scholarly journals Discovery, Development, Inventions, and Patent Trends on Mobocertinib Succinate: The First-in-Class Oral Treatment for NSCLC with EGFR Exon 20 Insertions

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1938
Author(s):  
Mohd Imran ◽  
Shah Alam Khan ◽  
Mohammed Kanan Alshammari ◽  
Meshal Ayedh Alreshidi ◽  
Abeer Abdullah Alreshidi ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Oral Treatment ◽  
Growth Factor Receptor ◽  
Lung Cancers ◽  
Patent Review ◽  
Patent Literature ◽  
Patent Applications ◽  
Exon 20 ◽  
Nsclc Patients ◽  
Process Composition

The majority of lung cancers are non-small-cell lung cancer (NSCLC) having a low survival rate. Recent studies have indicated the involvement of epidermal growth factor receptor (EGFR) oncogene mutations like EGFR exon 20 insertions (EGFRex20ins) mutation among NSCLC patients. The response of patients of NSCLC with the EGFRex20ins mutation to the currently available EGFR inhibitor is negligible. Mobocertinib is the first oral treatment that has been approved by the USFDA, on 15 September 2021, to treat NSCLC with the EGFRex20ins mutation. This patent review discusses the inventions and patent literature of mobocertinib that will help the scientific community to develop additional and improved inventions related to mobocertinib. The structure of mobocertinib was first reported in 2015. Therefore, this article covered the patents/patent applications related to mobocertinib from 2015 to 25 October 2021. The patent search revealed 27 patents/patent applications related to compound, method of treatment, salt, polymorph, process, composition, and drug combinations of mobocertinib. The authors foresee an exciting prospect for developing a treatment for NSCLC with EGFRex20ins mutation, and other cancers employing a combination of mobocertinib with other approved anticancer agents. The inventions related to novel dosage forms, processes, and intermediates used in the synthesis of mobocertinib are also anticipated.

The predictive value of uncommon EGFR mutation in patients with non-small-cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9028-9028
Author(s):  
Haiyan Tu ◽  
Ee Ke ◽  
Yue-Li Sun ◽  
Ming-Ying Zheng ◽  
Jin-Ji Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Exon 20 ◽  
Egfr Tki

9028 Background: Non-small-cell lung cancers with uncommon epidermal growth factor receptor ( EGFR) mutations are regarded as a heterogeneous group with variable responses to EGFR-targeted drugs. Here we designed this retrospective study to describe the epidemiology and clinical outcomes of uncommon EGFR mutations in a Chinese cohort of lung cancer patients. Methods: Between June 2007 and June 2014, 5363 lung cancer patients whose EGFR genotyping was performed successfully at Guangdong Lung Cancer Institute (GLCI, Guangzhou, China) were screened. 1837 patients were included in the epidemiological analysis. The clinical outcome was analyzed in 97 advanced-stage patients harboring uncommon EGFR mutations with follow-up data. Results: 218 patients harbored uncommon EGFR mutations, making up 11.9% of all cancers with documented EGFR mutations. Compared with common mutants, those with uncommon mutations were more commonly found in smokers and male patients. The most frequently detected uncommon mutations were exon 20 insertions, G719X mutations and L858R complex mutations, occurring in 30.7%, 21.1% and 17.0% of all EGFR-uncommon-mutation cases. G719X and L858R complex mutations were associated with similar benefit from EGFR-TKI; median PFS was 15.2 (95% CI 8.7-21.7) and 11.6 (95% CI 3.6-19.6) months, respectively. T790M or 20INS was associated with a poorer EGFR-TKI response; median PFS was 1.0 (95% CI 0.0-2.2) and 3.0 (95% CI 1.3-4.7) months, respectively. Of note, two patients with 23% and 65% tumor shrinkages had N771_P772insN and H773_V774insQ, with PFS of 5.7 and 6.1 months respectively. Conclusions: Favorable responses were observed in specific subtypes including complex L858R and G719X, and our results suggested first-line EGFR-TKI should be preferable in such patients.

scholarly journals Pyrotinib combined with thalidomide in advanced non-small-cell lung cancer patients harboring HER2 exon 20 insertions (PRIDE): protocol of an open-label, single-arm phase II trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xinghao Ai ◽  
Zhengbo Song ◽  
Hong Jian ◽  
Zhen Zhou ◽  
Zhiwei Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Advanced Nsclc ◽  
Phase Ii Trial ◽  
Growth Factor Receptor ◽  
Small Cell Lung ◽  
Open Label ◽  
Once Daily ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Nsclc Patients

Abstract Background Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. Methods This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. Discussion The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. Trial registration ClinicalTrials.gov Identifier: NCT04382300. Registered on May 11, 2020.

Frequency of EGFR mutations in Greek non-small-cell lung cancer (NSCLC) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21141-e21141
Author(s):  
Samuel Murray ◽  
Eirini Papadopoulou ◽  
George Nasioulas
Keyword(s):  
Mutation Frequency ◽  
Growth Factor Receptor ◽  
Smoking History ◽  
Egfr Mutations ◽  
Analytical Sensitivity ◽  
Cell Content ◽  
Diagnostic Practice ◽  
Asian Populations ◽  
Exon 20 ◽  
Nsclc Patients

e21141 Background: NSCLC patients harboring activating somatic mutations within the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) significantly benefit from EGFR targeted therapy. Treatment with the recently approved EGFR inhibitor IRESSA (gefitinib) leads to improved response and survival outcomes, therefore screening for EGFR mutations has entered routine clinical practice. Several clinico-pathological factors correlate with these mutations including gender, smoking history, and histology. The frequency of EGFR mutations is also ethnicity-dependent, wherein the incidence in Asian populations is ~30%, while in Caucasians (Whites) it is lower, ~ 15%. However, limited data is available on intra-ethnic differences throughout Europe. Aim: The aim of this study was to determine the frequency and spectrum of EGFR mutations in an unselected group of Greek NSCLC patients and investigate technical aspects of analysis. Methods: We set up High Resolution Melting Analysis (HRMA) assays to identify mutations in exons 18-21 of the EGFR gene and validated their analytical sensitivity by making serial dilutions of samples with known mutations and tumor cell content (TCC). A total of 698 NSCLC patients were screened with HRMA for somatic EGFR mutations in exons 18-21 and mutation status was verified by bi-directional sequencing. Pathological review was obtained for all samples and macro-dissection was used to ensure a %TCC of >75% in all possible cases. Results: The sensitivity of our HRM assays was found to be ≤1.5% Using HRMA and bi-directional sequencing a frequency of 19.05% was obtained; 105 x exon 19, 21 x exon 21, 6 x exon 20 and 1 x exon 18 . Conclusions: Applying a very sensitive mutation detection technique in a large cohort of unselected Greek NSCLC patients in routine diagnostic practice, we obtained an overall mutation frequency of 19.05%. This mutation frequency is similar to that found by the SLADB and EURTAC studies in European populations. Differences in sensitivity between techniques suggest that more than one technique should be advised in routine diagnostic practice.

scholarly journals Durable Response to Immunotherapy Plus Chemotherapy in a Patient With Untreated, Brain-metastatic, EGFR Exon 20 Insertion Mutation Lung Adenocarcinoma

2021 ◽  
Author(s):  
jingying nong ◽  
Yanfei Gu ◽  
Shuyang Yao ◽  
Yi Zhang
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Growth Factor Receptor ◽  
Insertion Mutation ◽  
Durable Response ◽  
Lung Cancers ◽  
Advanced Stage Lung Cancer ◽  
Exon 20

Abstract Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors showing encouraging antitumor activity, clinically obtainable management for this subset of patients remains an unmet need. Although immune checkpoint inhibitors (ICIs) have led to unprecedented clinical benefit in metastatic NSCLC, clinical evidence suggests that EGFR mutant lung cancers rarely derive benefit from treatment with ICIs. We report that a lung adenocarcinoma patient harboring an actionable gene mutation of EGFR exon 20 insertion, high PD-L1 expression, high tumor mutational burden, as well as alterations in immune-related genes including CTNNB1 (Catenin β1) S37F and ARID2 (AT-rich interactive domain-containing protein 2) E1056X responded to upfront PD-1 inhibitor plus chemotherapy. As an advanced-stage lung cancer with brain metastases indicating poor prognosis, the patient achieved an unusual and durable response over 15 months. Upfront ICIs plus chemotherapy might be an option for some NSCLC patients harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.

SHP2 Inhibition Benefits Epidermal Growth Factor Receptor mutated Non-Small Cell Lung Cancer Therapy

2020 ◽  
Vol 20 ◽  
Author(s):  
Leiming Xia ◽  
Lu Wen ◽  
Siying Wang
Keyword(s):  
Stem Cells ◽  
Synergistic Effects ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Combination Strategies ◽  
Lung Cancer Therapy ◽  
Src Homology ◽  
Nsclc Patients ◽  
Egfr Mutated ◽  
Egfr Tkis

: EGFR-TKIs are facing a big challenge of everlasting activated EGFR mutations which lack of effective binding sites, this barrier confers the dark sides that largely limited the outcome of NSCLC patients in clinic. Combination strategies show impressive anti-tumor efficacy comparing with EGFR-TKI mono-treatment, especially targeting both stem cells and non-stem cells. SHP2 (Src homology 2-containing phosphotyrosine phosphatase 2) plays an important role in regulating various malignant biology through hyper-activating intracellular pathways due to either over expression or catalytical mutation. Some pathways that SHP2 involved in were overlaps with EGFR downstream, and others were not subject to EGFR. Interestingly, SHP2 suppression was reported that can destroy the stemness of cancer. Therefore, we hypothesize SHP2 inhibitor might be an promising drug that could synergistically enhance or sensitize the anti-tumor efficacy of EGFR-TKIs in EGFR mutated NSCLC patients. Here, we summarized the mechanisms of SHP2 in regulating EGFR mutated NSCLC patients, attempted to reveal the potential synergistic effects of SHP2 inhibitor combined with EGFR-TKIs.

The intravenous to oral switch of taxanes: strategies and current clinical developments

2020 ◽  
Author(s):  
Marit AC Vermunt ◽  
Andries M Bergman ◽  
Eric van der Putten ◽  
Jos H Beijnen
Keyword(s):  
Clinical Trials ◽  
Anticancer Agents ◽  
Hospital Care ◽  
Oral Treatment ◽  
Chemotherapy Treatment ◽  
Intravenous Treatment ◽  
Improve Cost Effectiveness ◽  
Oral Switch ◽  
Tumor Types ◽  
Improve Cost

The taxanes paclitaxel, docetaxel and cabazitaxel are important anticancer agents that are widely used as intravenous treatment for several solid tumor types. Switching from intravenous to oral treatment can be more convenient for patients, improve cost–effectiveness and reduce the demands of chemotherapy treatment on hospital care. However, oral treatment with taxanes is challenging because of pharmaceutical and pharmacological factors that lead to low oral bioavailability. This review summarizes the current clinical developments in oral taxane treatment. Intravenous parent drugs, strategies in the oral switch, individual agents in clinical trials, challenges and further perspectives on treatment with oral taxanes are subsequently discussed.

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