Efficacy of Osimertinib in NSCLC Harboring Uncommon EGFR L861Q and Concurrent Mutations: Case Report and Literature Review.
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SUBMITTER: Lin R
PROVIDER: S-EPMC8445031 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:In the majority of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations, first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are ineffective. The second-generation TKI, afatinib, is considered effective in patients with uncommon mutations, however, long-term survivors have been rare. CASE REPORT:We report herein a patient with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations, who is free of disease 32 months after initiation of afatinib therapy. To our best knowledge, this patient has the longest response among other patients with double uncommon mutations. CONCLUSION:Patients with this type of NSCLC may obtain long-term survival with afatinib.
| S-EPMC7279823 | biostudies-literature
Project description:The discovery of epidermal growth factor receptor (EGFR) somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have altered the therapeutic prospects of advanced non-small-cell lung cancer (NSCLC). G719X and S768I are uncommon mutations, and they often exist as compound mutations. A few reports have described the efficacy of first- and second-generation EGFR-TKIs. However, the efficacy of osimertinib in patients with these uncommon compound mutations is unknown. In this study, we reported the postoperative outcome of a patient with NSCLC and uncommon compound EGFR G719X and S768I mutations. After postoperative recurrence, the patient was treated with osimertinib, and an excellent and long-lasting clinical response was achieved. The patient has taken osimertinib for 31.0 months and exhibited a partial response, and her follow-up is ongoing.
| S-EPMC7273558 | biostudies-literature
Project description:BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data.Patients and methodsIn this retrospective, global, multi-center study (NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or "other" mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS).ResultsOverall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years.ConclusionIn a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.
| S-EPMC8982383 | biostudies-literature
Project description:PurposeApproximately 10% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) harbor uncommon mutations. Here, we report the efficacy and safety of osimertinib in patients with NSCLC harboring uncommon EGFR mutations.Patient and methodsThis was a multicenter, single-arm, open-label, phase II study in Korea. Patients with histologically confirmed metastatic or recurrent NSCLC harboring EGFR mutations other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion were eligible for the study. The primary end point of objective response rate was assessed every 6 weeks by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary end points were progression-free survival, overall survival, duration of response, and safety.ResultsBetween March 2016 and October 2017, 37 patients were enrolled. All were evaluable except one patient who withdrew consent after starting treatment. Median age was 60 years, and 22 (61%) were male. Among patients, 61% received osimertinib as first-line therapy. The mutations identified were G719X (n = 19; 53%), followed by L861Q (n = 9; 25%), S768I (n = 8; 22%), and others (n = 4; 11%). Objective response rate was 50% (18 of 36 patients; 95% CI, 33% to 67%). Median progression-free survival was 8.2 months (95% CI, 5.9 to 10.5 months), and median overall survival was not reached. Median duration of response was 11.2 months (95% CI, 7.7 to 14.7 months). Adverse events of any grade were rash (n = 11; 31%), pruritus (n = 9; 25%), decreased appetite (n = 9; 25%), diarrhea (n = 8; 22%), and dyspnea (n = 8; 22%), but all adverse events were manageable.ConclusionOsimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.
| S-EPMC7098834 | biostudies-literature
Project description:The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically treated by EGFR-TKI such as erlotinib and gefitinib. However, about 40% of individuals harboring EGFR-TKI sensitive mutations are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-κB activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and IκBα with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and IκBα (NF-κB inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. We first found that higher TG2 expression level and lower PTEN and IκBα expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IκBα and exhibited EGFR-TKI resistance. In reverse, When TG2 is downregulated by TG2 inhibitor in H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, reversed EGFR-TKI resistance via IκBα restoration. Moreover, combination treatment of TG2 inhibitor and EGFR-TKI decreased the tumor growth in mouse xenograft models of EGFR mutant NSCLCs. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-κB pathway. These results suggest that TG2 may be a useful predictive marker and also be a target for overcoming the resistance.
| S-EPMC6726998 | biostudies-literature
Project description:EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885-96. ©2018 AACR.
| S-EPMC5932243 | biostudies-literature
Project description:Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes.
| S-EPMC5342394 | biostudies-literature
Project description:PurposeThe uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known.Experimental designThe AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L).Resultsex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0-31.7) vs. 11.7 months (10.8-29.4); adjusted HR 0.52 (0.28-0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present.ConclusionsThe ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future.
| S-EPMC10493186 | biostudies-literature
Project description:Background Epidermal growth factor receptor (EGFR) exon 19 deletion (19del) and the exon 21 L858R point mutation are the most established predictive factors for the efficacy of EGFR-tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC). To date, more than 50 subtypes of EGFR 19dels have been documented in NSCLC. Evidence suggests that different subtypes of 19dels exhibit different survival outcomes to EGFR-TKI treatment. Whether patients harboring EGFR Leu747_Ser752 deletion (delL747_S752) as an uncommon subtype of 19dels benefit from EGFR-TKIs has not been investigated. BIM (B-cell chronic lymphocytic leukemia/lymphoma-like 1) deletion polymorphism is common in East Asian with EGFR-mutant NSCLC. Currently, the predictive role of BIM deletion polymorphism in patients with EGFR-mutant NSCLC treated with osimertinib remains debatable. Case Description A 34-year-old female patient was diagnosed with stage IV lung adenocarcinoma (LUAD) harboring somatic EGFR del L747_S752 and germline BIM deletion polymorphism in August 2018. She obtained benefit from the front-line treatment of osimertinib lasting for 8 months. After progression from osimertinib, the patient received bevacizumab combined with platinum-doublet chemotherapy, stereotactic radiosurgery plus osimertinib and crizotinib, anlotinib, and a programmed cell death-1 inhibitor sintilimab plus bevacizumab and docetaxel. She succumbed to her disease in June 2020 with an overall survival of 23 months. Conclusions Our work suggests that osimertinib might be a compromised treatment option for NSCLC patients with somatic EGFR delL747_S752 and germline BIM deletion polymorphism. Development of more effective regimens are needed for this small subset of NSCLCs.
| S-EPMC9641130 | biostudies-literature
Project description:An increasing number of driver genomic alterations with potential targeted treatments have been identified in non-small cell lung cancer (NSCLC). Much less is known about the incidence and different distribution of concurrent alterations, as identified by comprehensive genomic profiling in oncogene-addicted NSCLCs. Genomic data from advanced NSCLC consecutively analyzed using a broad next-generation sequencing panel were retrospectively collected. Tumors harboring at least one main actionable gene alteration were categorized according to the presence/absence of concurrent genomic aberrations, to evaluate different patterns among the main oncogene-addicted NSCLCs. Three-hundred-nine actionable gene alterations were identified in 284 advanced NSCLC patients during the study period. Twenty-five tumor samples (8%) displayed concurrent alterations in actionable genes. Co-occurrences involving any pathogenic variant or copy number variation (CNV) were identified in 82.8% of cases. Overall, statistically significant differences in the number of concurrent alterations, and the distribution of TP53, STK11, cyclines and receptor tyrosin kinase (RTK) aberrations were observed across the eight actionable gene groups. NGS analyses of oncogene-addicted NSCLCs showed a different distribution and pattern of co-alteration profiles. Further investigations are needed to evaluate the prognostic and treatment-related impact of these concurrent alterations, hooked to the main gene aberrations.
| S-EPMC8124171 | biostudies-literature