Uncommon Epidermal Growth Factor Receptor Research Articles

Non-small cell lung cancer cells with uncommon EGFR exon 19delins variants respond poorly to third-generation EGFR inhibitors

BackgroundThis study compared the clinical efficacy of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in previously untreated non-small cell lung cancer (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) exon 19delins variants. MethodsWe retrospectively analyzed the clinical outcomes of NSCLC patients with EGFR exon 19delins mutations who were treated with third- and first-generation EGFR TKIs. In vitro and in vivo studies were conducted to verify the sensitivity of these mutations to distinct generations of TKIs. Molecular simulation was used to investigate the structural characteristics of the EGFR mutant molecules. ResultsIn a multicenter cohort of 1,526 patients, 37 (2.4 %) had uncommon EGFR 19delins mutations. Twenty-four patients were treated with first-generation EGFR TKIs, and third-generation TKIs were administered to ten patients as frontline therapy. Patients carrying EGFR exon 19delins mutations who were given third-generation TKIs exhibited comparatively shorter progression-free survival (PFS) and overall survival (OS) in relation to those who received first-generation EGFR inhibitors; median PFS: 6.9 months vs. 19.1 months (p < 0.001), Median OS: 19.1 months vs. 32.6 months (p < 0.001). In vivo and in vitro studies revealed that uncommon EGFR 19delins variants exhibit limited sensitivity to third-generation EGFR inhibitors in contrast to first- and second-generation EGFR inhibitors. The molecular binding affinity of third-generation EGFR TKIs toward uncommon EGFR 19delins mutations was less than that of first- and second-generation EGFR inhibitors. ConclusionsUncommon EGFR 19delins variants respond poorly to third-generation EGFR inhibitors in NSCLC. Uncommon EGFR 19delins mutations may serve as an unfavorable predictive factor for the efficacy of third-generation EGFR TKI therapy, offering potential guidance for future clinical decision-making.

Clinical, Genomic, and Transcriptomic Featurses of Lung Adenocarcinoma With Uncommon EGFR Mutation

PurposeThe purpose of this study is to identify the clinical, genomic, and transcriptomic features of patients with lung adenocarcinoma (LUAD) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UCM) compared with common EGFR mutations (CM). Materials and MethodsIn this multicenter retrospective cohort study, clinicopathological data were collected from 1047 consecutive patients who underwent complete surgical resection for LUAD, as well as EGFR mutation analysis, between 2005 and 2012 at 4 institutions. Differences in postoperative overall survival (OS) and recurrence-free survival (RFS) according to EGFR mutation status were evaluated. For the genomic and transcriptomic analyses, 5 cohorts from public databases were evaluated. ResultsOf 466 eligible patients, 415 (89.1%) and 51 (10.9%) had CM and UCM, respectively. The 5-year OS and RFS rates in the CM/UCM groups were 86.8%/77.0% and 74.8%/59.0%, respectively. OS and RFS were significantly shorter in the UCM than CM group (both P < .01). Multivariable analysis of OS showed that UCM was an independent prognostic factor (hazard ratio 1.72, 95% confidential interval 1.01-2.93). According to the genomic analysis, tumors with UCM had a significantly higher tumor mutation burden and TP53 mutation frequency. Transcriptomic analysis showed that the T-cell-inflamed gene signature, a biomarker of the treatment for immunotherapy, was significantly associated with tumors with UCM. ConclusionUCM were associated with a poor prognosis in patients with surgically resected EGFR-mutated LUAD. Tumors with UCM had unique genomic and transcriptomic features suggestive of a tumor microenvironment responsive to immunotherapy.

LBA66 Afatinib versus chemotherapy for treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation: A phase III study (ACHILLES/TORG1834)

LBA66 Afatinib versus chemotherapy for treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation: A phase III study (ACHILLES/TORG1834)

The treatment of patients with non-small cell lung cancer carrying uncommon EGFR mutations, HER2 mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.

Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, human epidermal growth factor receptor 2 (HER2) mutations, or central nervous system (CNS) metastases. This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov. The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon EGFR mutations (including G719X, S768I, and L861Q). Both EGFR exon 20 insertional mutation (Ex20ins) and HER2 Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including EGFR D770delinsGY, A763_Y764insFQEA, and HER2 M774delinsWLV) were highly sensitive. Other uncommon EGFR mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Comparison of efficacy and safety of second- and third-generation TKIs for non-small-cell lung cancer with uncommon EGFR mutations.

The efficacy of definite for non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations has been preliminarily demonstrated. However, there is a paucity of data with which to compare the efficacy and safety of second- and third-generation TKIs in patients with NSCLC carrying uncommon EGFR mutations. We compared the efficacy and safety of second- and third-generation TKIs in all NSCLC patients in whom next-generation sequencing confirmed uncommon EGFR mutations, including G719X, S768I, and L861Q. The parameters analyzed included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The rate of treatment-related adverse events (AEs) reflected the safety of these TKIs. Eighty-four NSCLC patients with uncommon EGFR mutations were enrolled between April 2016 and May 2022 at Zhejiang Cancer Hospital, including 63 treated with second-generation TKIs and 21 treated with third-generation TKIs. The ORR for all patients receiving TKIs was 47.6%, and the DCR was 86.9%. The median PFS for NSCLC patients with uncommon EGFR mutations receiving TKIs was 11.9 months and OS was 30.6 months. There was no significant difference in PFS after treatment with second- or third-generation TKIs (13.3 vs. 11.0 months, respectively, P = 0.910) or in OS (30.6 vs. 24.6 months, respectively P = 0.623). The third-generation TKIs showed no severe toxicity. The efficacy of second- and third-generation TKIs for NSCLC with uncommon EGFR mutations does not differ, and so can be used to treat NSCLC patients with these mutations.

Dacomitinib for patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations: Do mutation patterns matter?

9106 Background: Previous evidence has revealed the potential efficacy of dacomitinib in patients with advanced non-small cell lung cancer (NSCLC) carrying uncommon epidermal growth factor receptor ( EGFR) mutations, but it remains unknown whether there are differences in its efficacy for different combination patterns of these uncommon mutations. Methods: The AFANDA cohort, an ambispective cohort including 121 NSCLC patients with uncommon EGFR mutations admitted from two tertiary hospitals in China, was employed for exploration. Meanwhile, a cohort of 63 patients with common mutations was included for comparison. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed between groups. Results: A total of 133 patients with advanced or recurrent NSCLC that received dacomitinib were eligible for analysis. Baseline characteristics were balanced between subgroups. A significant difference was observed between patients with common mutations (C group, n = 63), common mutation plus uncommon mutations (C+U group, n = 24), and uncommon mutations (U group, n = 46) regarding to PFS (mPFS: 7.07, 8.17, and 11.97 months; p = 0.026). Moreover, the highest ORR and DCR of the U group were observed among subgroups, although the differences were not statistically significant (ORR, 40.4%, 40.9%, and 61.4%; p = 0.085; DCR, 78.9%, 72.7%, 90.9%; p = 0.134). Furthermore, the multivariate analysis revealed that the mutation pattern was an independent prognostic indicator of PFS ( p = 0.049), with the C+U group having the highest risk of progression (HR [hazard ratio]: 1.438, 95% CI [confidence interval]: 0.818-2.528) while the U group having the lowest one (HR: 0.666, 95% CI: 0.409-1.084). For toxicity analysis, no significant difference was observed regarding grade 3-4 AEs among subgroups (12.7%, 8.3%, 13.0%; p = 0.827). The drug resistance analysis did not reveal a significant difference concerning the secondary T790M mutation rate (26.3%, 0%, 13.3%; p = 0.331). Conclusions: Dacomitinib demonstrated different therapeutic efficacy for patients with NSCLC harboring different combination patterns of uncommon EGFR mutation, which should be considered in clinical trials' design and clinical application. [Table: see text]

Chemotherapy outcomes in EGFR-TKI resistant patients with common and uncommon EGFR mutation: An exploratory retrospective cohort study.

Some prospective studies have shown that second-generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second-line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. Patients with EGFR-mutated advanced-stage NSCLC who received first-line EGFR-TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second-line chemotherapy were enrolled. We compared progression-free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan-Meier and log-rank tests. In total, 209 (54.8%) patients had a negative T790M mutation test and received second-line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations.

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the invitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And invivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation.

Uncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment. We performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan-Meier method. Data from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months). Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.

Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear. This retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database. Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively). Our study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors.

Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) harbor uncommon epidermal growth factor receptor (EGFR) alterations. This study aims to investigate the therapeutic responses and predict the binding activity of different tyrosine kinase inhibitors (TKIs) for EGFR uncommon alterations. Methods: Between May 2014 and June 2021, clinical outcomes of NSCLC patients harboring EGFR uncommon alterations who received diverse treatment modalities: first-generation (1G) EGFR-TKI, second-generation (2G) EGFR-TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed, and structural analysis for the binding activity of major uncommon subtypes G719A, S768I, and L861Q to different TKIs were predicted. Results: A total of 102 NSCLC patients harboring EGFR uncommon alterations with treatment and survival outcomes were included and analyzed. The majority of patients presented compound mutations (54.9%), and G719X plus S768I was the predominant subtype (n = 33, 32.3%). There was a significant difference in median progression-free survival (mPFS) between therapeutic patterns (p = 0.015) and EGFR alteration subtypes (p = 0.017). Rather than almonertinib and furmonertinib, afatinib, dacomitinib and osimertinib revealed favorable binding activity to G719A mutation. In contrast, S768I and L861Q mutation indicated an unaffected binding activity to these diverse kinds of EGFR TKIs. Conclusion: Together with afatinib, 1G-TKIs combined with chemotherapy might be another effective option for NSCLC patients harboring EGFR uncommon alterations. Based on computational findings, afatinib, dacomitinib, and osimertinib might confer favorable activity to G719A, S768I, and L861Q, whereas almonertinib and furmonertinib revealed less activity to G719A.

1201TiP MINOVA: A phase II, open-label, single arm, multicenter, exploratory study with osimertinib plus chemotherapy as first-line treatment in locally advanced or metastatic non-small cell lung cancer (NSCLC) with uncommon EGFR mutations

The majority of uncommon epidermal growth factor receptor mutations (EGFRm) showed decreased sensitivity to EGFR- tyrosine kinase inhibitor (TKI) when compared to common EGFRm. Osimertinib as first-line therapy showed promising efficacy in non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I mutations. While the addition of chemotherapy to gefitinib markedly improved the progression-free survival and overall survival of sensitive EGFRm NSCLC, with an acceptable toxicity profile, osimertinib in combination with chemotherapy may extend the clinical benefits in uncommon EGFRm NSCLC.

Insensitivity to T790M mutation? A pooled analysis of outcomes following osimertinib for the treatment of NSCLC patients harboring uncommon epidermal growth factor receptor mutation.

Background: In this pooled analysis, the aim was to investigate the clinicopathological characteristics of patients with uncommon epidermal growth factor receptor (EGFR) (ucm-EGFRms) along with their treatment responses and survival following osimertinib treatment. Methods: Univariate chi-square analysis was conducted to analyze the correlation between clinical characteristics, EGFR mutation type, and treatment response, and the Kaplan-Meier method was applied for survival analysis. Univariate logistic regression model and Cox proportional hazards model were performed to compare the efficacy and prognosis in subgroup analysis. Results: Seventy-two NSCLC patients in total were included in this pooled analysis. The objective response rate (ORR) for osimertinib treatment was 57.0%, with a median PFS of 7.1 months. Twenty-eight patients received osimertinib as first-line therapy with an ORR of 67.9%, which was higher than that in patients who received osimertinib as second- or later-line therapy, and their response rate was 50%, nevertheless, no statistically significant differences were found (p = 0.139). However, patients who received first-line osimertinib showed a more significant PFS benefit than those who received second- or later-line therapy (mPFS: 16.8 months vs 6.0 months HR: 2.453, 95%CI: 1.285-4.682, p =0.004). Subgroup analysis showed that patients with a single, non-ex20ins, ucm-EGFRm displayed a superior efficacy advantage and favorable survival benefit following osimertinib treatment, with an ORR of 68.8% and an mPFS at 15.1 months. By contrast, patients with a multiple ucm-EGFRm that contain T790M exhibited the worst outcome of osimertinib treatment, with an ORR of 47.6% and an mPFS of only 3.6 months, respectively. Conclusion: Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following osimertinib treatment, which is closely related to the mutation pattern and cooccurring partner mutant genes. Administering osimertinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances.

A novel EGFR exon 21 indel mutation in lung adenocarcinoma and response to dacomitinib: A case report

Rationale:Uncommon epidermal growth factor receptor (EGFR) mutations are increasingly being identified in non-small cell lung cancer. Insertion and deletion mutations have been detected in exons 18, 19, and 20, but not in exon 21. In patients with uncommon mutations, the second-generation EGFR tyrosine kinase inhibitor afatinib has shown good efficacy, whereas that of dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, remains unknown. Here, we reported a patient with a novel EGFR21 exon insertion-deletion (indel) mutation and demonstrated the efficacy of dacomitinib.Patient concerns:A 59-year-old nonsmoking Chinese male was admitted to the hospital with lung cancer after a chest computed tomography for coughing and sputum. The patient’s condition progressed after multiple treatments including surgery, chemotherapy, and radiotherapy.Diagnosis:The patient had clinical manifestations of cough and sputum and was pathologically confirmed to have T2bN1M0 (stage IIB) lung adenocarcinoma according to the seventh edition of tumor-node-metastasis staging. The patient underwent a second operation after detection of recurrence, and postoperative pathology confirmed adenocarcinoma of the lung. The patient progressed again after surgery, and the tumor-node-metastasis stage was changed to T4N0M1a (stage IVA) before treatment with dacomitinib.Interventions:After detection of the EGFR exon 21 indel mutation, the patient began treatment with dacomitinib (45 mg once a day) on March 12, 2021.Outcomes:After 1 month of targeted therapy, the patient showed a partial response to dacomitinib. As of March 19, 2022, his condition remained stable and he continued to receive dacomitinib. Progression-free survival reached 12.4 months. The patient experienced mild adverse reactions of pruritus during the use of dacomitinib, but recovered after drug treatment.Lesson:We reported a novel EGFR exon 21 indel mutation in a lung adenocarcinoma patient. Dacomitinib showed efficacy in the treatment of a patient with this mutation, suggesting that its efficacy in patients with uncommon mutations should be explored further. The next-generation sequencing is recommended as a guiding tool for the treatment of advanced non-small cell lung cancer.

Clinical outcomes of gefitinib and erlotinib in patients with NSCLC harboring uncommon EGFR mutations: A pooled analysis of 438 patients

BackgroundThe purpose of this study was to investigate the outcomes of gefitinib and erlotinib in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. MethodsRelevant researches were identified by a literature search of the PubMed database. Patients with EGFR mutations other than exon 19 deletion and L858R were eligible for the study. Clinical outcomes included objective response rate (ORR), progression free survival (PFS), and overall survival (OS). We categorized all uncommon EGFR mutations as: single uncommon EGFR mutations and compound mutations that containing 2 or more kinds of EGFR mutations. We also assessed outcomes in patients categorized by EGFR-TKIs: (1) gefitinib group; (2) erlotinib group. ResultsA total of 438 patients with NSCLC harboring uncommon EGFR mutations were included in this study. The ORR for gefitinib and erlotinib was 43.8 %, with a median PFS (mPFS) of 6.00 months and a median OS (mOS) of 20.50 months. Patients with compound mutations had an ORR of 56.3 % and an mPFS of 8.10 months. Both of them were significantly better than these in patients with single uncommon EGFR mutation, which were 29.3 % and 3.90 months, respectively (odds ratio (ORa): 2.74, 95 % confidence interval (CI): 1.86–4.05, P < 0.001; hazard ratio (HR): 0.58, 95 % CI: 0.48–0.71, P < 0.001). Moreover, patients with compound mutations containing 19 deletion or L858R had a superior response and survival benefits compared to patients with other compound mutation patterns. In addition, the gefitinib group showed a favorable efficacy advantage (P = 0.003) and PFS benefit (P = 0.021) compared to the erlotinib group. ConclusionsUncommon EGFR mutations exhibit favorable but inconsistent treatment responses and survival outcomes to gefitinib and erlotinib, which are closely related to the mutation pattern, the cooccurring partner mutant genes, and the type of EGFR-TKIs received.

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study.

BackgroundAfatinib 30 mg has been proved to be with comparable efficacy but more tolerable than the dose of 40 mg for Asian patients with non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical outcomes of afatinib at 30 mg/d in the treatment of advanced lung adenocarcinomas (LAD) with common and uncommon epidermal growth factor receptor (EGFR) mutations.MethodsEGFR-mutated advanced LAD patients receiving afatinib (30 mg/d) from January 2017 to November 2021 were retrospectively included. EGFR status was classified into three subtypes, namely common mutations including exon 19 deletions (19del) and exon 21 L858R (21L858R), uncommon mutations including G719X, L861Q, S768I, and complex mutations, and separately exon 20 insertions (20ins). Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs) were analyzed during regular follow-up.ResultsThe overall median PFS of totally 58 included patients was 9.83 [95% confidence index (CI): 5.76–13.91] months. The number of patients with common, uncommon, and 20ins mutations was 32 (55.2%), 19 (32.8%) and 7 (12.1%), respectively. Baseline characteristics did not differ significantly among the three subtypes. The corresponding median PFS was 13.97 (12.06–15.89), 8.48 (0.32–16.64), and 3.78 (1.93–5.64) months, respectively (P=0.002). In the first-line setting, patients with common and uncommon mutations had a significantly longer PFS compared to those with 20ins [14.53 (13.53–15.53) vs. 10.39 (4.87–15.91) vs. 2.37 (0.00–5.11) months, P<0.001]. The first-line ORR showed significant differences among the three subtypes (60% vs. 80% vs. 0.0%, P=0.023). All-grade AEs occurred in 22 patients (37.9%). AEs ≥ grade 3 mainly included diarrhea (8.6%), and none of the patients discontinued treatment due to severe AEs.ConclusionsAfatinib at 30 mg/d is associated with a favorable efficacy and tolerability in the treatment of advanced LAD with common and major uncommon EGFR mutations except 20ins. Further large-scale prospective studies are warranted to confirm our findings.

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.

Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study)

BackgroundDacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18–21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients.MethodsThis is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-β = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators’ review. The second endpoint is disease control rate (DCR), PFS, OS, and safety.DiscussionWe conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients.Trial registrationNCT04504071

First-line Afatinib in Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in South Korea

Non-small cell lung cancers (NSCLCs) harboring uncommon epidermal growth factor receptor (EGFR) mutations are heterogeneous and show variable prevalence and clinical responses to EGFR tyrosine kinase inhibitors. We investigated the characteristics of uncommon EGFR mutations and the clinical efficacy of afatinib in patients with NSCLC harboring uncommon EGFR mutations. In this multicenter, retrospective study, we analyzed patients with NSCLC with uncommon EGFR mutations in 16 South Korean institutes. Mutations were categorized according to their incidence: 1) major uncommon mutations (G719X and L861Q), 2) compound mutations, and 3) minor uncommon mutations (exon 20 insertion, S768I, and de novo T790M). Of 703 patients with EGFR-mutant NSCLC, 64 (9.1%) had uncommon EGFR mutations. Afatinib demonstrated activity against tumors harboring major uncommon mutations [median time of treatment (TOT): 20.3 months, 95% confidence interval (CI)=15.1-25.5; overall survival (OS): 30.6 months, 95% CI=26.3-34.8] and compound mutations (median TOT: 12.3 months, 95% CI=7.7-17.0; OS: 29.1 months, 95% CI=20.4-37.7) but not against tumors harboring minor uncommon mutations (median TOT: 3.8 months, 95% CI=1.7-6.0; OS: 8.5 months, 95% CI=5.2-11.7). The S768I mutation was present in 14 patients (1.99%). The median TOT and OS were not significantly different between S768I mutations and resistant exon 20 mutations. Afatinib is effective in patients with NSCLC harboring major uncommon and compound EGFR mutations.