scholarly journals Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

2020 ◽  
Author(s):  
Pedro E. N. S. Vasconcelos ◽  
Ikei S. Kobayashi ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Therapeutic Window ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Exon 20 ◽  
Egfr Tki ◽  
Insertion Mutations ◽  
Egfr Tkis

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

scholarly journals DDIS-17. DEVELOPMENT OF BRAIN-PENETRANT EGFR INHIBITORS FOR CNS MALIGNANCIES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi66-vi66
Author(s):  
Jonathan Tsang ◽  
Lorenz Urner ◽  
Christopher Tse ◽  
Lynn Baufeld ◽  
Kym Faull ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Tumor Response ◽  
Growth Factor Receptor ◽  
Structure Activity ◽  
Superior Efficacy ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Cns Malignancies

Abstract The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for patients with GBM. This can be attributed to the inability of clinically available EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib, cetuximab) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. Herein, we performed a structure-activity relationship (SAR) to obtain EGFR TKIs with both high brain penetrance and potency against EGFR-activated GBM cells. From over 80 novel compounds synthesized, our lead EGFR TKI—JCN068—exhibited exceptional BBB penetration (350% brain to plasma) while also having optimal ADME properties (60% oral bioavailability, ~5 hr half-life, >100 µg/mL solubility, etc). Moreover, JCN068 demonstrated picomolar potency against purified EGFR kinase, 1000-fold selectivity for EGFR relative to other kinases, and nanomolar activity against EGFR-altered, GBM patient-derived cells in culture. Importantly, JCN068 demonstrated superior efficacy—with negligible toxicity—compared to clinically available small molecule EGFR TKIs (erlotinib and lapatinib) against multiple EGFR-altered patient-derived orthotopic GBM xenografts. Due to these excellent drug-like properties, JCN068 is currently progressing towards clinical development for EGFR-activated GBM patients.

Activity of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients (pts) with NSCLC with uncommon EGFR mutations: A real-world cohort study (UpSwinG).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9072-9072
Author(s):  
Satoru Miura ◽  
Te-Chun Hsia ◽  
Jen-Yu Hung ◽  
Hyun Ae Jung ◽  
Jin-Yuan Shih ◽  
...  
Keyword(s):  
Real World ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Pathology Reports ◽  
Multi Center Study ◽  
Line Of Therapy ◽  
Ecog Ps ◽  
Egfr Tki ◽  
Egfr Tkis

9072 Background: EGFR TKIs are an established treatment (tx) option for pts with EGFR mutation-positive NSCLC with common mutations (Del19 or L858R); however, 7–23% of NSCLC tumors harbor uncommon EGFR mutations, where EGFR TKI efficacy is less established. These mutations are highly heterogeneous, and developments in detection by NGS are helping to identify mutations with little or no clinical data. Methods: In this non-interventional, global, multi-center study (NCT04179890), existing medical or electronic health records were identified for consecutive EGFR TKI-naïve pts with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q or S768I], ‘other’ or compound mutations) treated with erlotinib, gefitinib, afatinib, osimertinib or other systemic therapy. Endpoints were time to tx failure (TTF), ORR, OS and duration of response (DoR). Results: Overall, 246 pts (median age: 69.5 yrs; Asian: 84%; brain metastases: 8%; ECOG PS ≥2: 16%) were recruited from 9 countries. Most pts (n=226; 92%) received an EGFR TKI as 1st-line therapy; 132 (54%), 105 (43%) and 7 (3%) received afatinib, 1st-gen TKIs and osimertinib, respectively. 57% of pts received >1 line of therapy. Most pts (73%) had a major uncommon mutation, 9% had other mutations and 33% had a compound mutation; these were detected using PCR (75%) or sequencing (25%), mainly based on tissue biopsy (86%). Pathology reports varied in quality, often lacking detail on specific mutations e.g. 21% of ex18 and 72% of ex20ins were undefined. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 mos; ORR was 42%. In pts treated with 1st-line chemotherapy (n=20), median TTF and ORR were 6.6 mos and 41%. Outcomes were most favorable in major uncommon and compound mutations (Table). TTF appeared to be higher with afatinib vs 1st-gen EGFR TKIs. In most mutation categories, median OS was >2 yrs, possibly reflecting high subsequent therapy uptake. Conclusions: In a real-world setting, EGFR TKIs were the preferred tx option in pts with uncommon EGFR mutations; strongest outcomes were seen in major uncommon and compound mutations, and in pts treated with afatinib. Data were in line with recent analyses of afatinib in uncommon mutations. Tx with an EGFR TKI should be considered as standard for most pts with uncommon mutations. Optimal tx for pts with uncommon mutations requires improvements in pathology reports, with more emphasis on NGS methodology and precise definition of mutations. Clinical trial information: NCT04179890. [Table: see text]

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

scholarly journals Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario

2019 ◽  
Vol 20 (6) ◽  
pp. 1431 ◽  
Author(s):  
Alessandro Russo ◽  
Tindara Franchina ◽  
Giuseppina Ricciardi ◽  
Alessandra Battaglia ◽  
Maria Picciotto ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Egfr Mutated ◽  
Egfr Tkis ◽  
Exon 19

Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

scholarly journals EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3561
Author(s):  
Ikei S. Kobayashi ◽  
Hollis Viray ◽  
Deepa Rangachari ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Clinical Care ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Insertion Mutant ◽  
Preclinical Models ◽  
2Nd Generation ◽  
Clinical Scenarios ◽  
Exon 20 ◽  
Insertion Mutations ◽  
Egfr Tkis

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis

2015 ◽  
Vol 33 (17) ◽  
pp. 1958-1965 ◽  
Author(s):  
Chee Khoon Lee ◽  
Yi-Long Wu ◽  
Pei Ni Ding ◽  
Sarah J. Lord ◽  
Akira Inoue ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Never Smokers ◽  
Egfr Tkis ◽  
Exon 19

Purpose We examined the impact of different epidermal growth factor receptor (EGFR) mutations and clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated non–small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy. Patients and Methods This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-variance-weighted method. All statistical tests were two sided. Results In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged PFS overall (HR, 0.37; 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the benefit was 50% greater (HR, 0.24; 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution (HR, 0.48; 95% CI, 0.39 to 0.58; Pinteraction < .001). Never-smokers had a 36% greater benefit (HR, 0.32; 95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50; 95% CI, 0.40 to 0.63; Pinteraction < .001). Women had a 27% greater benefit (HR, 0.33; 95% CI, 0.28 to 0.38) than men (HR, 0.45; 95% CI, 0.36 to 0.55; treatment-sex interaction P = .02). Performance status, age, ethnicity, and tumor histology did not significantly predict additional benefit from EGFR TKIs. Conclusion Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.

scholarly journals Tetracyclines increase the survival of NSCLC patients treated with EGFR TKIs: a retrospective nationwide registry study

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000864
Author(s):  
Virve Alanen ◽  
Sanna Iivanainen ◽  
Martti Arffman ◽  
Jussi Pekka Koivunen
Keyword(s):  
Second Generation ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Prophylactic Use ◽  
Nsclc Patients ◽  
First And Second Generation ◽  
Egfr Tki ◽  
Egfr Tkis

BackgroundWith the first and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), clinical benefit and rash correlate together. EGFR TKI-induced rash can be alleviated with tetracyclines, but it is unknown whether the use of tetracyclines can increase the survival of non-small-cell lung cancer (NSCLC) patients treated with EGFR TKIs.MethodsWe collected all the patients (n=1271) who had reimbursement for EGFR TKIs (gefitinib, erlotinib and afatinib) in Finland 2011–2016, had purchased TKIs, and had data available at nationwide cancer registry. The survival was analysed from the first EGFR TKI purchase to death or end-of follow-up, and patients were stratified according to TKIs, purchases of antibiotics, their ATC class and timing.Results802 (63.1%) patients had antibiotic purchases −14 to +200 days from the first EGFR TKI purchase, 447 of these tetracyclines. 322 (25.3%) had had purchased antibiotics −14 to +14 days (prophylaxis) from the first EGFR TKI purchase, 188 of these tetracyclines. Purchase of antibiotics was associated with improved survival (HR 0.80, 95% CI 0.71 to 0.91), which limited to tetracycline purchases only (HR 0.72, 95% CI 0.64 to 0.82). The largest survival benefit was seen with the prophylactic use of tetracyclines (HR 0.74, 95% CI 0.62 to 0.88). The benefit from tetracyclines was limited to erlotinib only (HR 0.68, 95% CI 0.58 to 0.78) which was retained in multivariate analysis. Prophylactic use of tetracyclines was associated with a longer erlotinib treatment duration (HR 0.81, 95% CI 0.61 to 0.96) but not with dose reductions or treatment breaks.ConclusionsTetracyclines improve the survival of NSCLC patients treated with the first and second-generation EGFR TKIs and they should be considered as a prophylaxis when initiating EGFR TKIs with high incidence of rash.

scholarly journals A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

2021 ◽  
Author(s):  
Nirmal Vivek Raut ◽  
Siddharth Srivastava ◽  
Guarav Dilip Gangwani ◽  
Heena Sajid Ali
Keyword(s):  
Kinase Inhibitors ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Primary Resistance ◽  
Gene Testing ◽  
Comprehensive Genomic Profiling ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tki

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

Sign in / Sign up

Export Citation Format

Share Document