Other EGFR-dependent mechanisms of resistance to osimertinib include the development of EGFR tertiary mutations or amplifications, 26, 27 which are more likely to arise in cases in which the EGFR.. Jyoti D. Patel, MD, discusses the evolving use of osimertinib in EGFR-mutant NSCLC and emerging targeted agents for patients with EGFR exon 20 insertion mutations
Of that sample, 53 were treated with osimertinib and 45 treated with olmutinib. To the best of our knowledge, this is the first comprehensive data with an integrated genomic landscape to analyze the resistance mechanism of progression after osimertinib and olmutinib therapy, wrote the researchers Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion. Cancer Discov 2018;8:1529-39 Despite its efficacy, patients acquire resistance to osimertinib through various mechanisms including EGFR C797S mutations which eliminate the covalent bonding site for osimertinib, and amplification of MET or ERBB2 (HER2), among others [ 11, 12, 13 ] Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR -mutant lung cancers
Here, we provide the molecular landscape of osimertinib resistance investigated by clinical sample sequencing and patient-derived cancer models. Methods. The paired tumor tissue (n = 10) and plasma samples (n = 8) were collected from 12 EGFR-mutant NSCLC patients before and after osimertinib treatment in the ASTRIS trial (NCT02474355) Introduction:Small cell lung cancer (SCLC) transformation represents a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma, which dramatically impacts patients' prognosis due to high refractoriness to conventional treatments The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib has been demonstrated to have significant activity in patients with EGFR mutation-positive acquired resistance, overwhelmingly..
Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated efficacy against both classical epidermal growth factor receptor (EGFR) -sensitizing mutations and EGFR resistance T790M mutations. Yet, despite its increasing role in NSCLC, data regarding resistance mechanisms to this agent are limited Article Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer Nitin Roper,1,11,* Anna-Leigh Brown,2,12 Jun S. Wei,1 Svetlana Pack,4 Christopher Trindade,4 Chul Kim,1,13 Olivia Restifo,1,3 Shaojian Gao,1 Sivasish Sindiri,3 Farid Mehrabadi,5 Rajaa El Meskini,6 Zoe Weaver Ohler,6 TapanK.Maity, 1AbhilashVenugopalan, Constance M.Cultraro.
27. Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. (2018) 8:1529-39. doi: 10.1158/2159-8290.CD-18-102 Identifying, Treating Resistance to TKIs Are Next Step in EGFR+ NSCLC. Christina Baik, MD, MPH, highlights the evolving role of EGFR inhibition in the NSCLC space. Identifying how to best treat. Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8 (12):1529-1539. 9. Bivona TG, Doebele RC
Osimertinib works against tumors with the same EGFR activating mutations (known as exon 19 deletions and exon 21 L858R) targeted by the other EGFR-targeted drugs. However, it was also designed to specifically target tumor cells with an EGFR mutation known as T790M, which has been shown to cause resistance to the earlier-generation EGFR-targeted. Immunotherapy in non-small cell lung cancer harbouring driver mutations. The advent of molecular targeted therapies and the more recent introduction of immune checkpoint inhibitors (ICIs) have altered and improved the therapeutic landscape of non-small cell lung cancer (NSCLC). ICIs confer a durable response in a subset of patients; however.
Figure 2. Landscape of acquired resistance to osimertinib and savol itinib and clonal evolution during targeted therapy. ( A)A heatmap depictsthedistribution ofnonsilentsomaticmutatio ns among pre- andpost-treatment tissues These results suggested the potential of osimertinib and savolitinib as a new therapeutic option for patients with EGFR-mutant NSCLC with acquired MET amplification. The SAVANNAH study (NCT03778229) is further ongoing to evaluate the combination of osimertinib and savolitinib in patients with MET-driven resistance to osimertinib.Nevertheless, osimertinib and savolitinib treatment also faces. . Lancet Oncol 2011 Chemotherapy Chemotherapy ±anti-angiogenics To Date, First-line Osimertinib Resistance Mechanisms Are Similar to Second-line Osimertinib Resistance Mechanisms • EGFRC797S • HER2exm 20 • KRAS mutati KRAS • MEKI G 128
. Currently, only five cases have reported on the success of osimertinib rechallenge in EGFR T790M-positive NSCLC patients following osimertinib resistance (13,14) ation. However, patients eventually succumbed to resistance to first- and second-generation EGFR-TK inhibitors through activation of T790M mutation. Third-generation EGFR-TKI, Osimertinib exhibits high efficacy in patients with exon 19 deletion/L858R/T790M mutation but they experienced acquired resistance thereafter. Available treatment options in NSCLC patients remains a challenge due to. tifiable mechanism of resistance. The limited reports of resis-tance to osimertinib given as first-line therapy, reveal MET amplification and EGFR C797S mutation as possible predomi-nant mechanisms . Similarly, there may be significant het-erogeneity in resistance mechanisms to rociletinib [21,22] and nazartinib  A combination of osimertinib and trastuzumab-emtansine, a conjugate of the monoclonal antibody trastuzumab (Herceptin) and the cytotoxic agent DM1, was reported to overcome osimertinib resistance in T790M-positive EGFR-mutated NSCLC cell lines that gained HER2 amplification. 101 Similarly, combining osimertinib with drugs targeting other.
A phase III trial of osimertinib among patients with NSCLC who had tumors harboring EGFR T790 M (AURA 3) clearly demonstrated that liquid biopsy can predict efficacy of osimertinib by revealing T790 M in plasma. 9 However, level of efficacy varied from complete response to primary resistance even among patients in whom T790 M was detected Resistance mechanisms to osimertinib in Egfr-mutated non-small cell lung cancer. The evolving landscape of ALK inhibitors in non-small cell lung cancer: opportunities for pharmacists to optimize treatment selection. Specialty Pharmacy Times, August 2019. Google Scholar. 41 Evolution in Advanced NSCLC Therapeutic Landscape • Evolution in Biomarker Testing Guidelines • Evolution in understanding Mechanisms of Resistance to Therapy • Evolution in Assessing Changes in Tumor Biology: Biopsy-RebiopsyStrategies & Role of Plasma cfDNA. Generation EGFR TKI Osimertinib Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. 2018. PubMe
In the osimertinib arm, there was no evidence of acquired EGFR T790M, but the EGFR C797S mutation was detected in the plasma of 6 patients (6/91; 7%). 37 In their analysis of resistance mechanisms to osimertinib in a French multicentric retrospective study, Mehlman et al described the existence of a C797S mutation in 2 out of the 3 patients. Whereas resistance to first- and second-generation EGFR TKIs is frequently driven by the emergence of an acquired EGFR T790M mutation (in approximately 50% to 60% of cases), osimertinib resistance is EGFR-dependent in a smaller fraction of cases ranging from 6% to 38%.1, 2 On-target resistance mainly occurs via acquisition of additional. The impact of osimertinib' line on clonal evolution in EGFRm NSCLC through NGS-based liquid biopsy and overcoming strategies for resistance. Background: Resistance mechanisms following 1st line therapy with osimertinib in EGFR + NSCLC have become focus of investigation. This retrospective study aims to deepen the understanding and clarify possible mechanisms of osimertinib 1st line resistance. Mechanisms of drug resistance remain incompletely understood on both a genomic and proteomic level. The objective of Dr. Lovly's project is to find new targeted treatments and drug combinations that can tackle cancer evolution and osimertinib resistance In 2015, the FDA approved an unprecedented number of new therapies for non-small cell lung cancer (NSCLC), among them therapies addressing specific genomic tumor subsets in the setting of development of resistance to first-line targeted therapy. Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by.
This is a phase 2 single-arm, non-randomized multicentre and tissue acquisition study to evaluate acquired resistance mechanisms, efficacy, and safety in advanced, EGFR tyrosine kinase inhibitor-naïve NSCLC patients with EGFR-activating mutations who receive a first-line osimertinib orally at a dose of 80mg once daily The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, Marcoux N, Banwait MK, Digumarthy SR, Su W, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with Osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8(12):1529-39
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer . 2016. PlumX Metrics - Top Social Media Articles. Below is a recent list of 2020-2021 articles that have had the most social media attention. The Plum Print next to each article shows the relative activity in each of these categories of metrics: Captures, Mentions, Social Media and Citations. Go to Plum Analytics to learn more about PlumX Metrics Acquired resistance inevitably develops, with the EGFR T790M mutation comprising approximately 55% of the mechanisms of resistance following first- or second-generation EGFR-TKI therapy (e.g. gefitinib, erlotinib, afatinib, and dacomitinib). Patients without T790M are a heterogeneous group for whom platinum-based chemotherapy is currently. *January 2021* Osimertinib (Tagrisso) has a strong foothold as first-line therapy for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), but resistance to the third-generation EGFR tyrosine kinase inhibitor is a major stumbling block. Understanding osimertinib resistance mechanism Proposed model for IACS-13909 in overcoming both EGFR-dependent and EGFR-independent osimertinib resistance mechanisms. A, In tumors harboring an EGFR mutation that confers resistance to osimertinib (e.g., C797S), EGFR remains as the primary oncogenic driver and signals through SHP2. SHP2 inhibition by an allosteric SHP2 inhibitor such as IACS.
Treatment of non-small cell lung cancer (NSCLC) is evolving with the use of precision medicine for patients with sensitizing epidermal growth factor receptor (EGFR) mutation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) remained the standard of care for patients with EGFR-mutated advanced NSCLC for about a decade. However, treatment resistance eventually develops for. Target gene modification. The T790M mutation, which substitutes methionine for threonine at amino acid position 790 at exon 20 of EGFR, was the most commonly acquired resistance mechanism.It accounted for about 50-60% of cases with acquired resistance to gefitinib or erlotinib [9, 10].The 790 residue is in a key location at the entrance to a hydrophobic pocket of the ATP-binding cleft, so it. 20. Schoenfeld AJ, Chan JM, Rizvi H, Rekhtman N, Daneshbod Y, et al. Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers. J Clin Oncol 2019;37:9028. 21
Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR and T790M resistance mutations. A preliminary study in 60 treatment naive patients with EGFR mutations found that the median progression-free survival with osimertinib was 20.5 months, which was almost two-fold higher than. . Reada,b,1, Troy Dayc, and Silvie Huijbena aCenter for Infectious Disease Dynamics, Departments of Biology and Entomology, Pennsylvania State University, University Park, PA 16802; bFogarty International Center, National Institutes of Health, Bethesda, MD 20892; and cDepartments of Mathematics.
The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer. 1 Department of Medical Oncology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands. 2 Department of Pathology, Antwerp University Hospital, Antwerp 2650, Belgium. 3 Center for Oncological Research, University of Antwerp, Antwerp 2610, Belgium
Tolerance and resistance are two different plant defense strategies against herbivores. Empirical evidence in natural populations reveals that individual plants allocate resources simultaneously to both strategies, thus plants exhibit a mixed pattern of defense. In this review we examine the conditions that promote the evolutionary stability of mixed defense strategies in the light of. Geneva, Switzerland - Osimertinib improves cancer-related symptoms in patients with advanced lung cancer, according to an analysis of patient-reported outcomes from the AURA3 phase III clinical trial to be presented at the European Lung Cancer Conference (ELCC). 1 With my past experience conducting clinical trials, I often see new treatments that might be more effective, but are also. Piotrowska, Zofia; Isozaki, Hideko; Lennerz, Jochen K et al. (2018) Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion. Cancer Discov 8:1529-153 osimertinib group and the placebo group), as compared with the percentage in historical studies (approximately 30%).2 In the ADAURA trial, the natural history of NSCLC appeared to be significantly altered by osimertinib that was administered as adjuvant therapy, with reductions in both locoregional recurrence (7% in the osimertinib group vs
Osimertinib is administered orally at 80mg once daily. Doses should be taken approximately 24 hours apart at the same time point each day. The appropriate number of osimertinib tablets will be provided to patients to be self-administered at home. AstraZeneca will supply osimertinib as tablets for oral administration Acquired drug resistance, however, is a major challenge with all of these TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined
In addition, HSP90 inhibition alone reportedly overcame the MET amplification- or HGF-induced resistance to EGFR-TKIs in vitro. 45, 46 Luminespib combined with osimertinib exhibited a marked efficacy for intrinsic resistance to osimertinib by decreasing the phosphorylation of EGFR and MET and downregulating their downstream pathways. 47 Our. Afatinib and osimertinib combination therapy could not eradicate Ba/F3 cells with Del19 and the C797S mutations following the development of osimertinib resistance. (A) An overview of the experimental methods used for establishing resistant clones. (B) The numbers of resistant clones per 50 wells were counted Recently, second-generation nonreversible covalent bond inhibitors, such as osimertinib, dacomitinib, and afatinib, have been developed to overcome drug resistance conferred by the gatekeeper (T790M) mutation (46 ⇓ -48). We tested the responsiveness of activating αC-β4 loop insertion mutations to these nonreversible EGFR inhibitors. On the other hand, Oxnard et al. studying acquired resistance in osimertinib-treated NSCLCs with secondary T790M mutation, observed that in contrast to the patients maintaining T790M at the time of resistance (32%) and progressing after approximately 15 months of treatment mainly by acquisition of tertiary C797S mutation, the patients who had. Osimertinib is the preferred first-line therapy for EGFR-mutant NSCLC [[88, 89]]; however, resistance unavoidably develops in patients. Resistance is mediated by acquired secondary mutations in EGFR. In addition to C797S, others also occur, such as L718Q 
The patient was started on osimertinib and he was stable for 14 months until systemic and brain PD was exhibited in the PET scan and brain MRI. We found an EGFR c797s-resistance mutation in his blood. The patient was started on palliative nivolumab and ipilimumab; however, therapy eventually failed and he died from complications of pneumonia In conclusion, we report an uncommon mechanism of resistance to osimertinib, identified with a validated NGS approach, different from the classic point mutation p.C797S, which involved, in addition to the uncommon point mutation p.L792Q, the switch from the original sensitizing EGFR deletion (from p.E746_A750del to p.L747_A750>P) and the loss. We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance Osimertinib is an epidermal growth factor receptor-tyrosine kinase inhibitor that specifically targets the T790M mutation in cancer.Unfortunately, most non-small cell lung cancer (NSCLC) patients develop osimertinib resistance. Currently, the molecular biomarkers for monitoring osimertinib resistance are not available
High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer. 2016;98:59-61 130. Passiglia F, Bronte G, Castiglia M. et al. Prognostic and predictive biomarkers for targeted therapy in NSCLC: for whom the bell tolls EGFR tyrosine kinase inhibitor (TKI) therapy, the most common resistance mechanism involves the selection of a resistant clone carrying the exon 20 p.T790M point mutation. However, also for these patients, treated with a third-generation TKI (osimertinib) several mechanisms of acquired resistance are described Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU- 667 for acquired RET fusion. Cancer Discovery. 2018 Dec;8(12):1529. Nangia V, Siddiqui FM, Caenepeel S, , Benes CH, Hughes PE, Hata AN
The presence of activating EGFR mutations, mainly ex19del, strongly predicts response to EGFR-TKIs; however, in 50-60% of these patients, resistance is acquired through the development of T790M, a second missense mutation of EGFR, which is indeed targeted by osimertinib .Some patients retain EGFR oncogene addiction even after progression to osimertinib, as they may develop the C797S. Accordingly, as reported in this recent publication in the JCO, two cohorts of treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC were also enrolled in the AURA study: 30 patients received 80 mg of osimertinib once daily (the currently indicated dose for acquired resistance mediated by T790M) or 160 mg of osimertinib once. Two combination trials of osimertinib plus durvalumab were terminated before full accrual because of an increased rate of interstitial lung disease seen in 13 of 38 patients (38%) who received the combination compared with an incidence of 2% to 3% seen in those who received osimertinib monotherapy. 19, 20 Along with an increased risk of. The rapidly evolving tumor somatic mu-tational landscape must be grappled with. Some drug resistance events in more genom-ically simple (often non-carcinogen-induced) tumors are predictable and themselves ac-tionable. For example, the third-generation EGFR TKI osimertinib has proven remark - ably effective in the management of NSCLC
The rapidly evolving tumor somatic mutational landscape must be grappled with. Some drug resistance events in more genomically simple (often non-carcinogen-induced) tumors are predictable and themselves actionable. the third-generation EGFR TKI osimertinib has proven remarkably effective in the management of NSCLCs that harbor T790M EGFR. Osimertinib in Advanced Lung Cancer with EGFR Mutations - National Cancer Institute. Osimertinib Improves Survival in Advanced Lung Cancer with EGFR Mutations. December 12, 2019, by NCI Staff. Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined
Treatment with osimertinib was associated with improved overall survival (17.0 vs 5.5 months) regardless of T790M mutational status. The majority of patients (61%) received 80-mg dosing and the remainder received 160-mg. Osimertinib is an effective treatment in patients with EGFR-mutated leptomeningeal disease, regardless of T790M mutational. Treatment with osimertinib (Tagrisso) in the frontline has been the standard of care for patients with EGFR-mutant non—small cell lung cancer (NSCLC) since the pivotal FLAURA trial. However, more work is needed to introduce first- and second-generation tyrosine kinase inhibitors (TKIs) both alone and in combination to improve the treatment. Osimertinib was also better tolerated, as the proportion of patients with AEs of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). These results led to the approval of osimertinib for the treatment of patients with T790M-positive, EGFR-mutant advanced NSCLC after failure of initial EGFR-TKI. First-line treatment with osimertinib in patients with EGFR-mutated is associated with longer overall survival compared with other drugs in its class. FLAURA Trial: Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC - Journal of Oncology Navigation & Survivorshi Targeted therapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC) across a broad range of molecular aberrations. The epidermal growth factor receptor (EGFR), a member of the HER/ErbB family of membrane-bound proteins, was one of the first successful targets in lung cancer, and HER2, another member of the HER/ErbB family, is a valid target in breast and gastric. Osimertinib, a third-generation EGFR TKI that works by irreversibly binding to both EGFR TKI-sensitizing and T790M resistance-mutant forms while sparing wild-type EGFR, has demonstrated.