EGFR Mutation-positive Patients Research Articles

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 .

Real-World Analysis of Post-Progression Treatment Patterns and Outcomes for EGFR Mutation-Positive Patients Treated with First-Line Osimertinib.

Introduction: The use of osimertinib in the first-line (1L) setting is an effective treatment option for sensitizing EGFR-mutations (EGFRm+) and has significantly altered the standard of care practice for EGFRm+ disease in Canada. Unfortunately, acquired resistance to osimertinib is almost universal, and outcomes are disparate. Post-progression treatment patterns and the outcome of real-world Canadian EGFRm+ patients receiving 1L osimertinib were the focus of this retrospective review. Methods: The Glans-Look Lung Cancer Research database was used to identify and collect demographic, clinical, treatment, and outcome data on EGFRm+ patients who received 1L osimertinib in the Canadian province of Alberta between 2018 and 2022. Results: A total of 150 patients receiving 1L osimertinib were identified. In total, 86 developed progressive disease, with 56 (65%) continuing systemic therapy, 73% continuing osimertinib, and 27% switching to second-line (2L) systemic therapy. Patients were similar both in clinical characteristics at 1L osimertinib initiation and patterns of treatment failure at progression; those continuing 1L osimertinib post-progression had a longer time to progression (13.5 vs. 8.8 months, p = 0.05) and subsequent post-osimertinib initiation survival (34.7 vs. 22.8 months, p = 0.11). Conclusions: The continuation of osimertinib post-progression is an effective disease management strategy for select real-world EGFRm+ patients, providing continued clinical benefit, potentially due to different underlying disease pathogenesis.

Differences in Radiosensitivity According to EGFR Mutation Status in Non-Small Cell Lung Cancer: A Clinical and In Vitro Study.

Unlike drug selection, radiation parameters (field, dose) are not based on driver gene mutations in patients with metastatic non-small cell lung cancer (NSCLC). This study aimed to compare radiosensitivity in NSCLC with and without EGFR driver gene mutations using clinical and in vitro data. The clinical study included 42 patients who underwent whole-brain radiotherapy for brain metastases from NSCLC; of these, 13 patients had EGFR mutation-positive tumors. The Kaplan-Meier method was used to calculate the cranial control rate without intracranial recurrence. In the in vitro study, colony formation and double-strand DNA breaks were examined in two EGFR mutation-negative and three EGFR mutation-positive NSCLC-derived cell lines. Colony formation was assessed 14 days after irradiation with 0 (control), 2, 4, or 8 Gy. DNA double-strand breaks were evaluated 0.5 and 24 h after irradiation. EGFR mutation-positive patients had a significantly better cranial control rates than EGFR mutation-negative patients (p = 0.021). EGFR mutation-positive cells formed significantly fewer colonies after irradiation with 2 or 4 Gy than EGFR mutation-negative cells (p = 0.002, respectively) and had significantly more DNA double-strand breaks at 24 h after irradiation (p < 0.001). Both clinical and in vitro data suggest that EGFR mutation-positive NSCLC is radiosensitive.

Real-World Evidence of EGFR Targeted Therapy in NSCLC– A Brief Report of Decade Long Single Center Experience

The significance of EGFR targeted therapy in the lung adenocarcinoma is paramount. Several controlled clinical trials have reported considerable survival of EGFR mutation positive patients on receiving the EGFR tyrosine kinase inhibitor (TKI). However, the real-world evidence of benefits of EGFR TKI would be further useful to understand how the designated therapeutic regimen benefits the patients. In this study, we report a decade long real-world evidence of EGFR molecular testing in lung cancer at Tata Memorial Hospital (Mumbai, India). Laboratory and hospital records containing basic demographic details, clinical characteristics, treatment regimen, survival outcome were collected retrospectively. Statistical association and survival analysis were performed using the R programming. The cohort includes 9,053 lung cancer patients tested for EGFR mutations during 2011 to 2019. Baseline T790M and compound mutations were the only mutations observed co-occurring while all other EGFR mutations were mutually exclusive. Furthermore, the baseline T790M were also observed to be associated with TTF1 positivity, smoking and local metastasis. Overall survival of the patients harboring co-occurring compound mutations was significantly lesser than the other EGFR positive patients. Overall, our study suggests that EGFR TKI may provide real-world benefit to the lung cancer patients harboring mutually exclusive EGFR mutations. On the other hand, further systematic study is essential to develop better therapeutic regimen for co-occurring baseline EGFR T790M and other compound mutations.

Epidermal Growth Factor Receptor Mutation Status and the Impact on Clinical Outcomes in Patients with Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) mutation status differs according to ethnicity, gender, smoking history, and histology types. The present study aimed to evaluate EGFR mutation status in patients with non-small cell lung cancer (NSCLC) and further explore its association with clinical characteristics and prognosis in advanced NSCLC patients (Stage IIIB-IV). 238 NSCLC patients were enrolled in this study from October 2016 through December 2019. Patient characteristics and clinical data including age, gender, smoking history, histology types, tumor stage, survival status, and time were collected via electronic medical record system or telephone. 21 somatic mutations which spanned exons 18-21 of EGFR were detected using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, followed by analysis of links to clinical characteristics, progression-free survival (PFS) and overall survival (OS). 103 patients were detected harboring EGFR mutations among the 238 cases tested (43.3%), and exons 19 and 21 were the highest mutation frequencies, with 20.6% and 19.3% respectively. The EGFR mutation rate was much higher in female versus male (57.4% vs 31.5%, p <0.001), in non-smokers compared to smokers (56.8% vs 25.9%, p <0.001), and in those with adenocarcinoma than other histology types (48.3% vs 3.7%, p <0.001). For patients in advanced stage, median PFS was 11 months in patients harboring EGFR mutations, versus 4 months in patients with wild type EGFR (p <0.001); median OS was 24 versus 12 months (p <0.001). Never smoking (p = 0.042) and adenocarcinoma (p = 0.007) were independent favorable factors for EGFR mutations. Our data strengthen the findings of high prevalence of EGFR mutations in Asian patients with NSCLC. Mutations are prevalent in those patients who are female, adenocarcinoma, and have never smoked. Moreover, advanced EGFR mutation-positive patients have better PFS and OS than those with wild type EGFR.

Abstract 1026: A novel detection system of circulating tumor cells based on size-dependent enrichment with immunofluorescent staining of CK8/18 in advanced non-small cell lung cancer

Abstract Background: Detection of circulating tumor cells (CTCs) in the blood is a potentially noninvasive tool for cancer diagnosis, monitoring and prognosis evaluation. However, the CTC detection is difficult because of the rarity of CTCs, especially in non-small cell lung cancer (NSCLC), and the detection sensitivity of CTCs was reported to be less than 50% in NSCLC patients. Herein, we developed a novel CTC detection system and evaluated its performance in advanced NSCLC patients. Methods: Whole blood samples were collected from stage IV or recurrence NSCLC patients. CTC detection was performed with a novel system (Sysmex Corporation, Hyogo, Japan) by using size-dependent enrichment for capturing CTCs and immunofluorescent staining reagents including anti-cytokeratin (CK, AE1/AE3 or CK8/18) (specific for epithelial cells), anti-CD45 (specific for leukocyte) and Hoechst (for nucleus). Fluorescence intensity and cell images of each marker were obtained by Molecular Imaging Flow Cytometry (MI-FCM). Circulating cells that were positive for Hoechst and anti-CK but negative for anti-CD45 were defined as CTCs. To confirm whether CTCs detected were derived from lung cancer origin, CTCs obtained from patients with EGFR mutations were subjected to single cell sorting, whole genome amplification and PCR analysis for the mutation detection. Results: A total of 20 NSCLC patients (10 EGFR mutant, 10 EGFR wild-type) were enrolled in this study. Of these, CTCs were detected in 16 (80%) patients (number of CTCs, 1 to 66 in 4.5ml whole blood) when CK8/18 was used as epithelial cell staining, but in only 11 (55%) patients (1 to 6 CTCs) when using AE1/AE3. The detection sensitivity of CTCs based on CK8/18 was significantly higher compared to that based on AE1/AE3 in our novel system (80% vs. 50%, p = 0.03). The number of CTCs was significantly lower in EGFR mutation-positive patients than in EGFR wild-type patients (median number of CTCs, 3 vs. 22, p = 0.01). Furthermore, among 10 EGFR mutation-positive patients, EGFR mutations were detected in CTCs derived from 6 (60%) patients. All the mutation types detected in CTCs were matched with those identified in the corresponding primary tumors. Conclusion: Our novel CTC detection system demonstrated that the detection rate of CTCs (80%) was higher than those in previous studies. Further studies are needed for the clinical application of this system. Citation Format: Tetsuya Sakai, Yoshitaka Zenke, Mami Onishi, Eri Morita, Masatoshi Yanagida, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Hibiki Udagawa, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto. A novel detection system of circulating tumor cells based on size-dependent enrichment with immunofluorescent staining of CK8/18 in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1026.

Is there an advantage of monitoring via exosome-based detection of EGFR mutations during treatment in non-small cell lung cancer patients?

We know that detection of EGFR mutations is very important for individual therapy. Nowadays FFPE samples are commonly using to detect the EGFR mutation status. But it has a few handicaps such as, tumor heterogeneity and non-repeatable, it is need to examine mutation statues of EGFR after each treatment regimen for individually treatment of NSCLC patients. Therefore, there is still need to develop non-invasive and useable over and over again approach for monitoring EGFR mutation statues and other genes for individual therapy. So, we aim to examine whether exosomes are good target for detection of EGFR mutation status or not. Pyrosequencing was used to detect, EGFR mutation in FFPE and exosome samples in some NSCLC patients. For the patients given different chemotherapy regime (n=28), PFS was evaluated before and after treatment. In patients who were EGFR positive before treatment, the median PFS for EGFR mutation-positive patients after treatment was 101.7 weeks (95% CI: 0.09-3.21), while for patients who were negative after treatment, the median PFS was 42.43 weeks (95% CI: 0.31- 10.52). Likewise, in patients who were EGFR negative before treatment and EGFR mutation negative after treatment, the PFS was median 52 weeks (95% CI: 0.17-2.84), while in patients who were positive after treatment, the median PFS was 27.57 weeks (95% CI: 0.35-5.58). We show that exosomes are good tools for monitoring EGFR mutation status and exosomes can be use as semi-invasive method for isolation of tumor DNAs for detection of mutation statues for individually treatment of NSCLC patients.

Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy.

BackgroundFew treatment options are available for brain metastases (BMs) in EGFR-mutant non-small cell lung cancer (NSCLC) that progress with prior EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to evaluate the efficacy of immune checkpoint inhibitor (ICI) therapy in these patients.MethodsNSCLC patients with confirmed sensitive EGFR mutations and BMs were retrospectively reviewed. All patients experienced failure of EGFR-TKI therapy and were divided into two cohorts based on subsequent treatment. Cohort 1 included patients who received ICI therapy, while cohort 2 included patients treated with chemotherapy. Overall and intracranial objective response rates (ORRs) were used to evaluate the treatment response. Overall and intacranial progression-free survival (PFS) were calculated by Kaplan−Meier analysis and compared with the log-rank test. Univariate and multivariate Cox analyses were used to identify prognostic factors.ResultsA total of 53 patients treated with ICI therapy and 40 patients treated with chemotherapy were included in cohorts 1 and 2, respectively. In cohort 1, the overall ORR was 20.8%, with a median overall PFS of 4.2 months. The median intracranial PFS was 5.1 months. Of the 38 patients with measurable intracranial lesions, the intracranial ORR was 21.0%. Patients who received ICI combined with chemotherapy had the highest intracranial ORR of 37.5%. Compared to patients treated with chemotherapy in cohort 2, patients receiving ICI combined with chemotherapy had both longer intracranial PFS (6.4 vs. 5.1 months, p = 0.110) and overall PFS (6.2 vs. 4.6 months, p = 0.054), and these differences approached statistical significance. Univariate and multivariate Cox analyses demonstrated that high disease burden (p = 0.019), prior third-generation EGFR-TKI therapy (p = 0.019), and a poor lung immune prognostic index (LIPI) (p = 0.012) were independent negative predicators of overall PFS and that multiple BMs were negatively correlated with intracranial PFS among patients treated with ICI therapy.ConclusionsOur results suggested that ICI combined with chemotherapy had potent intracranial efficacy and may be a promising treatment candidate in EGFR-mutant NSCLC patients with BMs for whom prior EGFR-TKI therapy failed.

968TiP A phase II, multicenter study of lazertinib as consolidation therapy in patients with locally advanced, unresectable, EGFR mutation positive non-small cell lung cancer (stage III) who have not progressed following definitive, platinum-based, chemoradiation therapy (PLATINUM trial)

The PACIFIC trial has demonstrated that durable progression free survival (PFS) and sustained overall survival (OS) benefit with durvalumab as consolidation therapy after concurrent chemoradiation therapy (CCRT). In a subgroup analysis, the effect was not proven in patients with EGFR mutation positive. There is an unmet need for consolidative therapy after CCRT in patients with unresectable stage III EGFR mutation positive. A recent ADAURA trial showed that osimertinib had a significant prolongation of PFS in the postoperative adjuvant treatment in EGFR mutation positive patients.

Association of TP53 polymorphisms with the acquisition of EGFR T790M mutations in patients with first- or second-generation EGFR-TIK progression.

e20560 Background: Lung cancer is the leading cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (TKIs) has transformed management in those patients. However, the majority of patients will become resistant to EGFR-TKIs after a period of time. The T790M acquired mutation in exon 20 of the EGFR is the predominant molecular mechanism of acquired resistance. In first-line treatment of global patients with NSCLC, osimertinib had better efficacy compared to first-generation TKIs. In the FLAURA study, the median PFS with first-line osimertinib in Asians was only 16.5 months, compared to 18.6 months in the global population. Moreover, the OS benefit in the Asian population was relatively small. At the same time, the mechanism of resistance to osimertinib is very complex and patients have limited treatment options after first-line osimertinib resistance. A variety of factors can influence the decision for first-line treatment in EGFR mutation-positive patients, including follow-up regimens, the presence of brain metastases, and tolerability, all of which should be considered in the long-term treatment plan. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions. Previous studies have shown that TP53 Arg72Pro polymorphism (rs1042522) is associated with the risk and prognosis of lung cancer. Currently, the association between EGFR mutations and TP53 polymorphisms is unclear, but previous reports have suggested that patients with EGFRmutation demonstrated a higher rate of TP53 mutation than EGFR wild type patients. Therefore, this study aim to explore the association of TP53 polymorphisms (rs1042522) with EGFR T790M acquired mutations, considering the value of T790M in lung cancer treatment. Methods: We analyzed two independent cohorts of patients with EGFR-mutant NSCLC who progressed after first-line EGFR-TKIs treatment from 2013 to 2021 (cohort 1: n=108; cohort 2: n=148). All patients were tested with plasma next-generation sequencing (NGS). Results: The acquired T790M mutation rate was 36%, 30% and 43% in all patients (n = 256), cohort 1 and cohort 2, respectively. Logistic regression analysis showed that TP53 rs1042522 polymorphism was significantly associated with an increased risk of T790M acquired mutation in cohort 1 (GG versus CC: OR (95% CI) = 3.57 (1.15-12.2), P = 0.033) and cohort 2 (GG versus CC: univariable OR (95% CI) = 3.53 (1.30-10.3), P = 0.016; multivariable OR (95% CI) = 2.94 (1.04-8.87), P= 0.047). Conclusions: We found that the TP53 rs1042522 polymorphism GG was associated with EGFR T790M acquired mutations. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions.

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Objective To assess the clinical efficacy and side effects of EGFR-TKI with or without chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma. Methods A total of 103 IIIB or IV EGFR mutation-positive lung adenocarcinoma patients admitted to the oncology department of Fujian Provincial Hospital from January 2017 to October 2020 were selected. According to genetic mutation status, patients were divided into the following groups: 19del alone, 19del combined with TP53 or other co-mutations, L858R mutation alone, and L858R mutation combined with TP53 or other co-mutations. Targeted drugs or targeted drugs combined with chemotherapy were respectively administered in the four groups. In patients with simple 19 deletion, only targeted drugs with no combined therapy were applied, resulting in seven total groups. The difference between short-term treatment and long-term treatment effects and the occurrence of adverse reactions was calculated and compared. Results There was no statistical significance of difference in the incidence of adverse reactions in seven groups ( p &gt; 0.05). The short-term disease control rate of the combination group was higher than the targeted drug group with the difference yielding statistical significance ( p &lt; 0.001). The short-term objective response rate of the combination group was higher than the targeted drug group, also yielding statistical significance ( p &lt; 0.001). By October 2020, the median progression-free survival (PFS) was 16 months in the EGFR-TKI-targeted combined with chemotherapy group and 10 months in the single-drug EGFR-TKI group, and the PFS time was longer in the combination group than in the single targeted drug group, the difference being statistically significant ( p = 0.001). Conclusions In the treatment of advanced lung adenocarcinoma patients with EGFR-gene sensitive mutations, compared with single EGFR-TKI-targeted therapy, EGFR-TKI-targeted drug combined chemotherapy can control the disease progression more effectively, and does not increase adverse reactions.

First-line osimertinib in EGFR mutation-positive non-small cell lung cancer patients with poor performance status.

Background: The efficacy of osimertinib as a first-line treatment for patients with poor performance status (PS) remains unclear. Patients & methods: This multicenter retrospective study evaluated patients treated with osimertinib between 2018 and 2020, with PS 2-4. Results: Among 36 patients with PS 2, the median progression-free survival (PFS), 1-year PFS, median overall survival (OS) and 1-year OS were 14.5months, 65.4%, 18.1months and 72.7%, respectively. Among 20 patients with PS 3-4, the median PFS, 1-year PFS, median OS and 1-year OS were 3.0months, 27.1%, 5.0months and 46.1%, respectively. Conclusion: Osimertinib was not as efficacious as other EGFR-tyrosine kinase inhibitors.

P10.09 Efficacy and Toxicity of EGFR-TKI in Frail NSCLC with EGFR Mutation: A Retrospective Analysis in a Single Institution

EGFR-TKI is the standard treatment of care for sensitizing EGFR mutation-positive advanced non-small lung cancer (NSCLC) patients. However, the treatment strategy of first-line EGFR-TKI for frail patients has not been well established yet. In current NCCN guideline, osimertinib is preferred as first-line therapy for sensitizing EGFR mutation-positive patients regardless of their age and ECOG performance status (PS), while Japan Lung Cancer Society guideline 2020 recommends first generation EGFR-TKIs for the patients with PS 2-4.

Sensitivity and optimal clinicopathological features for mutation-targeted liquid biopsy in pN0M0 EGFR-mutant lung adenocarcinoma.

Liquid biopsy for early-stage lung cancer diagnosis is challenging, and optimal candidates' clinicopathological features are unknown. We investigated utility and clinicopathological features of optimal candidates in somatic mutation-targeted liquid biopsy using droplet digital polymerase chain reaction (ddPCR) in pN0M0 EGFR mutation-positive lung adenocarcinoma patients. We performed EGFR mutation-targeted ddPCR liquid biopsy in 100 patients with resected pN0M0 invasive lung adenocarcinoma, whose tumor diameter in high-resolution computed tomography (HRCT) was ≤ 5cm. Peripheral blood-derived serum was collected preoperatively. Two representative EGFR somatic variants (exon 19 [E746-A750 del (2235_2249 del)]; exon 21 (L858R)) were utilized as liquid biopsy targets. Clinicopathological features including radiological appearance, subhistology, and invasive status were compared between ddPCR-positive and ddPCR-negative patients. Among the 100 patients, 98 showed part-solid or pure-solid appearance in HRCT and 2 showed non-solid appearance; 98 were pathological stage IA1-IB. Of the 66 patients with EGFR mutation detection in ddPCR, 12 were significantly positive and 10 (83.3%, 10/12) exhibited pure-solid appearance in HRCT. Clinical invasive tumor ratio was significantly higher in ddPCR-positive than in ddPCR-negative patients (median: 100% vs. 85.4%, P = 0.0212), whereas other clinicopathological features were not significantly different. Mutation-targeted liquid biopsy using ddPCR detected lung cancer in 12.0% (12/100) of pN0M0 EGFR-mutant lung adenocarcinoma patients. In 83.3% of the ddPCR-positive patients, tumors showed pure-solid appearance in HRCT. The detection ratio increased to 21.3% (10/47) among patients with pure-solid appearance tumors. Tumor appearance might be useful for better selection of liquid biopsy candidates.

Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive NSCLC in Korea: KCSG LU-19-22.

9053 Background: While osimertinib showed impressive efficacy and safety profile in 1st-line setting for EGFR mutation-positive (EGFR M+) NSCLC patients, there are no standard targeted therapy following progression. Thus, interest has been growing on sequential treatment of osimertinib as 2nd-line treatment for patients acquiring T790M resistance mutation after 2nd generation EGFR TKIs. We did a retrospective study to support the hypothesis that sequential approach of afatinib followed by osimertinib represents a practical treatment option in ‘real-world’ practice. Methods: In this non-interventional, multicenter study, EGFR M+ NSCLC patients had to start 1st-line afatinib treatment ≥ 13 months prior to data entry. They were categorized into 4 cohorts according to 2nd-line treatments with retesting results: T790M+ patients sequentially treated with osimertinib in cohort A, T790M patients treated with chemotherapy or other treatments in cohort B, and patients with unknown mutation status in cohort C. Cohort D included patients who were still ongoing with afatinib. Primary outcome was the time on treatment (TOT) of patients receiving 1st-line afatinib (TOT-1) followed by 2nd-line treatments (TOT-2). Secondary endpoints were acquisition rate of T790M after progression, objective response rates of afatinib (ORR-1) and 2nd-line treatments (ORR-2), and overall survival (OS). Results: Among a total of 761 enrolled patients, 737 patients excluding 24 screening failures were allocated into cohort A (n=116), B (n=143), C (n=111), and D (n=367). Median age was 62 years (22 - 90) with 53.05% of female proportion. Brain metastasis was discovered in 38.94% at initial diagnosis. Regarding genotypes of EGFR mutations, del19 was 57.53%, 31.48% for L858R, 7.33% for uncommon mutations, and 3.66% for compound mutation. Median TOTs in cohort A, B, C, and D were 35.09 months (95% CI, 30.09 to 43.53), 18.76 months (95% CI, 16.92 to 20.20), 12.02 months (95% CI, 10.22 to 14.98), and 42.61 months (95% CI, 30.95 to 59.23), respectively. Particularly, in cohort A, median TOT-1 and TOT-2 were 17.43 months (95% CI, 15.21 to 19.32) and 11.04 months (95% CI, 7.10 to 14.13), respectively. Retesting was attempted in 262 of 370 patients (70.81%) with 44.27% of T790M detection rate. ORR-1 and -2 in cohort A, B, and C were 84.48% and 56.03%, 82.52% and 29.08%, 54.95% and 21.70%, respectively and 68.94% of ORR for cohort D. Median OS has was not reached. Conclusions: These data suggest that, in real-world practice, sequential afatinib followed by osimertinib be a feasible and effective therapeutic strategy for EGFR M+ NSCLC patients acquiring T790M during the period of afatinib treatment. Of note, median TOT in cohort D is over 3.5 years, suggesting that 1st-line afatinib potentially allow certain patients to maintain long-term, chemotherapy-free state. Further analysis is currently being undertaken and will be presented.

Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive metastatic non-small-cell lung cancer (NSCLC). EGFR mutations are relatively common in Asian patients with NSCLC, and there is an increasing number of studies supporting the effectiveness of the second-generation TKI afatinib in routine clinical practice in Asia. This article reviews these real-world studies investigating afatinib as first-line treatment for EGFR mutation-positive NSCLC in Asian patients. Evidence from real-world studies with afatinib in this patient population supports findings from randomized controlled trials (RCTs) showing that afatinib is associated with more favorable outcomes compared with the first-generation EGFR TKIs. The effectiveness of afatinib has also been shown in real-world studies in Asian patients with poor prognostic factors, who are often under-represented or excluded from RCTs, such as those with uncommon EGFR mutations, brain metastases, or poor performance status, and elderly patients. The tolerability profile of afatinib in the real-world setting reflects that seen in RCTs, with no new safety signals reported in real-world studies in Asian patients with EGFR mutation-positive NSCLC. Dose-modification strategies also seem to be effective in the real world, with results of the RealGido study, which included 44% Asian patients, confirming findings from prospective clinical trials showing that tolerability-guided afatinib dose modifications can reduce the incidence of adverse events without adversely affecting clinical outcomes. While further research, including clinical trial data, is needed, real-world data have also demonstrated the feasibility of sequential afatinib followed by the third-generation TKI osimertinib in T790M-positive EGFR mutation-positive patients, which showed longer overall survival. Together, these real-world results demonstrate the real-world clinical effectiveness of afatinib as first-line treatment for patients with EGFR mutation-positive NSCLC.

SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells

EGFR mutation-positive patients with non-small cell lung cancer (NSCLC) respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR-TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR-TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR-TKIs and that SHOC2 affects the sensitivity to EGFR-TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations. IMPLICATIONS: This study showed that SHOC2 works as a modulator of sensitivity to EGFR-TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR-TKIs.

1356P Disease monitoring and TKI resistance mutations of EGFR mutation-positive NSCLC patients via circulating tumour DNA

1356P Disease monitoring and TKI resistance mutations of EGFR mutation-positive NSCLC patients via circulating tumour DNA

Abstract 3081: SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells

Abstract Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKI) have become the first line treatment for patients with EGFR mutated non-small cell lung cancer (NSCLC) as a result of multiple clinical trials demonstrating superior response and less toxicity as compared to conventional cytotoxic agents. However, despite the clinical experience among nearly two decades, it is well known that EGFR-TKI monotherapy cannot cure EGFR mutation-positive lung cancer patients due to the occurrence of drug resistance. While dramatic initial tumor shrinkage is shown in most patients with EGFR-TKI treatment, therapeutic resistance is often observed in 1-2 years. This is likely caused by the outgrowth of rare pre-existing resistant clones and/or small fraction of drug tolerant persister cells (DTPs) which survive and acquire resistance to EGFR-TKIs. Several previous studies have clarified the acquired resistance mechanisms to EGFR-TKIs, but little is known how the DTPs survive during the initial phase of drug exposure and rapidly adapt to EGFR-TKIs. Utilizing the genome wide CRISPR/Cas9 screening, we have previously reported that DTPs were capable to exploit endoplasmic reticulum stress to survive EGFR-TKI exposure (Terai, et al, Cancer Research 2018). Further analysis of this data identified multiple genes which could affect the initial drug response to EGFR-TKIs, including the scaffold protein coding gene, SHOC2. In our present study we focused on this unique protein and revealed its critical function as a modulator of drug response to EGFR-TKIs in lung cancer cells. We confirmed that depletion/overexpression of SHOC2 in PC9 cells, an EGFR-dependent NSCLC cell line, renders the cells sensitive/resistant to all 1st to 3rd generation EGFR-TKIs. We have also confirmed similar findings with another EGFR dependent NSCLC cell line named H1975. Reduction of phosphorylation levels of ERK1/2 induced by EGFR-TKIs were stronger in PC9 or H1975 cells with SHOC2 knockout, indicating that SHOC2 can facilitate ERK1/2 reactivation during EGFR-TKI treatment. The above data indicate that SHOC2 is essential for DTPs and its function is correlated with MAPK-ERK pathway activity. Celastrol, a candidate SHOC2 inhibitor, inhibited the emergence of DTPs and synergized with EGFR-TKIs. Additionally, we showed that SHOC2 depletion enhanced the growth inhibitory effect of osimertinib in vivo. Lastly, we confirmed the increased expression of SHOC2 in clinical human samples which experienced EGFR-TKI failure. Our findings could offer a new treatment strategy for NSCLC patients with EGFR mutation leading to the increase of the degree and duration of EGFR TKIs response. Citation Format: Hideki Terai, Junko Hamamoto, Tadashi Manabe, Katsura Emoto, Takeshi Masuda, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga. SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3081.

A meta-analysis of the safety and effectiveness of pemetrexed compared with gefitinib for pre-treated advanced or metastatic NSCLC.

Background:The purpose of the current meta-analysis was to compare the oncological outcomes of pemetrexed versus gefitinib in pre-treated advanced or metastatic non-small cell lung cancer (NSCLC) patients.Methods:Search the online electronic databases on comparison the effectiveness and adverse effects of pemetrexed versus gefitinib in therapy outcomes of pre-treated NSCLC to September 2019. All studies analyzed the summary odds ratios (ORs) of the main outcomes, including survival efficacy and toxicity complications.Results:In all, 5 trials involving 676 subjects were included, with 332 receiving pemetrexed and 344 using gefitinib. The pooled analysis of overall survival (OS) (OR = 0.97, 95%CI = 0.77–1.21, P = .76) and progression-free survival (PFS) (OR = 1.17, 95%CI = 0.60–2.30, P = .65) showed that pemetrexed did not achieve benefit when compared with gefitinib. In the results of subgroup analysis among the EGFR mutation-positive patients, the comparison of gefitinib therapy versus pemetrexed did show PFS benefit 0.35 (95%CI 0.12–1.01; P = .05). In terms of grade 3 or 4 side effects, a similar toxicity profile of both pemetrexed and gefitinib was shown in the incidence rate of rash (P = .045), fatigue (P = .97), thrombocytopenia (P = .68) and anemia (P = .21) between the 2 groups.Conclusion:Pemetrexed was not associated with survival benefit than gefitinib therapy among pre-treated NSCLC patients. While, gefitinib showed superior PFS efficacy than pemetrexed for patients with EGFR mutation-type. Future investigations are required to identify relevant biomarkers in selected patients that would most likely benefit from pemetrexed or gefitinib treatment in pre-treated advanced NSCLC patients.