Primary T790M Mutation Research Articles

Initial Treatment of Aumolertinib in Combination with Bevacizumab for Advanced NSCLC with Primary EGFR T790M Mutation: A Report of Three Cases and Literature Review

With the development of sequencing technology, the detection rate of non-small cell lung cancer (NSCLC) with primary epidermal growth factor receptor (EGFR) T790M mutation is increasing. However, the first-line treatment for primary EGFR T790M-mutated NSCLC still lacks standard recommendations. Here, we reported three advanced NSCLC cases with EGFR-activating mutation and primary T790M mutation. The patients were initially treated with Aumolertinib combination with Bevacizumab; among which, one case was discontinued Bevacizumab due to bleeding risk after treatment for three months. Treatment was switched to Osimertinib after ten months of treatment. Another case switched to Osimertinib and discontinued Bevacizumab after thirteen months of treatment. The best effect response in all three cases was partial response (PR) after initial treatment. Two cases progressed after first-line treatment and progression-free survival (PFS) was eleven months and seven months respectively. The other one patient had persistent response after treatment, and the treatment duration has reached nineteen months. Two cases had multiple brain metastases before administration and the best response to intracranial lesions was PR. The intracranial PFS was fourteen months and not reached (16+ months), respectively. There were no new adverse events (AEs), and no AEs of grade three or above were reported. In addition, we summarized the research progress of Osimertinib in the treatment of NSCLC with primary EGFR T790M mutation. In conclusion, Aumolertinib combined with Bevacizumab in the treatment of advanced NSCLC with primary EGFR T790M mutation has a high objective response rate (ORR) and control ability of intracranial lesions, which can be used as one of the initial options for first-line advanced NSCLC with primary EGFR T790M mutation. .

Clinical outcomes of lung adenocarcinoma patients harboring uncommon epidermal growth factor receptor (EGFR) mutations treated with EGFR-tyrosine kinase inhibitors (TKIs).

This study aimed to explore the efficacy of different epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma (AC) patients harboring uncommon EGFR mutations. Between January 1st, 2013 and October 1st, 2019, 2,680 EGFR mutation-positive patients with confirmed stage IIIB/IV lung AC were enrolled from Zhejiang Cancer Hospital. Uncommon EGFR mutations were detected in 132 patients using next-generation-sequencing. Clinicopathological features between patients with uncommon EGFR mutations and common EGFR mutations were evaluated by the chi-square test. The clinical outcomes of patients with uncommon EGFR mutations were analyzed by the Kaplan-Meier method. Of 132 AC patients with uncommon EGFR mutations, 115 received EGFR-TKIs. Second-generation EGFR-TKIs were associated with longer progression-free survival (PFS) (P=0.116) and overall survival (OS) (P=0.005) than first or third-generation EGFR-TKIs. We also found that patients with compound mutations and double uncommon EGFR mutations had longer PFS (P=0.725) and OS (P=0.741) than those with single uncommon EGFR mutation, although the difference was not significant. In addition, third-generation EGFR-TKIs were more effective than the other two agents in patients with primary T790M mutation regarding PFS (P=0.150) and OS (P=0.033), although the difference in PFS was not significant. Patients with uncommon EGFR mutations treated with second-generation EGFR-TKIs showed better PFS and OS. EGFR-TKIs were more effective in patients with compound mutations or double uncommon mutations.

Multiple mutations in the EGFR gene in patients diagnosed with lung cancer.

e20542 Background: Lung cancer is the most common malignant tumor after breast cancer and is the main cause of cancer mortality. Mutations in the EGFR gene typical of lung cancer lead to constitutive activation of the epidermal growth factor receptor and malignant cell transformation. The purpose of this study was to identify associations between double and triple mutations in EGFR and clinical and pathological characteristics of patients in the South of Russia diagnosed with lung cancer. Methods: DNA was extracted from FFPE samples of 240 patients. Mutations in EGFR were detected using Cobas EGFR Mutation Test detection kit (Roche). Results: The mutant type of EGFR was identified in 24.6% of cases, and the most common activating mutations were ex19del (47.5%) and L858R (30.5%). Insertion in exon 20 was detected in 5.1% of mutation cases, G719X - in 3.4%. We also registered cases of identification of two or three mutations in one tumor: ex19del - L858R, ex19del - T790M, L858R - T790M with a frequency of 3.4% and G719X - ex20ins, ex19del - L858R - ex20ins with a frequency of 1.7%. Similar frequency is characteristic of the Caucasoid population of the USA. Multiple mutations in EGFR are associated with early manifestations of lung cancer and rapid progression of the disease. Two patients with two mutations EGFR T790M and L858R were of particular interest. According to the literature data, T790M is the most common somatic mutation that causes resistance to targeted therapy; however, rare cases could be associated with germinal variation of T790M. The primary T790M mutation is more common in patients with two or three mutations in EGFR. Conclusions: Mutations in the EGFR gene were detected in 24.6% of lung cancer cases in a patient population in the South of Russia. The frequency of two or three mutations in the EGFR gene was 0.33%. The timely detection of these mutations is particularly important for family cases when the risk group can be determined.

Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation.

Primary epidermal growth factor receptor (EGFR) T790M mutation can be occasionally identified in previous untreated nonsmall cell lung cancer (NSCLC) patients. To compare clinical characteristics and outcomes in patients with primary and acquired EGFR T790M mutation, we collected the data of patients diagnosed with EGFR mutation from 2012 to 2017 in Shanghai Chest Hospital. Primary EGFR T790M mutation was identified in 61 patients (1.1%; 95% confidence interval (CI): 0.8%-1.3%) of 5685 TKI-naive EGFR mutant patients. Acquired T790M mutation was detected in 98 patients (50.3%; 95%CI: 43.2%-57.3%) of 195 TKI-treated patients. T790M mutation always coexisted with sensitizing EGFR mutations. Primary EGFR T790M always coexisted with 21L858R (46/61) whereas acquired T790M coexisted with 19del (68/98), (p < 0.001). Among them, 18 patients with primary T790M mutation received osimertinib and 72 patients with acquired T790M mutation received osimertinib. The median progression-free survival (PFS) of osimertinib was significantly longer in primary T790M group (17.0 months, 95%CI:14.0-20.0 months) compared to acquired T790M group (10.0 months, 95%CI:8.6-11.4 months, p = 0.022). However, the median overall survival (OS) of acquired T790M mutation patients was significantly longer compared to that of primary T790M mutation patients who received osimertinib (50.4 months vs. 29.9 months, p = 0.016). Our findings suggest that primary T790M mutation likely coexists with 21L858R while acquired mutation likely coexists with 19del. Both mutations showed good response to osimertinib. Patients with primary T790M mutation experienced greater benefits from osimertinib. However, patients with acquired T790M mutation had a better overall survival during the entire clinical treatment.

MA15.07 Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients

Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients. We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed. Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively. Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.

Abstract 3192: Liquid biopsies for molecular profiling of mutations in non-small cell lung cancer patients lacking tissue samples

Abstract Introduction: Approximately 30% of patients with an adenocarcinoma of the lung have an actionable driver mutation. Further understanding the molecular mechanisms of acquired resistance to targeted therapies provides key information for determining subsequent treatment options. Access to tumor tissue to perform either the initial molecular profile or at the point of acquired resistance, however, is often limited. Circulating tumor DNA (ctDNA) can be used as a minimally invasive method for the detection and quantification of molecular abnormalities. We performed a prospective study to assess molecular alterations in the ctDNA of NSCLC patients in whom the initial molecular profile or profile at acquired resistance was unknown due to lack of tumor tissue biopsy or insufficient cellularity in the biopsy. Methods: Plasma samples were collected from 52 pre-treated advanced NSCLC patients at the Gustave Roussy. DNA was extracted from &amp;lt; 5 ml of plasma and analysed using Inivata's enhanced TAm-SeqTM assay covering regions from 35 cancer-related genes. Sequences were generated using Illumina sequencing. We also analysed plasma taken following treatments prescribed after the original molecular profile detected using plasma ctDNA. Results: From July 2015 to October 2015, 52 patients were included (63% female, 37% never-smoker, 95% diagnosed with an adenocarcinoma subtype, 95% with stage IV disease, and 54% had EGFR mutant tumors of which 68% had mutations in exon 19 and 32% had mutations in exon 21). ctDNA profiling was successfully performed for all patients, and mutations were detected in 38 of 52 patients. The median number of mutations detected in plasma samples was 1. Within the EGFR mutant subpopulation, T790M mutations were identified including 8 acquired cases (with a concomitant C797S mutation in 1 case) and 1 primary T790M mutation. Of these patients, 5 started personalised treatment with AZD9291 based on the results of ctDNA analysis. In the other 18 patients with EGFR mutant tumors, no acquired mutations associated with resistance were detected. Other results encompassed: 2 plasma samples with EGFR mutation exon 18 (G719A, G719C) leading to initiation of afatinib in one case, 1 case with EGFR mutation exon 21 (L861Q), 1 patients with ERBB2 exon 20 insertion, 3 KRAS mutant detected in plasma (G12C, G12S, G12F), 2 STK11 mutant samples, and 1 patient with a MET mutation (exon 14) who subsequently started crizotinib. Conclusions: ctDNA analysis with Inivata's enhanced TAm-Seq™ provides an alternative method of ‘liquid biopsy’ for obtaining molecular profile of mutations present in NSCLC patients in the absence of an invasive tissue biopsy. Liquid biopsy identified cancer mutations in 73% of the study population, and 18% of those patients subsequently received treatment tailored to the plasma ctDNA detected mutations. An update on the analysis of 75 patients will be presented during the conference. Citation Format: Jordi Remon, Jean Charles Soria, David Planchard, Cecile Jovelet, Chloe Pannet, Ludovic Lacroix, Annas Gazzah, Andrew Lawson, Sarah Smalley, Kenth Howarth, David Gale, Emma Green, Vincent Plagnol, Nitzan Rosenfeld, Ken Oulassen, Nathalie Chaput, Benjamin Besse. Liquid biopsies for molecular profiling of mutations in non-small cell lung cancer patients lacking tissue samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3192.

The application of real-time PCR technique to detect rare cell clones with primary T790M Substitution of EGFR gene in metastases of non-small cell lung cancer to central nervous system in chemotherapy naive patients.

The time-limited efficacy of reversible EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC) with EGFR gene activating mutations is associated with development of treatment resistance after some period of therapy. This resistance predominantly results from secondary mutations located in EGFR gene, especially T790M substitution. There is limited information available concerning the prevalence of primary T790M mutations in patients with metastatic NSCLC tumors before treatment with EGFR-TKIs. The aim of work was to assess the prevalence of de novo T790M mutations in EGFR gene in tissue samples from NSCLC metastatases in central nervous system (CNS) in both chemotherapy and EGFR-TKI naive NSCLC patients. We analyzed DNA samples isolated from paraffin-embedded tissue from CNS metastases for T790M mutations using real-time PCR and TaqMan probe against the T790M mutant sequence. The tissue samples were taken during palliative neurosurgery in 143 NSCLC patients. Amplification of the T790M-specific sequence was detected in 25 patients (17.5 %). The quantity of mutated DNA was less than 1 % in all samples with amplification, and in vast majority (20 patients, 14 % of all samples) it was even less that 0.1 %. In 5 patients (3.5 %) quantity of mutated DNA ranged from 0.1 to 1 % and true positive results of T790M mutation presence in these patients were most possible. Amplification of this sequence was not concurrent with common EGFR mutations and was not associated with sex, smoking status and pathological type of cancer. There is a possibility to detect the primary T790M mutation in brain metastases of NSCLC in EGFR-TKIs naïve patients.