scholarly journals Patients harboring uncommon EGFR exon 19 deletion-insertion mutations respond well to first-generation EGFR inhibitors and osimeritinib upon acquisition of T790M

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yurong Wang ◽  
Ruipan Zheng ◽  
Peizhu Hu ◽  
Ziheng Zhang ◽  
Shujing Shen ◽  
...  
Keyword(s):  
First Generation ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
First Line ◽  
T790m Mutation ◽  
First Line Therapy ◽  
Exon 19 Deletion ◽  
Egfr Tkis ◽  
Exon 19

Abstract Background In the existing next generation sequencing (NGS) system, epidermal growth factor receptor (EGFR) exon 19 deletion-insertion (19delins) is still interpreted into the category of EGFR exon 19 deletion (19del). However, the controversy exists whether the two mutation types have the similar responses and resistant mechanisms to first-generation EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. Methods We successively and retrospectively reviewed the NGS data of 3054 patients diagnosed as advanced NSCLC from November 2017 to September 2020. Finally, 41 patients with EGFR 19delins mutation and 41 patients with EGFR 19del mutation who received first-generation EGFR TKIs as first-line therapy were included in the study. Results A total of 17 genotypes were identified in this study, including L747_P753delinsS (10/41), L747_A750delinsP (9/41), L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, the population of EGFR 19delins respond well to first line EGFR TKIs as well as those of EGFR 19del, with little difference in median progression-free survival (mPFS): 10.4 months vs. 13.1 months, p = 0.1076). Interestingly, patients with L747_T751delinsP seem to have a better mPFS than others (18.7 months vs. 13.1 months, p = 0.035). After the disease progression, both EGFR 19delins and EGFR 19del had similar rates of developing EGFR T790M mutation resistance (45.8% vs. 57.8%), and those receiving osimeritinib as second-line treatment obtain the similar survival benefits (mPFS: 12.0 months vs. 12.2 months (p = 0.97). Conclusions This retrospective cohort study furnish the evidence that therapeutic responses and survival of untreated NSCLC population with EGFR 19delins mutation are equal to those with common EGFR 19del mutation after administration of EGFR TKIs therapy.

scholarly journals Patients Harboring Uncommon EGFR Exon 19 Deletion-insertion Mutations Respond Well to First-generation EGFR Inhibitors and Osimeritinib Upon Acquisition of T790M

2021 ◽  
Author(s):  
Yurong Wang ◽  
Ruipan Zheng ◽  
Peizhu Hu ◽  
Ziheng Zhang ◽  
Shujing Shen ◽  
...  
Keyword(s):  
First Generation ◽  
Resistance Mutation ◽  
Resistance Mechanisms ◽  
First Line ◽  
T790m Mutation ◽  
Similar Treatment ◽  
Significant Difference ◽  
Exon 19 Deletion ◽  
Egfr Tkis ◽  
Exon 19

Abstract Background: This study is to investigate the effects and resistance mechanisms of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients carrying rare EGFR exon 19 deletion-insertion (19delins) mutations. Methods: The next generation sequencing (NGS) data of 1783 patients diagnosed as advanced NSCLC from November 2017 to September 2020 were successively and retrospectively reviewed. 41 patients with EGFR 19delins and 41 patients with EGFR exon 19 deletion (19del) were enrolled in this study, who were given first generation EGFR TKIs as first-line therapy. Results: 17 mutation types of EGFR 19delins were identified in this study, L747_P753delinsS (10/41) and L747_A750delinsP (9/41) were the most frequent mutation types, followed by L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, median progression-free survival (mPFS) was similar in patients with EGFR 19delins to those with EGFR 19del (10.4 months vs. 13.1 months, p=0.1076). Interestingly, patients with L747_T751delinsP had a better mPFS than those with other variants (18.7 months vs. 13.1 months, p=0.035). No significant difference in mPFS was found among the three groups of gefitinib, icotinib, and erlotinb with 14.7 months, 10.9 months, and 13.1 months (p>0.05). After progression from first-line EGFR TKIs, both EGFR 19delins and EGFR 19del had similar rates of developing resistance mechanisms including EGFR T790M mutation (45.8% vs. 57.8%). Patients acquiring T790M mutation received osimeritinib as second-line treatment, and the mPFS was similar between the groups of EGFR 19delins (n=8) and EGFR 19del (n=10): 12.0 months vs. 12.2 months (p=0.97). Conclusion: Our results indicate that patients with uncommon EGFR 19delins can also benefit from first-generation EGFR TKIs treatment, having similar treatment responses and survival outcomes to those with EGFR 19del, even similar clinical outcomes from osimeritinib upon acquiring T790M resistance mutation.

scholarly journals Pazopanib as first-line therapy for patients with metastatic kidney cancer

2018 ◽  
pp. 70-76
Author(s):  
B. Ya. Alekseev ◽  
I. M. Shevchuk
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Endothelial Growth Factor

Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β and the stem cell factor receptor c-Kit. In preliminary experiments using mouse and rabbit models of angiogenesis, pazopanib inhibited angiogenesis caused by a combined vascular endothelial growth factor and a major fibroblast growth factor. Although the drug was developed as a therapeutic multi-tumour agent, it is currently approved in many countries for the treatment of advanced soft tissue sarcoma and renal cell carcinoma (RCC). In multicentre, randomized trials of the efficacy of pazopanib as a first-line therapy in patients with metastatic RCC, progression-free survival (PFS) was significantly greater in pazopanib recipients than in cytokine recipients and pazopanib was noninferior to sunitinib with respect to time to disease progression. In addition, side effects such as liver dysfunction and hypertension can be usually managed, and pazopanib is likely to be a more preferred cost-effective option and shows better quality-of-life compared to other alternative drugs.

Activity of osimetrinib/AZD9291 in pretreated patients (pts) with epidermal growth factor receptor mutant (EGFRmt) non-small cell lung cancer (NSCLC), according to EGFR mutations detected in circulating plasma DNA (ctDNA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20608-e20608
Author(s):  
Emmanouil Kontopodis ◽  
Jordana Nuria ◽  
Aliki Ntzifa ◽  
Panayiotis Katsaounis ◽  
Charalambos Haris Charalambous ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Plasma Dna ◽  
T790m Mutation ◽  
Egfr Tki ◽  
Egfr Tkis

e20608 Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI), selective for EGFR TKI-sensitizing mutations and the T790M resistance mutation. We sought to determine the activity of osimertinib after progression on EGFR TKIs in pts with T790-negative ctDNA. Methods: A multicenter phase II study ( clinicaltrials.gov NCT02771314) of osimertinib (80 mg daily) was conducted in pts with metastatic EGFRmt NSCLC, who had progressed after previous treatment with EGFR TKIs. Serial serum and/or plasma samples were drawn for ctDNA analysis at enrollment, 1 month and every 3 months of treatment, until disease progression. Efficacy outcomes in pts without the T790M mutation in ctDNA at baseline are reported. Results: Thirty-seven NSCLC patients with undetectable baseline T790M in the plasma have been enrolled. Median age was 67 years, 21.6% were male, and histology was adenocarcinoma in 100%. More frequent adverse events (grade 1/2) included diarrhea (12.5%), fatigue (12.5%), anorexia (12.5%) and acneiform rash (10.4%). The overall response rate (ORR) was 40.5% (95% CI, 24.7-56.4%) and the disease stabilization rate 37.8%; the median progression-free survival (PFS) was 8.9 months (range, 1.6-30), and the estimated median overall survival (OS) 26 months (range, 2.2-30). At enrollment, EGFR mutations del19 and L858R were detected in ctDNA in 9 and 3 pts, respectively. After one month of treatment with osimertinib, EGFR mutations in ctDNA were not detectable in 4/9 and 2/3 of pts with del19 and L858R at baseline, respectively. Pts without detectable EGFRm ctDNA at baseline remained negative throughout the study. Efficacy according to baseline ctDNA status was as follows: Clinical trial information: NCT02771314. Conclusions: Osimertinib was effective in EGFR TKI pretreated pts without EGFR T790M mutation in plasma. Pts with detectable del19 or L858R mutations in ctDNA before treatment had worse clinical outcomes, despite the elimination of EGFRmt ctDNA.[Table: see text]

Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation

2017 ◽  
Vol 24 (5) ◽  
pp. 379-388 ◽  
Author(s):  
Meredith K Bollinger ◽  
Amanda S Agnew ◽  
Gerard P Mascara
Keyword(s):  
First Generation ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
First Line ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Platinum Doublet

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) in patients failing previous TKI therapy. The T790M mutation is an acquired resistance mechanism found in over half of patients with NSCLC progressing on first-generation TKIs. First- and second-generation TKIs do not inhibit the T790M mutation at clinically relevant concentrations. Osimertinib is selective for mutated forms of EGFR, including the TKI-sensitizing mutations L858R and exon 19 deletions, as well as the acquired T790M resistance mutation. In a trial comparing osimertinib to platinum doublet therapy among patients with the T790M mutation progressing on first-line TKI therapy, median progression-free survival was significantly longer in patients receiving osimertinib. Osimertinib has a favorable safety profile compared to platinum-doublet chemotherapy. Common adverse events include diarrhea, skin rash, dry skin, and paronychia; however, because it spares wild-type EGFR, these toxicities appear to occur with less frequency and severity compared to other TKIs. Serious, but rare, adverse events include pneumonitis, interstitial lung disease-like events, QT interval prolongation, and reduced ejection fraction. Osimertinib has the unique ability to distribute readily into brain tissue compared with other TKIs, giving it a potential role in the treatment and/or prevention of CNS metastases; future studies are warranted in this area. An ongoing study evaluating osimertinib versus first-generation TKIs as first-line treatment for patients with EGFR mutation-positive NSCLC may help to define the role of osimertinib as front-line therapy.

scholarly journals The impact of different first-line EGFR-TKIs on the clinical outcome of sequential osimertinib treatment in advanced NSCLC with secondary T790M

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yen-Hsiang Huang ◽  
Jeng-Sen Tseng ◽  
Kuo-Hsuan Hsu ◽  
Kun-Chieh Chen ◽  
Kang-Yi Su ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Subsequent Treatment ◽  
First Line ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractThe impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR-mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR-mutant NSCLC patients with acquired T790M mutation.

scholarly journals Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis

BMJ ◽  
2019 ◽  
pp. l5460 ◽  
Author(s):  
Yi Zhao ◽  
Jingting Liu ◽  
Xiuyu Cai ◽  
Zhenkui Pan ◽  
Jun Liu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Combination Treatments ◽  
Exon 19 Deletion ◽  
Egfr Mutated

AbstractObjectiveTo compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.Eligibility criteria for selecting studiesPublished and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.Results18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.ConclusionsThese results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.Systematic review registrationPROSPERO CRD42018111954.

scholarly journals Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC

2019 ◽  
Vol 12 (2) ◽  
pp. 625-630 ◽  
Author(s):  
Mike Ralki ◽  
Brigitte Maes ◽  
Karin Pat ◽  
Jokke Wynants ◽  
Kristof Cuppens
Keyword(s):  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
First Line ◽  
T790m Mutation ◽  
Her2 Mutation ◽  
Egfr Mutant ◽  
Egfr Tki

Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response.This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.

Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with EGFR-mutated NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9031-9031
Author(s):  
Daria Gaut ◽  
Myung Shin Sim ◽  
Brian R. Wolf ◽  
Phillip A. Abarca ◽  
James M. Carroll ◽  
...  
Keyword(s):  
Medical Records ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Resistance Mutation ◽  
Progression Free Survival ◽  
First Line ◽  
T790m Mutation ◽  
Free Survival ◽  
Egfr Mutant ◽  
Nsclc Patients

9031 Background: The secondary T790M mutation accounts for more than 50% of acquired tyrosine kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant NSCLC patients. Recent reports suggest this resistance mutation may be more common among patients with longer progression-free survival (PFS) on first-line TKI therapy, but much is still unknown about this resistance mechanism’s association with response to other therapies. Methods: Our group collected medical records from patients who underwent a biopsy for T790M mutation testing in the process of screening for clinical trials involving third generation EGFR inhibitors. Medical records were retrospectively analyzed for demographic data, PFS, best response (BR) to previous therapies, and presence or absence of an acquired T790M mutation. Progression-free survival was estimated using the Kaplan-Meier method and compared across two groups using the log-ranked test followed by univariate and multivariate cox proportional hazard regression analysis. Response rates were compared using Fisher’s exact test. Results: Out of 102 patients who obtained a diagnostic biopsy, 73 patients had a T790M mutation. Patients who later developed a T790M mutation had a longer PFS on first-line TKI therapy (12.0 months in T790M+ vs. 8.0 months in T790M-, p = 0.038, HR 1.66, 95% CI 1.03-2.67), though there was no difference in response rate (75.5% in T790M+ vs 77.3% in T790M-, p = 1.00). T790M+ patients also had a longer PFS on initial chemotherapy treatment (5.0 months in T790M+ vs. 4.0 months in T790M-, p = 0.020, HR 1.97, 95% CI 1.11-3.49) and a higher response rate to chemotherapy (22.7% in T790M+ vs 0% in T790M-, p = 0.033). Median PFS was short (3.0 months) for patients treated with immunotherapy with no difference based on T790M mutation status (p = 0.33). Conclusions: Our study confirms that tumors expressing T790M have a more indolent progression of disease compared to their T790M negative counterparts when treated with both first-line TKI and cytotoxic chemotherapy. This data provides context for therapeutic decision making in EGFR-mutant NSCLC patients.

Erlotinibversuscarboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504

2015 ◽  
Vol 46 (5) ◽  
pp. 1440-1450 ◽  
Author(s):  
Jacques Cadranel ◽  
Radj Gervais ◽  
Patrick Merle ◽  
Denis Moro-Sibilot ◽  
Virginie Westeel ◽  
...  
Keyword(s):  
Disease Control ◽  
Dominant Role ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
First Line ◽  
First Line Therapy ◽  
Epidermal Growth ◽  
Progression Risk ◽  
Pathological Subtypes

The IFCT-0504 phase II trial evaluated the efficacy of erlotinibversuscarboplatin–paclitaxel (CP) as first-line treatment in 130 cases of advanced lepidic-predominant adenocarcinoma (ADC).The primary objective of the study was treatment efficacy, evaluated based on an end-point of disease control at 16 weeks.The primary objective was met, with a disease control in 35 (53%) out of 66 patients treated with CP and in 25 (39.1%) out of 64 patients treated with erlotinib. Median progression-free survival (PFS) for the total population was 3.6 months. The disease control rate did not differ between either the therapeutic arms or pathological subtypes, whereas there was a strong interaction between treatment arms and tumour pathological subtypes for PFS (p=0.009). Mucinous tumour patients treated with erlotinib exhibited an increased progression risk (hazard ratio 3.4, 95% CI 1.7–6.5; p≤0.001). The PFS for nonmucinous tumour patients was similar in both arms. Median overall survival was 20.1 months and did not differ between therapeutic arms. These findings were not further elucidated by molecular analyses and the toxicity profiles were as expected.Our study demonstrated the dominant role of CP alongside erlotinib in the management of advanced lepidic ADC. Based on these findings, erlotinib should not be administered in first-line therapy to patients with lepidic ADC in the absence of an epidermal growth factor receptor mutation.

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