Third-generation Tyrosine Kinase Inhibitors Osimertinib Research Articles

Clinical Utility of Mobocertinib in the Treatment of NSCLC - Patient Selection and Reported Outcomes.

Mobocertinib is an oral tyrosine kinase inhibitor (TKI) that selectively targets epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations. It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. This is accomplished via a carboxylated isopropyl ester moiety at the C5-position of mobocertinib's central pyrimidine core. In Phase 1/2 dose-escalation and dose-expansion studies, mobocertinib was found to have an investigator-confirmed overall response rate (ORR) of 56% (9/16; 95% CI: 30-80%) and 25% (3/12; 95% CI: 5-57%) in patients without and with baseline brain metastasis, respectively. Median investigator-assessed progression-free survival (mPFS) was 10.2 months (95% CI: 5.6 - not reached) and 3.7 months (95% CI: 1.8-15.9) in patients without and with baseline brain metastasis, respectively. A third phase evaluated patients who had received pre-treatment with platinum-based chemotherapy (PPP) and included an extension cohort (EXCLAIM cohort) which evaluated patients treated previously with 1 or 2 lines of therapy. An Independent Review Committee (IRC) found both cohorts to have similar outcomes in terms of ORR, median time to response, mPFS, and disease progression or death. The treatment-emergent adverse events (TEAE) related to mobocertinib are similar to other EGFR inhibitors and are predominately gastrointestinal (eg diarrhea, nausea, vomiting) and cutaneous (eg rash). In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.

Biological Electric Fields Guide Directional Migration and Promote Epithelial–Mesenchymal Transition in Lung Cancer

Background: Endogenous direct-current electric fields (dcEFs), as one of the essential biophysical signals that naturally occur in the tumor microenvironment, were previously demonstrated to suppress the cytotoxicity of the third-generation tyrosine kinase inhibitor osimertinib in epidermal growth factor receptor (EGFR)-mutant lung cancer. Materials and Methods: In the current study, we further investigated the electrotactic response of EGFR-mutant lung cancer with different osimertinib sensitivity, including osimertinib-sensitive PC-9GR cells and osimertinib-resistant PC-9GROR cells. Results: Firstly, in murine subcutaneous xenografts, robust endogenous electric currents were detected at the surface of tumors derived from osimertinib-resistant cells with a highly sensitive vibrating probe. Next, the electrotactic responses of two cell lines under EFs of different intensities were studied. Both PC-9GR and PC-9GROR cells exhibited directionally cathodal migration in a voltage-dependent manner, and osimertinib-resistant PC-9GROR cells displayed higher migration speeds. Epithelial-mesenchymal transition (EMT), which was previously reported to be closely related to tumor invasion and metastasis and could be suppressed by osimertinib, was enhanced under EF stimulation as reflected by increased vimentin and decreased E-cadherin in PC-9GR cells via western blotting and immunofluorescent staining regardless of osimertinib treatment. Additionally, pharmacological inhibition of phosphoinositide 3-kinase/protein kinase B (AKT) signals reduced electrotaxis and EMT. Conclusion: Taken together, these results suggested that activation of AKT pathway may play an important role in electrotaxis and EMT of EGFR-mutant lung cancer.

Abstract 1032: Progesterone receptor antagonist can provide marked palliative benefits and extend life by years in advanced lung cancer when no other treatment options are available

Abstract Metastatic lung cancer has a poor prognosis. The aim of chemotherapeutic agents, targeted therapies, or immunotherapies at this stage is to extend life and diminish suffering. Frequently the extension of life is for a few months, but amelioration of suffering is not always accomplished including side effects of medication. Mifepristone, a progesterone (P) receptor modulator/antagonist has been given to patients orally (200-300 mg/day) with Food and Drug Administration (FDA) approval to patients with advanced metastatic lung cancer that had no more treatment options. Several of these cases have been presented at the AACR and showed significant extension of a good quality of life with well tolerated mifepristone therapy (Case 1 - rapidly progressing probable small cell lung cancer (SCLC) with marked hypoxia and marked hyponatremia, AACR 2016; Case 2 - Stage IV non-small cell lung cancer (NSCLC) with brain metastasis with no tumor markers for targeted therapy, AACR 2017; Case 3 - NSCLC positive for programmed cell death protein 1 (PD-1), AACR 2018). In case 1 her PO2 and serum sodium normalized within 3 weeks of single agent mifepristone and her lung nodules were no longer detectable. At time of presentation in 2016 she was 3 ½ years on single agent mifepristone treatment. She died 5 years from treatment at age 85 from a myocardial infarction with no return of her lung cancer and normal serum sodium. Case 2 also received single agent mifepristone and had no new lung or brain lesions (predominantly stable disease), but he stated he felt perfectly normal. After 2 ½ years his primary lung lesion started growing slowly. He died 5 years later not from extensive lung cancer but from pneumonia complicating his chronic obstructive lung disease (COPD). Case 3 had progressed despite standard chemotherapy and nivolumab. With mifepristone her lung and brain metastases showed some regression, but she was enjoying a good quality of life. Her clinical status deteriorated after 1 year not from her cancer but worsening COPD and she died 1 ½ years after initiating mifepristone therapy. Two female cases (age 56 and 46) that were never presented at AACR were treated with mifepristone when their advanced lung cancer with brain metastases progressed despite the third-generation tyrosine kinase inhibitor osimertinib (they were positive for the EGFR mutation). These women had a good quality of life and are still alive after 4 years of treatment. Evidence suggests that mifepristone inhibits cancer by blocking membrane P receptors inhibiting the immunosuppressive protein called the progesterone induced blocking factor. The “parent” 90 kDa form helps the tumor to proliferate and invade normal tissue whereas smaller splice variants inhibit cellular immunity. Mifepristone may actually be more effective for cancers negative for the classical nuclear P receptor. Citation Format: Jerome H. Check, Diane Check, Trina Poretta. Progesterone receptor antagonist can provide marked palliative benefits and extend life by years in advanced lung cancer when no other treatment options are available [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1032.

Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management.

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both 'on-target' mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and 'off-target' mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.

Treatment Response To Osimertinib In EGFR-Mutated Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Series.

Therapy for leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) is challenging, and conventional treatments have little impact on the disease course. We report three cases that were definitively diagnosed as LM from NSCLC with a mutation of epidermal growth factor receptor (EGFR) L858R. The systemic therapies of chemotherapy, local radiotherapy, and early generation tyrosine kinase inhibitors (TKIs) were implemented but ineffective. Three patients were treated with the third-generation TKI osimertinib at 80 mg daily, despite their different detection levels of T790M in the cerebrospinal fluid (CSF) and plasma, and achieved symptomatic remission, a decline of carcinoembryonic antigen (CEA) levels, and stable lesions. After the progression of LM, osimertinib at 160 mg daily further lengthened the quality of life and survival time of patients without any notable side effects during treatment. Recent related studies and our cases indicate that osimertinib has a positive effect on LM from EGFR-mutant NSCLC, regardless of T790M status.

Afatinib helped overcome subsequent resistance to osimertinib in a patient with NSCLC having leptomeningeal metastasis baring acquired EGFR L718Q mutation: a case report

BackgroundThe epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib.Case presentationA 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis.ConclusionThe acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic.

A Novel Acquired Exon 20 EGFR M766Q Mutation in Lung Adenocarcinoma Mediates Osimertinib Resistance but is Sensitive to Neratinib and Poziotinib

IntroductionOsimertinib is an effective third-generation tyrosine kinase inhibitor (TKI) for EGFR-mutant lung cancers. However, treatment for patients with acquired resistance to osimertinib remains challenging. We characterized a novel EGFR mutation in exon 20 that was acquired while on osimertinib. MethodsA 79-year-old woman had disease progression during third-line treatment with osimertinib for an EGFR L858R/T790M–mutant lung cancer. Sequencing of circulating cell-free DNA showed EGFR L858R, an acquired novel EGFR M766Q mutation in exon 20, and no evidence of EGFR T790M. Homology modeling was performed to investigate the effects of M766Q on binding to osimertinib. L858R and L858R/M766Q mutations were retrovirally introduced into Ba/F3 and NIH/3T3 cells and evaluated for sensitivity to first-generation (erlotinib), second-generation (afatinib, neratinib, and poziotinib), and third-generation TKIs (osimertinib) by cell viability and colony-formation assays. EGFR-mediated signaling pathways were interrogated by western blotting. ResultsModeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (concentration that inhibits 50%, 4.3 and 1.3 nM, respectively). This was corroborated by the effects of the TKIs on colony formation and EGFR signaling. ConclusionsAcquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. EGFR-mutant lung cancers with an acquired EGFR M766Q mutation in the setting of osimertinib resistance may be sensitive to neratinib and poziotinib.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in mutated non-small cell lung cancer: new avenues and strategies to overcome resistance

The most common driver mutation in non-small cell lung cancer (NSCLC) is found within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). It commonly affects younger, female, and non-smoking patients. To date, there are five approved tyrosine kinase inhibitors (TKIs) for the treatment of EGFR-mutated NSCLC: erlotinib, gefitinib, the second-generation TKI afatinib and dacomitinib, and the third-generation TKI osimertinib. Sequencing TKI treatment or starting with osimertinib first are reasonable treatment strategies. Nevertheless, patients develop resistance to these TKIs, which can be primary or acquired. Primary resistance includes resistance mutations such as EGFR insertion 20, acquired resistance comprises the development of resistance mutations, activation of bypass signaling, or histological transformation into small cell lung cancer. This article summarizes the current landscape of treatment in EGFR-mutated lung cancer and discusses the different resistance mechanisms. It gives a perspective on novel EGFR TKIs and potential combination strategies to overcome resistance.

Epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer: what is the preferred first-line therapy?

Epidermal growth factor receptor (EGFR) mt+ nonsmall cell lung cancer (NSCLC) were the first molecularly described NSCLC with an established 'targeted' therapy inhibiting mutated EGFR [EGFR tyrosine kinase inhibitor (TKI)]. EGFR TKI of first and second generation have led to an unprecedented improvement in objective response rate, progression-free survival (PFS) and overall survival (OS) compared with chemotherapy with a significantly reduced toxicity and improved quality of life. Fast elucidation of the most frequent resistance mechanism against first and second-generation TKI, T790M, led to the approval of the third-generation TKI osimertinib in second line. Recently, the FLAURA study showed an impressive PFS benefit and immature OS data for osimertinib against solely first-generation TKI's. Also, the ARCHER study comparing dacomitinib against first-generation TKI showed a PFS and also OS benefit. Two studies combining EGFR TKI and antiangiogenesis showed PFS but no OS benefit. Lately, the combination of TKI and chemotherapy has seen a revival with the NEJ009 study, resulting in an impressive median OS of 55 months. Therefore, potentially four different therapeutic options are available in first-line therapy of EGFR mt+ NSCLC, first, second, third generation, TKI + antiangiogenic agent and TKI + chemotherapy. The purpose of the review is to help to guide physicians to decide in their treatment choice and discuss potential directions of research.

MA27.10 EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies

Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immune approach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy. We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry. Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment. Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.

Reactivation of Mutant-EGFR Degradation through Clathrin Inhibition Overcomes Resistance to EGFR Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKI) targeting mutant EGFR in non-small cell lung cancer (NSCLC) have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR, for example, T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here, we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, and Ex20Ins). This panel included mutant-EGFR (T790M) resistant to the first- and second-generation EGFR inhibitors and to the third-generation TKI osimertinib and occurs through both mutational (C797S) and nonmutational EGFR mechanisms. Clathrin-mediated endocytosis inhibition of mutant EGFR induced a macropinocytosis-dependent lysosomal pathway associated with a loss of mutant-EGFR-dependent signaling (pAKT, pERK). Moreover, induction of this macropinocytic pathway led to robust apoptosis-dependent death across all mutant-EGFR cell lines tested, including those resistant to TKIs. We, therefore, propose a novel strategy to target mutant-EGFR refractory to approved existing TKI treatments in NSCLC and where new treatment strategies remain a key area of unmet need.Significance: These findings extend our mechanistic understanding of NSCLC mutant EGFR trafficking biology, the role that trafficking may play in resistance of mutant EGFR to tyrosine kinase inhibitors, and provide new therapeutic and biological insights to tackle this fundamental issue and improve benefit to patients. Cancer Res; 78(12); 3267-79. ©2018 AACR.

Molecular Testing for Stage IV Non-Small Cell Lung Cancer Patients With Targetable Mutations Following Disease Progression.

Molecular Testing for Stage IV Non-Small Cell Lung Cancer Patients With Targetable Mutations Following Disease Progression.