, p = 0.449 &gt; 0.05). 19Del co-mutation and L858R co-mutation median PFS were not observed in the analysis of the same simple 19del first-line targeted therapy survival benefit was significantly better than the similar survival benefit of L858R, whose median PFS was 6.1 months vs. 5.8 months, respectively, p = 0.449&gt;0.05, the difference was not statistically significant. Conclusions: The survival benefit of first-line targeted therapy for 19Del in the real world is superior to that of L858R, while the clinical benefit of first-line targeted therapy is poor for classical mutations in EGFR with co-mutations, and combinations with other therapeutic modalities should be considered.

Investigation of RBM10 mutation and its associations with clinical and molecular characteristics in EGFR-mutant and EGFR-wildtype lung adenocarcinoma

BackgroundRBM10 is commonly mutated in lung adenocarcinoma (LUAD). However, its role in the pathogenesis of LUAD remains undefined. EGFR-mutant LUAD represents a distinct subset of non-small cell lung cancer (NSCLC). The function of RBM10 in tumor pathogenesis is supposed to differ between EGFR-mutant and EGFR-wt LUAD. This study aimed to interrogate the prevalence of RBM10 mutation in a large cohort of Chinese patients with LUAD and investigate the association of RBM10 mutation with clinical and molecular characteristics of EGFR-mutant and EGFR-wt LUAD. MethodsTumor sequencing data from 2848 Chinese patients with LUAD were retrospectively reviewed and analyzed. The prevalence of RBM10 was also compared with other three cohorts: OrigMed (n = 1222), MSKCC (n = 1267), and TCGA (n = 566). The associations of RBM10 mutation with clinical and molecular characteristics were assessed. An external cohort of 182 patients with LUAD who received PD-1 inhibitor were used to investigate the association of RBM10 mutation with clinical outcomes upon immunotherapy. ResultsOur cohort showed a higher prevalence of RBM10 in EGFR-mutant LUAD than in EGFR-wt LUAD (14.8 % vs. 6.5 %, p < 0.001). The enrichment of RBM10 mutations in EGFR-mutant LUAD was also seen in another Chinese cohort (OrigMed: 14.9 % vs. 7.8 %, p < 0.001), but not in the two western cohorts (MSKCC: 7.4 % vs. 9.5 %, p = 0.272; TCGA: 8.1 % vs. 6.7 %, p = 0.624). RBM10 mutations co-occurred more frequently with EGFR L858R mutations (23.7 %) than with other types of EGFR mutations (19 del: 7.7 %; other: 7.1 % in others, p < 0.001). In EGFR-mutant LUAD, RBM10 mutations were more commonly found in stage I (18.2 %) and II (21.8 %) vs. stage III (9.4 %) and IV (11.3 %) tumors (p < 0.001). The proportion of PD-L1 positive expression in EGFR-mutant LUAD with concomitant RBM10 mutation was not different from that those without RBM10 mutations (41.8 % vs. 47.9 %, p = 0.566). In contrast, RBM10 mutation occurred more frequently in EGFR-wt LUAD at stage II-IV (stage II: 12.0 %, stage III: 8.7 %, stage IV: 6.6 %) than at stage I (2.8 %). EGFR-wt LUAD with concomitant RBM10 mutations had higher proportions of PD-L1 expression positivity (78.9 % vs. 61.9 %, p = 0.014) and higher tumor mutational load (8.97 vs. 2.99 muts/Mb, p < 0.001) than those without. Patients with EGFR-wt LUAD who also harbored RBM10 loss of function (LOF) mutations had a longer median PFS upon immunotherapy than those with RBM10 non-LOF mutations (7.15 m vs. 2.60 m, HR = 4.83 [1.30–17.94], p = 0.010). ConclusionWe comprehensively investigated RBM10 mutations in a Chinese cohort with LUAD. Compared to western cohorts, a significant enrichment of RBM10 mutations in EGFR-mutant LUAD compared to EGFR-wildtype LUAD in the Chinese population. RBM10 mutation shows different associations with clinical and molecular characteristics between EGFR-mutant and EGFR-wt LUAD, suggesting a divergent mechanism between these two subsets via which RBM10 deficiency contribute to tumor pathogenesis. The findings contribute to our understanding of the molecular landscape of LUAD and highlight the importance of considering population-specific factors in cancer genomics research.

Abstract 2503: The role of APOBEC in early stage-EGFR mutant non-small cell lung cancer

Abstract Background: The APOBEC family of zinc-coordinating enzymes converts cytosines to uracils in single-strand DNA. APOBEC plays a crucial role in the mutation process of non-small cell lung cancer (NSCLC) and is essential for both adaptive and innate immune responses. This study aims to evaluate the role of the APOBEC mutation signature in early-stage non-small cell lung cancer (NSCLC). Methods: We conducted whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or formalin-fixed paraffin-embedded samples from 100 patients diagnosed with pathologic stage II-IIIA non-squamous NSCLC, all of whom underwent complete resection between January 2014 and December 2020 at Samsung Medical Center. This study aimed to assess the impact of APOBEC enrichment on disease-free survival (DFS), progression-free survival (PFS) of EGFR-TKI, and overall survival following recurrence. Results: Median follow-up duration was 58.2 months (range, 11.3-141.1). Of the patients, 74% were never-smokers, and 52% had stage III disease. Among the 100 patients, 18 (18%) exhibited APOBEC enrichment (≥ 2). The median RFS was 25.2 months (95% CI, 17.3-33.2). Notably, APOBEC enrichment did not show a significant association with DFS (P=0.14). Among the 76 patients who experienced radiological recurrence, 69 received EGFR-TKI as first-line treatment. The median PFS for EGFR-TKI was 22.9 months (95% CI, 13.0-32.8). However, within this group, patients with APOBEC enrichment showed a shorter PFS compared to those without APOBEC enrichment (8.1 months vs. 24.6 months, P=0.014). In multivariate analysis, poor PFS of EGFR-TKI was associated with the type of EGFR mutation (L858R vs. exon 19 deletion, HR=1.9, P=0.04), TP53 mutation (mutation vs. wild type, HR=2.1, P=0.03), and APOBEC enrichment (≥ 2 vs. &amp;lt;2, HR=2.2, P=0.02). Overall survival from the starting EGFR-TKI was 61.1 months and 21.7 months for patients with APOBEC enrichment or patients without APOBEC enrichment, respectively (P=0.027). Conclusions: APOBEC mutation signature may be presented at initial diagnosis of early-stage EGFR mutant NSCLC and it was associated with poor PFS of EGFR-TKI and overall survival. Citation Format: Hyun Ae Jung, Jinyeong Lim, Yoon-La Choi, Sehhoon Park, Jong-Mu Sun, Myung-Ju Ahn, Se-Hoon Lee. The role of APOBEC in early stage-EGFR mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2503.

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer

BackgroundEGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published.MethodsMedical records of patients with resectable NSCLC stage I–III diagnosed during 2015–2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher’s exact test. Survival analysis was done by cox-regression method.ResultsTotal 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity).ConclusionThe prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Differential efficacy of tyrosine kinase inhibitors according to the types of EGFR mutations and agents in non-small cell lung cancer: a real-world study

BackgroundBoth first and second-generation EGFR-TKIs are recommended in advanced NSCLC with common EGFR mutations. However, there are few data on the difference in efficacy of EGFR-TKIs based on the type of EGFR mutation and agents.MethodsThis retrospective real-world study evaluated the outcomes and clinicopathologic characteristics, including the type of EGFR mutations, of 237 advanced NSCLC patients treated with first- or second-generation (afatinib) EGFR-TKIs as first-line therapy.ResultsThe median progression-free survival (PFS) and overall survival (OS) of all patients were 11 months (M) and 25M, respectively. In the univariate analysis, patients with exon 19 deletion (del) (n=130) had significantly longer median OS compared to those with other mutations (L858R: 84, others: 23) (30 vs. 22 M, p=0.047), without a difference in PFS (p=0.138). Patients treated with afatinib (n=60) showed significantly longer median OS compared to those treated with first-generation TKIs (gefitinib: 159, erlotinib: 18) (30 vs. 23 M, p=0.037), without a difference in PFS (p=0.179). In patients with exon 19 del, there was no significant difference in median PFS (p=0.868) or OS (p=0.361) between patients treated with afatinib and those treated with first-generation TKIs, while significantly better PFS (p=0.042) and trend in OS (p=0.069) were observed in patients receiving afatinib in other mutations. Exon 19 del was independently associated with favorable OS (p=0.028), while age >70 years (p=0.017), ECOG performance status ≥2 (p=0.001), primary metastatic disease (p=0.007), and synchronous brain metastasis (p=0.026) were independent prognostic factors of poor OS.ConclusionsThe EGFR exon 19 del was associated with favorable OS in advanced NSCLC patients receiving first-line EGFR-TKIs. Moreover, in patients with exon 19 del, first-generation TKIs seem to be a reasonable treatment option if osimertinib is unavailable.

Abstract C022: Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results

Abstract Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (r/rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver (L858R, Ex19del), intrinsic (atypical) driver (L718Q, L861Q, S768I), and acquired resistance mutation (C797X). BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preliminary results from the Phase 1 dose escalation study (NCT05256290) are presented. Methods: BDTX-1535-101 is a first-in-human study enrolling patients with locally advanced or metastatic NSCLC harboring EGFR mutations, with or without CNS disease, following standard of care EGFR inhibitor therapy, or patients with r/rGBM expressing EGFR alterations. The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Using an adaptive Bayesian optimal interval design, eligible patients are enrolled and dosed daily for 21-day cycles until treatment discontinuation. Results: As of 20 May 2023, 51 patients (24 NSCLC, 27 r/rGBM) were enrolled and treated across 7 dose cohorts (15mg – 400mg QD). For NSCLC, mean age was 65 years (range 47-81), patients had a median of 2 prior lines of treatment (1-9), and 79% received prior osimertinib. For r/rGBM, the mean age was 58 years (41-85) with a median of 2 prior lines of treatment (range 1-4). The most common all-grade treatment-related AEs (TRAE) were rash (76%), diarrhea (51%), stomatitis (29%), paronychia (20%) and nausea (20%), vast majority Gr 1 to Gr 2. Gr 3 TRAEs greater than or equal 10% were diarrhea (12%) and rash (10%). Plasma exposure of BDTX-1535 increased dose proportionally with a half-life of ~15h supporting once daily dosing. The maximum tolerated dose is 300mg QD. Circulating tumor DNA (ctDNA) assessment in NSCLC patients with classical and intrinsic drivers as well as acquired resistance mutations revealed significant ctDNA reductions across all EGFR mutation types. Five of 12 patients with either intrinsic driver (eg, L718Q) or acquired resistance (C797S) mutations in a subgroup of NSCLC efficacy evaluable patients at doses at or above 100mg had a confirmed partial response (PR) by RECIST1.1; 1 patient had unconfirmed PR, while the remaining 6 patients had stable disease. Additional GBM data will be shared separately.Conclusions:BDTX-1535 was well-tolerated at a daily dose up to 300mg and promising preliminary clinical activity was observed in NSCLC patients harboring either intrinsic driver or acquired resistance EGFR mutations post-progression with an EGFR inhibitor. A preliminary RP2D dose is being explored in NSCLC patients in dose expansion cohorts. : Citation Format: Helena Yu, Melissa Johnson, Jason T. Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C022.

Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites

Acquired drug resistance occurred in the treatment of non-small-cell lung cancer is a persistent challenge, especially in EGFR mutant type. In this study, we present design, synthesis and biological evaluation of novel quinazoline and pyrrolopyrimidine derivatives that simultaneously occupy the orthosteric and allosteric sites of EGFR. Among them, compound A-7 was confirmed as a potential EGFRL858R/T790M/C797S and EGFRDel19/T790M/C797S inhibitor. Docking study indicated that compound A-7 could simultaneously occupy two binding sites of EGFR and form three key H-bonds with the residues Met793, Lys745 and Met766 in two regions.

Real-world study of PD-1/L1 immune checkpoint inhibitors for advanced non-small cell lung cancer after resistance to EGFR-TKIs.

Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) inhibitors have achieved good efficacy and safety in patients with advanced EGFR mutation-negative non-small cell lung cancer (NSCLC), but their efficacy in patients with previous EGFR mutations is limited. The aim of the present study was to explore the efficacy of PD-1/L1 immune checkpoint inhibitors for the treatment of patients with advanced NSCLC who are resistant to EGFR-TKIs. This retrospective study included 123 patients with stage IV NSCLC who received treatment in Shanghai Changzheng Hospital between January 2019 and January 2022 after failure of first-line EGFR-TKIs. Of them, 39 received ICIs + chemotherapy and anti-angiogenic drugs (ICIs+BCP group), 51 received ICIs monotherapy (ICIs group), and 33 received chemotherapy and anti-angiogenic drugs (BCP group). The gender, age, smoking history, ECOG score, EGFR mutation type, PD-L1 TPS expression, and the first routine blood index before second-line treatment of all enrolled patients were recorded, and their clinical outcomes and prognosis factors were analyzed. There was no significant difference in the objective response rate (ORR) and disease control rate (DCR) between the three groups. Patients in ICIs+BCP group had better prognosis than those in ICIs monotherapy group (PFS:9.5 vs. 4.64 months, p<0.001; OS: 16.97 vs. 7.9 months p<0.001) or BCP group (9.5 vs. 6.48 months, p<0.005; OS: 16.97 vs. 11.39 months p<0.005). Our findings suggest that in the real-world practice in China, PD-1/L1 immune checkpoint inhibitors combined with chemotherapy and anti-angiogenic drugs are effective for the treatment of patients with advanced NSCLC who are resistant to EGFR-TKIs.

Differential efficacy of tyrosine kinase inhibitors (TKIs) according to the types of EGFR mutations and agents in non-small cell lung cancer (NSCLC): A real-world study.

e21040 Background: Both 1st and 2nd-generation (gen) EGFR-TKIs are recommended in advanced NSCLC with common EGFR mutations. However, there are few data about the difference in the efficacy of EGFR-TKIs according to types of EGFR mutations and agents. Methods: This retrospective real-world study evaluated the outcome and clinicopathologic characteristics including the type of EGFR mutations in 237 advanced NSCLC patients (pts) treated with 1st or 2nd-gen (afatinib) EGFR TKIs as first-line therapy. Results: The median progression-free survival (PFS) and overall-survival (OS) of all pts were 11 months (M) and 25M, respectively. In univariate analysis, pts with exon 19 deletion (del) (n = 130) had significantly longer median OS compared to those with other mutations (L858R: 84, others: 23) (30 vs. 22 M, p = 0.047), without difference in PFS (p = 0.138). Pts treated with afatinib (n = 60) showed significant longer median OS compared to those treated with 1st gen TKIs (gefitinib: 159, erlotinib: 18) (30 vs. 23 M, p = 0.037). In pts with exon 19 del, there was no significant difference in median PFS (p = 0.868) and OS (p = 0.361) between pts treated with afatinib and those with 1st gen TKIs, while significantly better PFS (p = 0.042) and trend in OS (p = 0.069) were observed in pts receiving afatinib in other mutations. Exon 19 del was independently associated with favorable OS (p = 0.028), while age &gt; 70 years (p = 0.017), ECOG performance status ≥2 (p = 0.001), primary metastatic disease (p = 0.007), and synchronous brain metastasis (p = 0.0026) were independent prognostic factors of poor OS. Conclusions: The EGFR exon 19 del was associated with favorable OS in advanced NSCLC pts receiving first-line EGFR TKIs. Moreover, in pts with exon 19 del, first generation TKIs seem to be a reasonable option if osimertinib is unavailable.

EE145 Real-World Healthcare Resource Use, Costs, and Treatment Patterns in Advanced or Metastatic Non-Small Cell Lung Cancer Patients with Different Epidermal Growth Factor Receptor Mutation Types

This study described healthcare resource utilization (HRU), costs, and treatment patterns among advanced or metastatic non-small cell lung cancer (a/mNSCLC) patients with different EGFRmutation types.

Clinical and genomic landscape of EGFR-mutant lung cancers (LCs) with squamous and adenosquamous differentiation.

9129 Background: Outcomes to first-line therapy with osimertinib in patients (pts) with EGFR-mutant (EGFR+) squamous (sq) or adenosquamous (adenosq) LC have not been well described. Pts also undergo adenocarcinoma to squamous transformation (transformed) after treatment with EGFR tyrosine kinase inhibitor (TKI). The clinical and genomic characteristics of pts with EGFR+ sq and adenosq LC are largely unknown. Methods: We clinically and genomically characterized all pts with EGFR+ LC with baseline sq or adenosq histology and transformed histology at Memorial Sloan Kettering Cancer Center. Next-generation sequencing was performed with the MSK-IMPACT. We compared clinical outcomes (time to discontinuation (TTD), overall survival (OS), and post-progression survival after osimertinib discontinuation (PPS)) among the different cohorts. Results: A total of 51 pts were identified: 14 with baseline sq/adenosq treated with first-line (1L) osimertinib; 8 transformed cases post 1L osimertinib; 13 with baseline sq/adenosq treated with early generation TKI; 3 transformed cases post early generation TKI; the remainder of pts had early-stage EGFR+LC with baseline sq/adenosq. Median age was 63, and 57% were female. Eighteen (35%) were former or current smokers. Among pts with baseline sq/adenosq histology who were treated with 1L osimertinib, median TTD was 11.1 months (95%CI 7.7, not reached (NR)), and median OS was 24.3 months (95%CI 11.1 months, NR). Compared to a non-overlapping time-matched cohort with baseline adenocarcinoma treated with 1L osimertinib (N = 55), TTD was numerically shorter in the sq/adenosq cohort (11 vs. 17 months, HR 1.8, p = 0.076), and median OS was significantly shorter (24 vs. 33 months, HR 2.64, p = 0.03). PPS was shortest in baseline sq/adenosq (5 months, HR 2.94, p = 0.023), but similar in transformed (11 months, HR 0.89, p = 0.8) compared to adeno (11 months). The sq/adenosq cohort had significantly higher proportion of L858R EGFR (48% vs 31% p &lt; 0.001) and atypical EGFR mutations at baseline (17% vs 7.3%, p &lt; 0.001) compared to the adenocarcinoma cohort. PIK3CA mutations were enriched at baseline in the sq/adenosq cohort. In the transformed cases, RB1 alterations were present in 13% at baseline. There was a similar distribution of type of EGFR mutations in the non-overlapping pts in the AACR GENIE EGFR+ LC cohort with sq/adenosq histology (N = 4, 50% L858R, 25% atypical). Conclusions: Pts with EGFR+ sq/adenosq LCs exhibit inferior TTD and OS with 1L osimertinib compared to adenocarcinoma controls. Sq/adenosq LCs appear to be molecularly distinct with enrichment in EGFR L858R and atypical EGFR mutations. Transcriptomic profiling of a subset of samples will be presented. Our findings highlight the need for novel therapeutic strategies among pts in this high-risk subgroup.

Afatinib for the treatment of non-small-cell lung cancer with unusual EGFR mutations: a plain language summary.

EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung cancer (NSCLC). Afatinib is a medicine that blocks mutated EGFR and helps kill cancer cells. Many different types of EGFR mutation have been identified in people with NSCLC. Over three quarters of cases are caused by two types of EGFR mutation, known as common EGFR mutations, but some cases are caused by unusual/uncommon EGFR mutations. People with NSCLC who have these unusual/ uncommon EGFR mutations are often excluded from clinical trials. Consequently, researchers don't really know how well medicines like afatinib work in these people. This is a summary of a study reporting findings from a large database of people with non-small-cell lung cancer (also called NSCLC) who have unusual or uncommon changes in a gene called EGFR and who received afatinib. The researchers used the database to see how effective afatinib is in people who have different types of unusual EGFR mutation. Afatinib seems to work well in people with NSCLC who have not already been treated. Part of the study also looked at people who had received a similar treatment, called osimertinib, in the past compared to those who had not been treated with this medicine. The researchers found that afatinib works well in most people with NSCLC who have unusual/uncommon EGFR mutations, although it seems to work better against certain types of these mutations than others. The researchers concluded that afatinib is a treatment option for most people with NSCLC and unusual/uncommon EGFR mutations. It is important for doctors to identify the precise type of EGFR mutation in a tumor before starting treatment.

Abstract A023: Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution

Abstract The aims of the study were 1) to perform the review of non-small cell lung cancer (NSCLC) patients with brain metastasis in our institution, 2) to investigate the response and prognostic factor of brain metastasis after institution’s best treatment, and 3) to suggest the shift of treatment paradigms for brain metastasis. From Jan. 2007 to Oct. 2018, A total 214 NSCLC patients with brain metastasis were enrolled. Female to male ratio was 0.65 and median age at diagnosis of NSCLC was 64 years (range, 30-90). 54 patients had a solitary brain metastasis and 76 patients had more than 10 lesions. Supratentorial, infratentorial and both locations were 106, 17, and 91 patients, respectively. 116 patients (54%) had symptoms associated with brain metastasis at the diagnosis of brain metastasis. Radiation only, radiosurgery, craniotomy with whole brain radiotherapy (WBRT), and supportive care were given for brain metastasis in 111 (52%), 10 (5%), 13 (6%) and 61 (29%) patients, respectively. Overall survival (OS) was associated with age, treatment modality, histology, egfr mutation. Median OS of Radiation only, radiosurgery, craniotomy with WBRT, and supportive care was 13, 15, 15 and 9 months, respectively (P-value 0.044). Median OS of adenocarcinoma and squamous cell carcinoma was 15 and 4 months, respectively (P-value &amp;lt;0.05). Median OS of egfr mutation and wild type was 18 and 9 months, respectively (P-value 0.016). The number and location of brain metastasis, symptoms and sex were not associated with OS Serial brain imaging was performed in 99 patients. 61 out of them (62%) developed shrinkage of brain metastasis (response group). Median OS of response and non-response group were 23 and 17 months (p-value 0.618). Age is significantly associated with response of brain metastasis to the institution’s best treatment (p-value 0.047). Interestingly, 3 patients developed complete remission of brain metastasis following WBRT and chemotherapy. The response duration was 431, 390, 641 days, respectively. Our data show that the prognosis of brain metastasis primarily depends on the age of NSCLC patients rather than the number, location of brain metastasis, treatment modality. Survival of NSCLC patients with brain metastasis was about 15 months despite the institution’s best treatment. The authors suggest that we should update our institution’s treatment policy and provide the latest treatments for patients. Citation Format: Seung Ho Yang. Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A023.

Landscape and Predictive Significance of the Structural Classification of EGFR Mutations in Chinese NSCLCs: A Real-World Study

Background: Non-classical EGFR mutations demonstrate heterogeneous and attenuated responsiveness to EGFR TKIs. Non-small cell lung cancer (NSCLC) patients with atypical EGFR mutations have limited therapeutic options. A recent study established a novel structural-based classification of EGFR mutations and showed its value in predicting the response to TKI. We sought to interrogate the distribution of different structural types and to validate the predictive value in Chinese NSCLCs. Methods: A total of 837 tumor samples were retrospectively recruited from 522 patients with unresectable EGFR-mutant NSCLC. EGFR mutations were classified into four groups: classical-like, T790M-like, Ex20ins-L, and PACC. Treatment information and clinical outcomes were obtained from 436 patients. The time to treatment failure (TTF) was determined on a per-sample basis. Results: Of the 837 EGFR-mutant samples, 67.9%, 18.5%, 9.0%, and 3.1% harbored classical-like, T790M-like, PACC, and Ex20ins-L mutations, respectively. Thirteen (1.6%) samples carried mutations beyond the four types. Among the 204 samples with atypical mutations, 33.8%, 36.7%, 12.7%, and 10.3% were classical-like, PACC, Ex20ins-L, and T790M-like, respectively. In patients with PACC mutations, second-generation TKIs demonstrated a significantly longer TTF than first-generation TKIs (first-line: 15.3 vs. 6.2 months, p = 0.009; all-line: 14.7 vs. 7.1 months, p = 0.003), and a trend of longer TTF than third-generation TKIs (all-line: 14.7 vs. 5.1 months, p = 0.135). Conclusions: Our study depicted the landscape of structural types of EGFR mutations in Chinese NSCLC patients. Our results also suggest that the structural classification can serve as a predictive marker for the efficacy of various EGFR TKIs, which would guide therapeutic decision making.