Epidermal Growth Factor Receptor Mutation Type Research Articles

Real world treatment patterns, healthcare resource use and costs in patients with advanced or metastatic non-small cell lung cancer by EGFR mutation type

Aims This study described treatment patterns, healthcare resource utilization (HRU) and costs among advanced or metastatic non-small cell lung cancer (a/mNSCLC) patients with different epidermal growth factor receptor (EGFR) mutation types. Materials and methods This retrospective study leveraged NeoGenomics NeoNucleus linked with IQVIA PharMetrics Plus between 01 January 2016 to 30 April 2021 (study period). Patients with evidence of a/mNSCLC between 01 July 2016 to 31 March 2021 (selection window) with EGFR test results indicating exon 19 deletion (exon19del), exon 21 L858R (L858R), or exon 20 insertion (exon20i) mutations were included; date of first observed evidence of a/mNSCLC was the index date. Treatment patterns, all-cause HRU and costs during ≥1 month follow-up were reported for each cohort (exon19del, L858R, and exon20i). Results A total of 106 exon19del, 75 L858R, and 13 exon20i patients met the study criteria. The prevalence of hospitalization was highest in the exon20i cohort (76.9%), followed by L858R (62.7%) and exon19del (55.7%) cohorts. A higher proportion of patients had evidence of hospice/end-of-life care in the exon20i (30.8%) and L858R (29.3%) cohorts relative to the exon19del cohort (22.6%). The exon20i cohort had higher median total healthcare costs per patient per month ($27,069) relative to exon19del ($17,482) and L858R ($17,763). EGFR tyrosine kinase inhibitors (TKI) were the most frequently observed treatment type for exon19del and L858R cohorts, while chemotherapy was the most observed treatment in exon20i cohort. Limitations The sample size for the study cohorts was small, thus no statistical comparisons were conducted. Conclusions This is one of the first real-world studies to describe HRU and costs among a/mNSCLC patients by specific EGFR mutation type. HRU and costs varied between EGFR mutation types and were highest among exon20i cohort, potentially reflecting higher disease burden and unmet need among patients with this mutation.

Genomic heterogeneity at baseline is associated with T790M resistance mutations in EGFR-mutated lung cancer treated with the first-/second-generation tyrosine kinase inhibitors.

This study analyzed whether extended molecular profiling can predict the development of epidermal growth factor receptor (EGFR) gene T790M mutation, which is the most frequent resistance alteration in non-small cell lung cancer (NSCLC) after treatment with the first-/second-generation (1G/2G) EGFR inhibitors (tyrosine kinase inhibitors [TKIs]), but only weakly associated with clinical characteristics. Whole exome sequencing (WES) was performed on pretreatment tumor tissue with matched normal samples from NSCLC patients with (n = 25, detected in tissue or blood rebiopsies) or without (n = 14, negative tissue rebiopsies only) subsequent EGFR p.T790M mutation after treatment with 1G/2G EGFR TKI. Several complex genetic biomarkers were assessed using bioinformatic methods. After treatment with first-line afatinib (44%) or erlotinib/gefitinib (56%), median progression-free survival and overall survival were 12.1 and 33.7 months, respectively. Clinical and tumor genetic characteristics, including age (median, 66 years), sex (74% female), smoking (69% never/light smokers), EGFR mutation type (72% exon 19 deletions), and TP53 mutations (41%) were not significantly associated with T790M mutation (p > 0.05). By contrast, complex biomarkers including tumor mutational burden, the clock-like mutation signature SBS1 + 5, tumor ploidy, and markers of subclonality including mutant-allele tumor heterogeneity, subclonal copy number changes, and median tumor-adjusted variant allele frequency were significantly higher at baseline in tumors with subsequent T790M mutation (all p < 0.05). Each marker alone could predict subsequent development of T790M with an area under the curve (AUC) of 0.72-0.77, but the small number of cases did not allow confirmation of better performance for biomarker combinations in leave-one-out cross-validated logistic regression (AUC 0.69, 95% confidence interval: 0.50-0.87). Extended molecular profiling with WES at initial diagnosis reveals several complex biomarkers associated with subsequent development of T790M resistance mutation in NSCLC patients receiving first-/second-generation TKIs as the first-line therapy. Larger prospective studies will be necessary to define a forecasting model.

Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta-analysis of real-world survival outcomes of East Asian patients with advanced non-small cell lung cancer treated with first-line EGFR-TKIs.

Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there is limited real-world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta-analysis (NMA) compared survival outcomes among first-line EGFR-TKIs in different subgroups of East Asian patients with advanced NSCLC. This NMA included real-world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types. In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33-0.71 and HR: 0.54 with 95% CI: 0.36-0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33-0.87) or ECOG status 0-1 (HR: 0.37, 95% CI: 0.23-0.59). This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0-1, and with baseline brain metastasis.

Retreatment with EGFR inhibitor in non-small cell lung cancer patients previously exposed to EGFR-TKI: A systematic review and meta-analysis.

e21159 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard therapy for EGFR-mutated non-small cell lung cancer (NSCLC) patients. Unfortunately, patients eventually develop resistance to EGFR-TKI and disease progression. Re-exposure after a drug-free interval may be an alternative to overcome tumor resistance. We performed a systematic review and meta-analysis to assess EGFR-TKI retreatment’s efficacy in advanced NSCLC. Methods: We systematically searched PubMed, Embase, and Cochrane databases for clinical trials and observational cohort studies evaluating EGFR-TKI retreatment in advanced NSCLC patients. We aimed to assess the objective response rate (ORR), disease control rate (DCR), and survival outcomes. Subgroup analyses were performed according to the type of EGFRmutation and the TKI drug used in retreatment. We further stratified studies to assess the efficacy of rechallenging with the same drug used initially or a different one. Heterogeneity was assessed using the Cochran Q test, and I2 statistics and random effects models were fitted. Results: We included 16 studies (7 prospective clinical trials, and 9 retrospective cohorts) with 806 patients. Most of them had adenocarcinoma (70.8%), were females (58.1%), and were non-smokers (74.5%). The most frequently TKI given as the initial treatment was gefitinib (58.1%), whereas in the rechallenge it was erlotinib (36.6%) followed by gefitinib (31.6%). In a pooled analysis of patients who were retreated with TKI, the median PFS was 4.1 months (95%CI 3.0 - 4.4), and OS was 12.6 months (95%CI 10.2 - 12.6). ORR was 16% (95%CI 10 - 22%) and DCR was documented in 63% (95%CI 0.54 - 0.72%). Patients harboring a sensitive EGFR mutation had a significantly higher DCR, compared to patients with EGFRT790M mutation, and those with unknown mutational status, (DCR: 70%, 62%, and 48%, respectively, p = 0.02). Patients rechallenged with gefitinib, erlotinib, or afatinib had a similar DCR of 60%, while patients re-exposed to osimertinib had a greater DCR of 70% (95%CI 59 - 80%), (p &lt; 0.01). Regarding ORR, no significant difference was observed amongst the groups defined by the type of EGFR mutation (p = 0.74) or type of TKI used (p = 0.05). Rechallenge using the same versus a different TKI resulted in similar ORR and DCR. In a subgroup analysis of 102 patients who had disease control with the first TKI, 62% (95%CI 45 – 79%) achieved disease control with TKI rechallenge. Conclusions: Our meta-analysis suggests that a subgroup of advanced EGFR-mutated NSCLC patients who failed TKI treatment benefit from rechallenge with an EGFR-TKI after a TKI-free interval. Re-exposure with either the same or a different TKI was shown to be equally effective. Patients treated with osimertinib and those with EGFR-sensitive mutations have better responses to the treatment.

Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study).

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated. The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023. The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established. UMIN Clinical Trial Registry: UMIN000049225.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study

Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. Betta Pharmaceuticals (China). For the Chinese translation of the abstract see Supplementary Materials section.

A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non–small cell lung cancer

BackgroundRecent reports suggested combining ramucirumab with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) to overcome EGFR resistance in non–small cell lung cancer (NSCLC). Nonetheless, evidence supporting the activity of afatinib and ramucirumab is lacking. This study investigated the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated, metastatic NSCLC.Materials and methodsThe medical records of patients with EGFR-mutated NSCLC were retrospectively retrieved. Patients who received first-line sequential afatinib followed by ramucirumab and the first-line combination of afatinib plus ramucirumab were included. The Kaplan-Meier was used to estimate the progression-free survival (PFS) of all included patients, patients on sequential afatinib followed by ramucirumab (PFS1), and patients on the up-front combination of afatinib and ramucirumab (PFS2).ResultsThirty-three patients were included (25 women; median age: 63 [45–82] years). The median follow-up of the included patients was 17 months (range 6–89 months). the median PFS for the whole cohort was 71 months (95% CI 67.2–74.8) with eight events during the follow-up. The median PFS1 and PFS2 were 71 months (95 CI not defined) and 26 months (95% CI 18.6–33.4), respectively. In terms of OS, the median OS for all patients and patients on sequential treatment was not defined, while the median OS for patients on upfront combination was 30 months (95% CI 20.9–39.1). There was no significant association between EGFR mutation type and PFS1 or PFS2.ConclusionsAfatinib plus ramucirumab could improve the PFS of patients with EGFR-positive NSCLC at a predictable safety profile. Our data also suggest a survival benefit of adding ramucirumab to afatinib in patients with uncommon mutations, which should be investigated further.

New prognostic system specific for epidermal growth factor receptor-mutated lung cancer brain metastasis.

Brain metastases (BM) from lung cancer are heterogeneous, and accurate prognosis is required for effective treatment strategies. This study aimed to identify prognostic factors and develop a prognostic system exclusively for epidermal growth factor receptor (EGFR)-mutated lung cancer BM. In total, 173 patients with EGFR-mutated lung cancer from two hospitals who developed BM and received tyrosine kinase inhibitor (TKI) and brain radiation therapy (RT) were included. Univariate and multivariate analyses were performed to identify significant EGFR-mutated BM prognostic factors to construct a new EGFR recursive partitioning analysis (RPA) prognostic index. The predictive discrimination of five prognostic scoring systems including RPA, diagnosis-specific prognostic factors indexes (DS-GPA), basic score for brain metastases (BS-BM), lung cancer using molecular markers (lung-mol GPA) and EGFR-RPA were analyzed using log-rank test, concordance index (C-index), and receiver operating characteristic curve (ROC). The potential predictive factors in the multivariable analysis to construct a prognostic index included Karnofsky performance status, BM at initial lung cancer diagnosis, BM progression after TKI, EGFR mutation type, uncontrolled primary tumors, and number of BM. In the log-rank test, indices of RPA, DS-GPA, lung-mol GPA, BS-BM, and EGFR-RPA were all significant predictors of overall survival (OS) (p ≤ 0.05). The C-indices of each prognostic score were 0.603, 0.569, 0.613, 0.595, and 0.671, respectively; The area under the curve (AUC) values predicting 1-year OS were 0.565 (p=0.215), 0.572 (p=0.174), 0.641 (p=0.007), 0.585 (p=0.106), and 0.781 (p=0.000), respectively. Furthermore, EGFR-RPA performed better in terms of calibration than other prognostic indices.BM progression after TKI and EGFR mutation type were specific prognostic factors for EGFR-mutated lung cancer BM. EGFR-RPA was more precise than other models, and useful for personal treatment.

CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations.

Afatinib is a potent, irreversible second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has demonstrated efficacy in advanced non-small cell lung cancer (NSCLC) patients harboring either common or uncommon EGFR mutations. However, data on its activity against brain metastases are limited. This study aimed to retrospectively evaluate the efficacy and safety of afatinib as first-line treatment for EGFR-mutant NSCLC patients with brain metastases. Treatment-naive advanced NSCLC patients harboring EGFR mutations and brain metastases treated with afatinib were retrospectively reviewed to assess the central nervous system (CNS) efficacy and also the systematic benefits. Totally 43 patients with measurable or non-measurable brain metastases were enrolled in the CNS full analysis (cFAS) set. Among them, 23 patients with measurable brain metastases were included in the CNS evaluable for response (cEFR) set. The CNS ORR was 48.8% (95% CI, 33.3 - 64.5%) in the cFAS set and 82.6% (95% CI, 61.2 - 95.0%) in the cEFR set, respectively. CNS mDoR was 8.9 months (95% CI, 4.7 - 13.1 months) and CNS mPFS was 12.7 months (95% CI, 6.9 - 18.5 months) in the cFAS set. In the subgroup analysis stratified by EGFR mutation types, CNS ORR of cEFR set in the common mutation cohort was 100% (95% CI, 75.3 - 100%) and 60% (95% CI, 26.2 - 87.8%) in the uncommon mutation cohort (p = 0.024); CNS ORR of cFAS set was 57.7% (95% CI, 36.9 - 76.6%) and 35.3% (95% CI, 14.2 - 61.7%), respectively (p = 0.151). CNS mPFS was 14.4 months in patients with common mutations and 6.1 months in patients with uncommon mutations (hazard ratio, 0.47; 95% CI, 0.22 - 1.00; p = 0.045). Patients with common mutations showed a significantly lower cumulative incidence of CNS failure than uncommon mutation cohort (p = 0.0026). Most of patients experienced grade 1/2 treatment-related adverse events. First-line afatinib demonstrated encouraging efficacy on brain metastases in NSCLC patients harboring either common or major uncommon EGFR mutations in a real-world setting, with manageable toxicities. Patients with common mutations showed better CNS outcomes than those with uncommon mutations.

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2–IA3 EGFR-Mutated NSCLC: ADAURA2

IntroductionOsimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non–small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2–IA3 EGFRm NSCLC, following complete tumor resection. Patients and MethodsADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated. ResultsStudy enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.

Predictors of response in EGFR-mutant metastatic non-small cell lung cancer patients treated with tyrosine kinase inhibitors.

The goal of the study was to evaluate the efficacy of tyrosine kinase inhibitors in patients with epidermal growth factor receptor (EGFR)-mutant metastatic non-small cell cancer and to determine the factors that predict objective response. In the study, data from metastatic non-small cell lung cancer patients with EGFR mutations treated with tyrosine kinase inhibitors were retrospectively reviewed. Factors predicting objective response were evaluated with logistic regression analysis. The study evaluated the data of 105 patients. The most common EGFR mutations detected in patients were exon 19 (56.2%) and exon 21 (23.8%). The median progression-free survival (PFS) associated with EGFR tyrosine kinase inhibitors was 20.1 (95% confidence interval [CI], 13.4-26.7) months. The median overall survival (OS) in the post-metastasis period was found to be 30.8 (95% CI, 20.2-41.4) months. Five- and seven-year OS was determined as 28.7% and 22.9%, respectively. Factors predicting the objective response were analyzed. Presence of drug-related toxicity (P = 0.02), histopathologic type (P = 0.01), metastasis burden (P = 0.03), and EGFR mutation type (P = 0.04) were found to be statistically significant in multivariate analysis. In our study, we found that EGFR tyrosine kinase inhibitors are effective and safe. Better response to EGFR inhibitors was observed in the presence of drug-induced toxicity, adenocarcinoma histology, low metastasis burden, and exon 19 mutation.

Frequency of EGFR mutations in lung adenocarcinoma patients - A study from tertiary cancer center of South India.

Epidermal growth factor receptor (EGFR) mutation analysis has become an important part of the initial workup of non-squamous non-small cell lung cancer (NS-NSCLC) patients. This study is attempted as South Indians population is comprised of ethnic groups with diverse genetic makeup and only very limited data on EGFR mutation is available from south India. A detailed understanding of EGFR mutation profile will help in better planning of treatment strategies and resource allocation. A retrospective analysis of EGFR mutation frequency in 350 patients diagnosed with adenocarcinoma of lung and its association with pathological characteristics was done. Out of 350 cases of pulmonary adenocarcinoma, within an age group ranging from 30 to 86 years. EGFR mutations were identified in 34.8% (n = 122) cases, out of which 35.24% (n = 43) were in non-smoker females (P = 0.001). Of the 14 cases with resistant type of EGFR mutations, nine were in smoker males and the remaining five in non-smoker females. Overall EGFR mutation frequency observed in our study was similar to other Indian studies. However, in our study, we observed that mutation in exon 21 was less frequent compared to other studies. A similar slightly increased frequency of rare mutations and double mutations were observed in our study. A detailed study of the molecular epidemiology of lung cancer and its association with different geographical zones of India is needed. This understanding will help in better planning of treatment strategies and resource allocation.

Correlation Analysis of Ki67 Expression and EGFR Mutation on the Risk of Recurrence and Metastasis in Postoperative Patients with Stage I Lung Adenocarcinoma

The prognosis of stage I non-small cell lung cancer (NSCLC) is generally good. However, some of the stage I NSCLC patients still may have early recurrence and metastasis, and there is no standard method to screen this part of the population. The aim of this study is to investigate the relationship between Ki67 expression as well as epidermal growth factor receptor (EGFR) mutation and the risk of recurrence in postoperative patients with stage I lung adenocarcinoma. We retrospectively enrolled 118 postoperative patients with stage I lung adenocarcinoma. EGFR mutation was tested using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) , and Ki67 level was detected by immunohistochemistry (IHC), followed by the collection of the patients' clinical characteristics. Kaplan-Meier method, Log-rank test, and Cox proportional hazards regression model were used for the prognostic statistical analysis. Among the 118 patients, the rate of high Ki67 expression was 43.22% (51/118), which is related to gender, smoking status, surgical method, differentiation degree, and postoperative stage (P<0.05). Meanwhile, EGFR mutation rate was 61.02% (72/118), of which EGFR exon 19 deletion mutation rate was 19.49% (23/118), and the EGFR exon 21 L858R mutation rate was 41.53% (49/118). However, Ki67 expression was not associated with EGFR mutation status (χ2=1.412, P=0.235). Survival analysis showed that high Ki67 expression was inversely associated with disease-free survival (DFS) and overall survival (OS) in stage I lung adenocarcinoma (P<0.05), but EGFR mutation status was not significantly associated with DFS and OS (P>0.05). In the subgroup analysis, the DFS of the EGFR exon 19 deletion group was significantly decreased compared with the EGFR exon 21 L858R mutation group (P=0.031), but there was no significant difference in OS (P=0.308). Multivariate analysis showed that there was statistical significance between Ki67 expression (P=0.001) and DFS in stage I lung adenocarcinoma; Ki67 expression (P=0.03) and gender (P=0.015) were associated with OS in stage I lung adenocarcinoma. Ki67 expression is an independent influencing factor for postoperative recurrence and OS of stage I lung adenocarcinoma and it is not significantly associated with EGFR mutation. There is no significant difference between EGFR mutation status and the prognostis of stage I lung adenocarcinoma. However, the prognosis differed in EGFR mutation types; the patients with EGFR exon 19 deletion are at higher risk of recurrence than EGFR exon 21 L858R mutation.

Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation.

Uncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment. We performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan-Meier method. Data from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months). Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.

12P The efficacy of EGFR tyrosine kinase inhibitors and its clinical prognostic factors in lung adenocarcinoma patients harboring different types of EGFR mutations: Real-world data

Lung cancer has the highest incidence and mortality among all cancers, with a 5-year survival rate of 15%. Presently, epidermal growth factor receptor (EGFR) mutation is the most common type of gene mutations detected in patients (pts) with advanced non-small-cell lung cancer, and EGFR is identified as the therapeutic target of EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have become the standard treatment. However, the most of the trials were developed in Asian countries, with a lack of data in western population.

Insensitivity to T790M mutation? A pooled analysis of outcomes following osimertinib for the treatment of NSCLC patients harboring uncommon epidermal growth factor receptor mutation.

Background: In this pooled analysis, the aim was to investigate the clinicopathological characteristics of patients with uncommon epidermal growth factor receptor (EGFR) (ucm-EGFRms) along with their treatment responses and survival following osimertinib treatment. Methods: Univariate chi-square analysis was conducted to analyze the correlation between clinical characteristics, EGFR mutation type, and treatment response, and the Kaplan-Meier method was applied for survival analysis. Univariate logistic regression model and Cox proportional hazards model were performed to compare the efficacy and prognosis in subgroup analysis. Results: Seventy-two NSCLC patients in total were included in this pooled analysis. The objective response rate (ORR) for osimertinib treatment was 57.0%, with a median PFS of 7.1 months. Twenty-eight patients received osimertinib as first-line therapy with an ORR of 67.9%, which was higher than that in patients who received osimertinib as second- or later-line therapy, and their response rate was 50%, nevertheless, no statistically significant differences were found (p = 0.139). However, patients who received first-line osimertinib showed a more significant PFS benefit than those who received second- or later-line therapy (mPFS: 16.8 months vs 6.0 months HR: 2.453, 95%CI: 1.285-4.682, p =0.004). Subgroup analysis showed that patients with a single, non-ex20ins, ucm-EGFRm displayed a superior efficacy advantage and favorable survival benefit following osimertinib treatment, with an ORR of 68.8% and an mPFS at 15.1 months. By contrast, patients with a multiple ucm-EGFRm that contain T790M exhibited the worst outcome of osimertinib treatment, with an ORR of 47.6% and an mPFS of only 3.6 months, respectively. Conclusion: Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following osimertinib treatment, which is closely related to the mutation pattern and cooccurring partner mutant genes. Administering osimertinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances.

Abstract 5499: Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE)

Abstract Background: Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been proved to significantly improve the clinical outcome of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Icotinib is an oral, reversible and selective first-generation EGFR-TKI. The survival benefits of 1-year and 2-year adjuvant icotinib in patients with EGFR-mutant NSCLC have been confirmed in previous studies. However, the optimal duration of adjuvant icotinib remains unknown. This study (ICAPE) evaluated the efficacy of 1.5-year adjuvant therapy with icotinib for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Methods: Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. Primary endpoint was disease-free survival (DFS). Secondary endpoints included 1-year, 3-year, as well as 5-year OS rates, and the DFS according to the BIM mutation status (mutant-type and wild-type) and EGFR mutation types (19 del and 21 L858R). Results: Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p=0.75) and no significant difference was found in the median DFS according to EGFR mutation types (all p&amp;gt;0.05). Conclusions: The phase II ICAPE study demonstrated that 1.5-year adjuvant therapy with icotinib had a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma with a long median DFS and high 5-year OS rates which is consistent with other icotinib’s study. Icotinib is suggested to be used as an adjuvant therapy option in IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Citation Format: Kun Qian, Bin Hu, Ming He, Zi-Tong Wang, Yu Liu, Hua-Gang Liang, Zhi-Yong Su, Yu-Shang Cui, Li-Jun Liu, Yi Zhang. Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5499.

Radiotherapy with continued EGFR-TKIs for oligoprogressive disease in EGFR-mutated non-small cell lung cancer: A real-world study.

Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) develops resistance to tyrosine kinase inhibitors (TKIs). Here, we evaluated the efficacy of radiotherapy and continuation of TKIs in patients with advanced NSCLC with oligoprogression after EGFR-TKIs. From January 2011 to January 2019, 33 patients with EGFR-mutated NSCLC on TKIs were treated by radiotherapy and continuation of TKIs for oligoprogressive disease. The primary endpoints were median progression-free survival 1 (mPFS1), mPFS2, and median overall survival (mOS). PFS1 was measured from the start of EGFR-TKIs therapy to the oligoprogression of the disease. PFS2 was measured from the date of oligoprogression to the further progression of the disease, while OS was calculated from oligoprogression to death from any cause or was censored at the last follow-up date. The mPFS1, mPFS2, and mOS were 11.0 (95% CI, 4.4-17.6), 6.5 (95% CI, 1.4-11.6) and 21.8 (95% CI, 14.8-28.8) months, respectively. Univariate analysis showed that EGFR mutation type (p=0.024), radiotherapy method (p=0.001), and performance status (p=0.017) were significantly correlated with PFS2. Univariate analysis showed that sex (p=0.038), smoking history (p=0.031), EGFR mutation type (p=0.012), and radiotherapy method (p=0.009) were significantly correlated with OS. Multivariate analysis suggested that radiotherapy method (p=0.001) and performance status (p=0.048) were prognostic factors for PFS2, and radiotherapy method (p=0.040) was a prognostic factor for OS. Radiotherapy with continued TKIs is effective for EGFR-mutated NSCLC with oligoprogression, and it should be conducted as soon as possible. T790M+ patients have higher sensitivity to radiotherapy, and patients with good performance status and stereotactic body radiation therapy have better PFS2 andOS.

The impact of EGFR Exon 20 mutation subtypes on lung cancer prognosis.

e20557 Background: Many lung cancer patients with epidermal growth factor receptor (EGFR) mutations benefit from tyrosine kinase inhibitors (TKIs). However, patients with EGFR exon 20 mutations usually have worse response rates than other types of EGFR mutations. Here we investigated how different mutation subtypes of EGFR exon 20 affected the prognosis. Methods: Clinical and genomic data from 3 studies (MSKCC2020, MSKCC2021, and OncoSG) of patients with lung adenocarcinoma (LUAD) were reviewed (n = 1,001). Four hundred and seventeen patients harbored EGFR mutations and 52 of them had EGFR exon 20 mutations. The correlation of mutation subtypes with OS data was analyzed using R package. Results: In lung cancer patients with EGFR mutations (n = 417), 52 of them (12.5%) had a total of 64 EGFR exon 20 mutations, and could be categorized into 16 different subtypes, with top 5 subtypes being T790M (n = 28), S768I (n = 8), C797S (n = 7), A767_V769dup (n = 6) and S768_D770dup (n = 3). Patients with S768I (p = 0.0038) and A767_V769dup (p = 0.03) were found to have significantly worse OS than patients without these mutations by log-rank test. EGFR T790M, which was the most prevalent exon 20 mutation in these patients, did not present significant correlation in survival analysis. Conclusions: Although patients with EGFR exon 20 mutations accounted for only about 5% LUAD patients, and had worse response rates in general, certain subtypes had significantly different prognoses compared with other subtypes.

The landscape of EGFR mutation in Chinese patients with glioma.

e14028 Background: Epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase, consists of an extracellular ligand-binding domain (ECD), a single transmembrane domain (STMD) and an intracellular kinase domain (ICD). Glioma is the most common primary brain tumor, and variations of EGFR are frequently reported in glioma patients. This study aimed to analysis the landscape of EGFR mutation subtype in Chinese patients with glioma. Methods: We retrospectively collected 1779 patients with glioma. In all patients enrolled, the comprehensive genomic profiling containing EGFR gene was detected using tumor tissue, including WES, 539 tumor related-gene panel or 131+4 gene panel (Simceredx). And the somatic mutations including SNV, INDEL, CNV, fusion were analyzed correspondingly. Results: Among 1779 patients with glioma, EGFR mutations were identified in 392 (22.03%) patients. The age was significantly higher in patients with EGFR-mutant group than in patients without EGFR-mutant group, with median age 54 vs. 45 (p = 4.81e-19). The sex didn’t reach statistical significance in two group. The incidence rate of different EGFR mutation types among all patients with EGFR-mutant were amplification (314,80.10%), SNV(198,50.51%), Indel(24,6.12%) and fusion(44,11.22%) respectively. 162 (46.69%) had two or more mutation types simultaneously. The main partner gene of EGFR fusion was LOC100996654, followed by ELDR and SEC61G, and the main EGFR breakpoints were in intron24, intron7, exon7. Within 347 SNV and Indel mutations, exon7, 15, 20, 6 and 8 were detected in 103(29.68%), 50(14.41%), 28 (8.07%), 25(7.20%) and 18 (5.19%) respectively. The top three mutaton subtypes within exon7 were account for 19.31%, which included p.A289V,p.A289T,p.T263P. Meanwhile, the mutation frequency within ICD encoded by exons 18-24 was 17.00%, in which exon20 mostly distributed (8%). In exon20, the most common mutation subtypes were p.V774M,p.H773dup,p.T790M, while in the second proportion exon18 (3.46%), the main subtype were p.G719A/D. Conclusions: 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. The relationship between subtypes occurrence and cancer will be further studied in the future.