Mutation-positive Non-small Cell Lung Research Articles

A multicenter, prospective phase II trial of first-line osimertinib treatment for patients with poor performance status and EGFR mutation–positive non-small cell lung cancer (OPEN/TORG2040).

A multicenter, prospective phase II trial of first-line osimertinib treatment for patients with poor performance status and <i>EGFR</i> mutation–positive non-small cell lung cancer (OPEN/TORG2040).

A phase II, open-label, single-arm, multicenter, efficacy and safety study of 80 mg osimertinib in patients with leptomeningeal metastases (LM) associated with epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer (NSCLC): BLOSSOM.

A phase II, open-label, single-arm, multicenter, efficacy and safety study of 80 mg osimertinib in patients with leptomeningeal metastases (LM) associated with epidermal growth factor receptor (EGFR) mutation–positive non-small cell lung cancer (NSCLC): BLOSSOM.

Development and validation of a prediction model for the recurrence of stage 1 EGFR mutation positive NSCLC in patients using machine learning with WES-based gene sets.

8563 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in EGFR mutation positive ( EGFR-m) non-small cell lung cancer (NSCLC). Only a few reports conducted whole exome sequencing (WES) for genomic profiling in large scale EGFR-m NSCLC cases. Methods: We conducted WES and analyzed the clinical course of patients (pts) with NSCLC who underwent surgery between 1985 and 2019 in the PRISM project of our institute. We evaluated the EGFR-m patients’ characteristics, recurrence-free survival (RFS), and developed a prediction model using machine learning, Overlapping Group LASSO to predict whether the EGFR-m patients will recur within 5 years or not as "high-risk" and "low-risk". To develop and validate the prediction model, we divided the data from 2006 as the training cohort data set and the data before 2006 as the validation cohort data set. After the development of the prediction model, we performed a stratified Cox proportional hazards model to compare the RFS between the predicted groups. Results: A total of 585/1351(43.3%) pts were EGFR-m included in the PRISM project. Of all pts, stage I, EGFR-m were 205 pts. The median RFS of the stage I, EGFR-m 123.1 months (m). In the training cohort, the model detected 43 pts for high-risk and 88 pts for low-risk. In the validation cohort, the model predicted 29 pts for high-risk and 45 pts for low-risk. Median RFS of high-risk vs. low-risk were 52.2 m vs. 105 m (HR 2.43, p=0.01). The 1-year RFS rate, 2-year RFS rate, and 5-year RFS rates for high-risk and low-risk pts were 100% vs. 98.5%, 66.7% vs. 89.2%, and 41.7% vs. 66.1%, respectively. Twenty-eight gene set coefficients were non-zero in the prediction model. The gene sets with large positive coefficients that were considered important for prediction as "high risk" were the gene sets affected by KRAS gene overexpression and p53 gene knockdown. In contrast, gene sets repressed by mTOR inhibition and genes repressed by TBK1 gene knockdown and KRAS gene overexpression had large negative coefficients. Conclusions: We developed and validated the prediction model whether the EGFR-m patients will recur within 5 years or not. EGFR-m NSCLC recurrence appears to be high risk with pathways associated with KRAS and p53 genes, and low risk with mutations in the gene sets suppressed by the mTOR pathway and TBK1 gene. [Table: see text]

310P Clinical characteristics and real-world progression-free survival of patients with EGFR mutation positive non-small cell lung cancer treated with afatinib as first-line: A retrospective cohort study from Indonesia

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib, demonstrated superiority to chemotherapy as a first-line treatment and improved survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. This study aimed to investigate the clinical risk factors affecting progression-free survival (PFS) of patients treated with first-line afatinib in Indonesia.

1077P An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of the advanced EGFR mutation positive non-small cell lung cancer

TKIs are standard care option in patients of NSCLC with EGFR mutation. TKIs-based combination treatment modes have shown encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on OS.

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.

933MO Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage IA-IIIA EGFR mutant non-small cell lung cancer

For patients with early stage epidermal growth factor receptor mutation positive (EGFR-M+) non-small cell lung cancer (NSCLC), curative surgery followed by adjuvant chemotherapy is considered the standard of care. Recently, based on the ADAURA study, osimertinib was approved in resected stage IB-IIIA EGFR-M+ NSCLC. The circulating tumor DNA (ctDNA) provides a potential biomarker for detection of minimal residual disease (MRD) and recurrence. We investigated the longitudinal monitoring of ctDNA test in early stage EGFR-M+ NSCLC. Between August 2015 and October 2017, 278 patients with curative resected, stage IA-IIIA EGFR-M+ NSCLC were enrolled. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet digital PCR from baseline and follow-up per protocol until 5 years or recurrence. Median follow-up duration was 62.0 months (range, 1.5-774). Among 278 patients, stage IA, IB, IIA, IIB, and IIIA comprised 60.1%, 18.3%, 10.1%, 2.2%, and 9.4%, respectively. The EGFR exon 19 del was 60.1% and L858R was 39.9%. The 3-year DFS rate for each stage was 95%, 78%, 58%, 50%, and 32%, respectively. Among 278 patients, baseline ctDNA was detected in 67 (24.1%) patients: 23.4% (stage IA), 17.6% (IB), 17.9% (IIA), 50.0% (IIB), and 42.3% (IIIA) (P=0.06). In 76.1% (51 of 67) of patients with baseline ctDNA, it was cleared up 4 weeks after surgery. Patients were classified into three groups according to the positivity of ctDNA (Group A: baseline ctDNA negative (n=211), Group B: baseline ctDNA positive, but MRD negative (n=51), Group C: baseline ctDNA positive, but MRD positive (n=16)). The 3-year DFS rate was significantly different among the three groups (83.3% for Group A, 78% for Group B, and 50% for Group C, respectively, P=0.02). After adjusting for clinicopathologic variables, ctDNA group (HR 1.27, 95% CI 1.03-1.57, P=0.03) still remains an independent risk factor regardless stage for DFS. These results suggest that patients with baseline ctDNA positive or MRD positive were associated with poor DFS in curative resected stage IA-IIIA EGFR M+ NSCLC. Further detailed results of longitudinal monitoring of ctDNA and clinical recurrence will be presented.

Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. A retrospective observational cohort study was performed, including patients receiving 40-80mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166µg/L was taken to explore the exposure-efficacy relationship. A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3-19.1) months and 9.3 (95% CI: 7.2-11.1) months for patients with Cmin,pred < 166µg/L and Cmin,pred ≥ 166µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60-2.01;p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18-7.08;p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer

ObjectivesTyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).Materials and methodsRandomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.ResultsEighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.Conclusion1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.

Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.

Population-Based Analysis of Outcomes for Patients With Brain Metastases From Epidermal Growth Factor Receptor Mutation Positive Non-Small Cell Lung Cancer Treated With Tyrosine Kinase Inhibitor Alone or Combined With Radiotherapy

With modern therapies, the median survival of patients with brain metastases (BrM) from non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutation (EGFRm) may exceed 1-2 years. BrM directed therapies must therefore carefully balance treatment efficacy and late toxicity. Although some tyrosine kinase inhibitors (TKI) exhibit intracranial activity, there is no level-one evidence to support up-front treatment of BrM using TKI without radiotherapy (RT). This study aimed to compare the outcomes of patients with BrM from EGFRm NSCLC treated with initial RT and TKI, versus TKI alone.All patients who received a TKI (gefitinib, erlotinib, afatinib, or osimertinib) in British Columbia for NSCLC between January 2010 to 2018 were identified in a provincial pharmacy database. Patients were then screened for pathologic diagnosis of EGFRm, and radiologic diagnosis of BrM. These patients were categorized as receiving either TKI alone or RT with TKI for treatment of their BrM. Patients who received RT were cross-referenced with a provincial RT database to determine radiotherapy prescriptions and were classified as having received whole brain (WBRT) with TKI or stereotactic RT/radiosurgery (SRS) with TKI. Patients were excluded if they discontinued TKI after RT or ever received surgery for BrM. Overall survival (OS) and intracranial progression free survival (iPFS) were calculated from the date of BrM diagnosis using Kaplan-Meier analysis. Log rank test was used for comparison between groups, and Cox proportional hazards model was used for multivariate analysis.A total of 167 patients were included for analysis with a median follow up of 45 months. Median OS was 19 months with WBRT (n = 76), 21 months with SRS (n = 45), and 6 months with TKI alone (n = 46), P < 0.01. In patients who had WBRT, iPFS was better than in those having TKI alone [HR 4.68 (2.07-10.56); P < 0.01] or SRS [HR 2.43 (1.20-4.91); P < 0.01]. On multivariate analysis: advanced age, worse performance status, presence of extracranial metastasis, greater than 10 B.M. and type of treatment (TKI alone versus RT with TKI) were associated with inferior OS.This study showed that compared to treatment with TKI alone, the addition of RT for BrM is associated with an improved OS in patients with EGFRm NSCLC. These results are complementary to the growing body of retrospective data suggesting an inferior survival associated with TKI alone compared to RT with TKI for treatment of BrM in patients with EGFRm NSCLC. Prospective studies are required to further guide the best approach to managing this patient population.T. Kong: None. A. Nichol: None. C. Ho: None. A. Benny: None. N. Chooback: None. I.M. Fraser: None. L. Gondara: None. S. Lefresne: None.

24: Population-Based Analysis of Outcomes for Patients with Brain Metastases from Epidermal Growth Factor Receptor Mutation Positive Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitor Alone Or Combined with Radiotherapy

24: Population-Based Analysis of Outcomes for Patients with Brain Metastases from Epidermal Growth Factor Receptor Mutation Positive Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitor Alone Or Combined with Radiotherapy

Abstract CT024: Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D

Abstract Background/Purpose: MET-amplification is a resistance mechanism seen in ≤22% of patients (pts) with epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC) following progression on osimertinib, a third generation (3G), irreversible, oral EGFR tyrosine kinase inhibitor (TKI). In the Ph1b TATTON (NCT02143466) expansion cohorts (Parts B and D), pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR TKI, received osimertinib 80 mg + savolitinib 600 or 300 mg once daily; savolitinib is an oral, potent and highly selective MET TKI. Part B was split into three cohorts by prior therapy and tumor T790M status. Part D pts had received no prior 3G EGFR TKI and were T790M negative. For pts who eventually develop resistance to the combination, it is unclear which driver mutation(s) mediates this resistance. Methods: In this analysis, paired plasma samples collected at baseline and following disease progression and/or treatment discontinuation up to data cut-off date 4 March 2020, were assessed. Next generation sequencing (Guardant Health, Guardant360 73 gene panel or Omni 500 gene panel) was used to analyze the plasma ctDNA samples. All 73 genes on the Guardant360 panel were included in the Omni 500 gene panel. Analyses from each pt were reported only for genes included across the panels used. Genomic alterations were identified using Guardant Health's pipeline, which included mutations and amplifications of EGFR and MET. Disease progression was assessed by the investigator, according to the RECIST version 1.1. Assessments were completed for pts with progression-free survival (PFS) of over 2 months. Results: Of 180 pts who received study treatment, 70 provided baseline and progression/discontinuation ctDNA plasma samples. Of these, 45 pts were used for the analysis: 18/70 were not evaluable for ctDNA detection and 7/70 had a PFS of 2 months or shorter. Of the evaluable samples, the following acquired mutations were recorded (exclusivity between genes in most pts): MET D1228X, Y1230X, L1212X (20%, 9/45), EGFR C797X (16%, 7/45), KRAS G12X, G13X (11%, 5/45) and PIK3CA E545K (4%, 2/45). Most pts who developed MET-based resistance (7/9) developed more than one MET mutation, suggestive of polyclonal resistance. Across both Parts B and D, the resistance profiles appeared similar by prior EGFR TKI status and by savolitinib dose. Conclusions: In this analysis, approximately half of all evaluable pts had an identifiable acquired resistance mechanism; resistance appeared to be predominantly mediated by either MET, EGFR or KRAS. Co-occurring mutations across multiple genes were rarely detected. However, multiple acquired mutations were often detected in a specific gene, particularly MET, suggesting individual tumors showed inherent resistance dependencies. Citation Format: Aleksandra Markovets, Ji-Youn Han, Byoung Chul Cho, Mireille Cantarini, Pasi A. Janne, Ryan Hartmaier. Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT024.

Abstract CT127: Tumor response and MET-detection methods exploratory biomarker analysis of Part B of the Ph 1b TATTON study

Abstract Background/Purpose Following disease progression on osimertinib, a third generation (3G), irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), ≤22% of patients (pts) with EGFR mutation positive (EGFRm) non-small cell lung cancer (NSCLC) develop MET-amplification as a resistance mechanism to treatment. In the Ph1b TATTON (NCT02143466) Part B expansion cohort, pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR-TKI received osimertinib + savolitinib, an oral, potent and highly selective MET TKI. Previous analyses have compared MET patient selection assays and found that different methods identify different but partially overlapping proportions of pts with MET amplification or overexpression. Here, we report the response rates observed in the subgroups defined by the different central MET assays in TATTON Part B. Methods MET testing (central, or local with central confirmation) was performed on tumor tissue collected after the most recent therapy. MET assays included FISH (MET gene copy number ≥5 or MET-CEP7 ratio ≥2) and IHC (MET +3 expression in ≥50% of tumor cells). TATTON Part B was split into 3 pt cohorts: pts previously treated with a 3G EGFR TKI and not previously treated with a 3G EGFR TKI (T790M positive/negative). This analysis uses the final study data (cutoff 4 March 2020) to compare the objective response rate (ORR) of subgroups identified by each assay. Results For pts who had received prior treatment with a 3G EGFR TKI, ORR by MET assay was as follows: FISH-positive overall (n=53) 30%; FISH polysomy (n=18) 28%; FISH amplification (n=35) 31%; IHC (n=13) 46%. For FISH-positive tumors, ORR trended higher for tumors with ≥10 MET gene copies (n=29, 35%) vs tumors with 5-9 copies (n=24, 25%). For pts with no prior treatment with a 3G EGFR TKI (T790M negative), ORR was as follows: FISH-positive overall (n=34) 65%; FISH polysomy (n=14) 57%; FISH amplification (n=20) 70%; IHC (n=4) 75%. For FISH-positive tumors, ORR trended higher for tumors with ≥10 MET gene copies (n=14, 79%) vs tumors with 5-9 copies (n=20, 55%). In tumors with both central FISH and IHC data available (n=34), IHC positivity (n=20) and FISH positivity (n=27) were correlated, specifically IHC and FISH amplification: 13/16 cases of FISH amplification were also IHC positive. In FISH-positive tumors IHC expression tended to increase with increasing gene copy number (≥10), but outcomes were largely comparable. Conclusions Overall, the MET assays were comparable with regards to ORR, thus supporting continued use of both FISH and IHC for detection of MET in pts following disease progression on any 3G EGFR TKI, though IHC data were limited. Further study is warranted in this area: the SAVANNAH (NCT03778229; FISH and IHC) and ORCHARD (NCT03944772; NGS) studies will provide opportunity for further analyses. Citation Format: Ryan Hartmaier, Ji-Youn Han, Byoung Chul Cho, Aleksandra Markovets, Nisha Kurian, Mireille Cantarini, Pasi A. Janne. Tumor response and MET-detection methods exploratory biomarker analysis of Part B of the Ph 1b TATTON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT127.

Alectinib in first-line treatment for advanced anaplastic lymphoma kinase mutation-positive (alk+) non-small cell lung cancer (NSCLC): a cost-effective change.

Alectinib in first-line treatment for advanced anaplastic lymphoma kinase mutation-positive (alk+) non-small cell lung cancer (NSCLC): a cost-effective change.

80 - Real world prospective data on tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor mutation positive non-small cell lung cancer at the Edinburgh Cancer Centre

80 - Real world prospective data on tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor mutation positive non-small cell lung cancer at the Edinburgh Cancer Centre

Overall survival comparison in patients with and without brain metastases treated with osimertinib for metastatic EGFR mutation positive non-small cell lung cancer (NSCLC).

e21216 Background: With the development of Epidermal Growth factor receptor (EGFR) tyrosine kinase inhibitors such as Osimertinib, the landscape of lung cancer treatment and outcomes has changed. We aimed to describe the outcomes of patients treated with Osimertinib who have brain metastasis compared to those without brain metastases. Methods: This study involved patients diagnosed with metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, from January 2010 to December 2018, who had treatment with Osimertinib at a dose of 80 mg daily. Retrospective data was collected through the electronic medical records from Sunnybrook Health Sciences Centre. Descriptive statistics were used to summarize the population characteristics. The log rank test was used to compare the survival distributions. Results: A total of 56 patients were included, the mean age at initial diagnosis was 63 years (range 27 – 85 years). Overall, 82.2% of this patient population received Osimertinib in 2nd line setting. A total of 50% (n = 28) had brain metastasis, and14.3% (n = 8) had leptomeningeal metastasis. Of the patients with brain metastasis, 14.3% (n = 4) had brain surgery. All patients with brain metastasis received central nervous system (CNS) radiation. With respect to radiotherapy modalities, 67.9% (n = 19) of patients with brain metastasis received gamma knife radiation, 42.85% (n = 12) were treated with stereotactic radiosurgery (SRS), and whole brain radiation was given to 57.1% (n = 16). Of those with brain metastasis, equal numbers of patients, 46.4% (n = 13), had EGFR mutations with exon 19-deletion and exon 21-L858R, 7.1% (n = 2) had unknown gene location EGFR mutation. The median OS for patients without brain metastasis was 38.6 months (95% confidence interval [CI] 37.5 – 39.8 months], compared to 35.9 months (95% [CI] 28.3 – 43.5 months] for those with brain metastasis ; log Rank (Mantel-Cox) p = 0.874. The median OS for patients diagnosed with leptomeningeal metastasis was 21 months (95% [CI] 2.9 – 39.0 months); log rank (mantel-cox). When brain metastasis was examined by EGFR mutation sub-groups, the median OS for patients with EGFR-exon 19-deletion was 26.4 months (95% CI [14.3 – 38.4 months], compared to 36.8 months, 95% CI [34.3 – 39.2 months] for those with EGFR-Exon 21-L858R; log Rank (Mantel-Cox) p = 0.49. Conclusions: Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases. However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.

A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).

TPS9131 Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

P37.25 Clinical Validation of Low-costs Next Generation Sequencing Panels in Solid Tumors

The implementation of personalized medicine has revolutionized the current strategies in oncology. Numerous comparisons of technology platforms for mutation testing conclude that the methods should offer high sensitivity, tissue economy and short turnaround time for physicians to guide treatment decisions. In the current study, we were trying to validate the low cost NGS panels in different solid tumors. In addition, validation sample tumors include lung cancers, colorectal cancers and thyroid cancers from both Taiwan and Vietnam. A total of 180 tumor samples were retrospectively collected from Cardinal Tien Hospital (Taiwan) and Bach Mai Hospital (Vietnam) between 2015∼2019. Thirty EGFR mutation positive non-small cell lung cancer (NSCLC) samples, thirty KRAS/NRAS mutation positive colorectal cancer (CRC) samples, and thirty BRAF mutation positive thyroid cancer (TC) samples were chosen from each hospital. All the mutations were tested by Sanger sequencing and NGS. There were 38 EGFR L858R mutation cases, 22 EGFR 19 deletion mutation cases, 2 EGFR T790M mutation cases, 29 KRAS G12D mutation cases, 24 KRAS G12V mutation cases, 5 KRAS G13C mutation cases, 2 NRAS G12S mutation cases, and 60 BRAF V600E mutation cases. The 2 EGFR T790M cases were also positive for the EGFR L858R mutation. The results were the same with Sanger sequencing which give the sensitivity, specificity, positive predict value and negative predict value to be 100%. The low cost RaSeqTM molecular testing system is an accessible, rapid, and reliable testing option for both routine and challenging FFPE specimens. It can serve well as a routine molecular diagnostic tool in most pathology laboratories. The high sensitivity and high accuracy with different gene tests simultaneously are the most advantage in the clinical cancer molecular diagnosis.