scholarly journals Erlotinib Efficacy in NSCLC Patients with High Polysomy of Chromosome 7 and EGFR/KRas Wild-Type Tumors

2015 ◽  
Vol 10 (2) ◽  
pp. 392-396 ◽  
Author(s):  
Francesca Toffalorio ◽  
Filippo de Marinis ◽  
Fabio Conforti ◽  
Gianluca Spitaleri ◽  
Chiara Catania ◽  
...  
Keyword(s):  
Chromosome 7 ◽  
Wild Type ◽  
Nsclc Patients

scholarly journals 562 Real-world assessment of current treatment patterns and clinical outcomes among patients with EGFR and ALK wild type non-small cell lung cancer (NSCLC) in the US

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A591-A591
Author(s):  
Lyudmila Bazhenova ◽  
Jonathan Kish ◽  
Beilei Cai ◽  
Nydia Caro ◽  
Bruce Feinberg
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Treatment Patterns ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
First Line ◽  
The Us ◽  
Nsclc Patients

BackgroundTreatment for advanced non-small cell lung cancer (NSCLC) has dramatically advanced in the past 5 years with the advent of immunotherapy (IO). This study sought to describe treatment patterns and clinical outcomes in a representative sample of NSCLC patients.MethodsPatients were identified by physicians from a voluntary sample of community practices across the US. Stage IIIB/IV NSCLC patients with EGFR/ALK wild-type initiating any first-line (1L) systemic therapy between 01/01/2016 and 12/31/2019 with at least 2 months of follow-up (unless deceased) were included, and were followed until November 2020. Sampling quotas included 250 patients who initiated 1L in 2016/2017 and 250 patients who did so in 2018/2019. Best tumor response was collected from patient charts during each line of therapy (LOT). Progression-free survival (PFS) and overall survival (OS) were calculated from initiation of 1L by Kaplan-Meier method. Baseline characteristics and clinical outcomes are described and presented by treatment regimen received.ResultsOf 500 submitted patients, 497 were included post QA/QC. Across all patients, mean age at 1L initiation was 65 years, 57.3% were male, 92.9% had stage IV disease, and 68.6% were ECOG-OS 0/1 (Table 1). Overall, 60.2% (n=299), 33.2% (n=165), and 6.6% (n=33) received 1, 2, or =3 LOTs during the study period. Most common 1L regimens (%) were platinum-doublet chemotherapy plus IO (PDC+IO) (40.6%), PDC (29.4%), IO monotherapy (20.7%), PDC+bevacizumab (6.2%); while most common 2L regimens were IO monotherapy (42.4%), single-agent chemotherapy (SAC) (18.2%), SAC+VEGF inhibitor (15.7%), PDC (8.1%), and PDC+bevacizumab (5.6%). Over 90% of pts who received IO monotherapy had PD-L1 >50%. Moving from 2016/2017 to 2018/2019, utilization of 1L PDC declined from 45.0% to 13.7% while utilization of 1L PDC+IO increased from 27.3% to 54.0%. Among those who received only one LOT (n=299), 44.5% were still on 1L, 14.0% stopped receiving 1L, and 41.5% were deceased. Overall response rates were 67.3%, 35.6%, 60.2%, and 61.3% for 1L PDC+IO, PDC, IO monotherapy, and PDC+bevacizumab, respectively (Table 1). First-line median PFS/OS (months) was 15.6/26.5, 5.3/13.7, 17.8/NR, and 10.8/18.6, respectively for PDC+IO, PDC, IO monotherapy, and PDC+bevacizumab (table 1).Abstract 562 Table 1ConclusionsData from 2016 to 2020 was used provide a contemporary assessment of treatment patterns among EGFR/ALK wild-type NSCLC patients. Although 1L treatment utilization shifted to IO-based regimens in recent years, 41.5% of patients did not survive to receive second-line therapy, 1L PFS did not exceed 1.5 years, and median OS remained limited across all 1L treatment groups.Ethics ApprovalOn August 20, 2020, Western Institutional Review Board (WIRB) approved a request for a waiver of authorization for use and disclosure of protected health information (PHI) for this research. The study is exempt under 45 CFR § 46.104(d)(4).

scholarly journals Role of Genetic Evolution and Germline Mutations in SAMD9 and SAMD9L Genes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-33-SCI-33
Author(s):  
Jason R Schwartz ◽  
Marcin W. Wlodarski ◽  
Jeffery M. Klco
Keyword(s):  
Bone Marrow ◽  
Germline Mutation ◽  
Bone Marrow Failure ◽  
Hematopoietic Cells ◽  
Germline Mutations ◽  
Chromosome 7 ◽  
Chromosome Loss ◽  
Wild Type ◽  
In Vivo Models ◽  
Monosomy 7

Acquired deletions on chromosome 7 (monosomy 7/del7q) are common in myeloid neoplasms, especially pediatric MDS and AML. Although these tumors have historically been reported to occur within families, suggesting a genetic predisposition, the genetic lesion(s) that initiate these diseases has remained elusive until the last few years. Following a series of publications in which germline mutations in SAMD9 and SAMD9L were reported in a MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively, our group and others described similar heterozygous missense germline mutations in pediatric MDS, especially non-syndromic familial MDS with monosomy 7. Mutations in SAMD9 and SAMD9L have now also been reported in transient monosomy 7, inherited bone marrow failure and AML. Collectively, it is estimated that germline mutations in these genes are present in nearly 20% of children with MDS, with a strong enrichment in those with monosomy 7. Surprisingly, SAMD9 and SAMD9L are paralogous genes adjacently located on human chromosome 7 at band 7q21, and the monosomy 7 clone that expands in children universally lacks the pathologic germline variant. Expression of the mutant proteins in cells results in profound growth suppression, suggesting that there is strong selective pressure for hematopoietic cells to not express the mutant alleles. In addition to chromosome loss, additional methods that suppress expression of the pathologic allele have been described. These include copy neutral loss of heterozygosity (CN-LOH) with duplication of the wild-type allele or the somatic acquisition of additional mutations in cis with the germline mutation that counteract the growth suppressive effect of the germline mutation. The clinical phenotype is largely dictated by the revertant mutation in the dominant hematopoietic clone within the patient's bone marrow. Those with an expansion of a CN-LOH clone are more commonly asymptomatic, in contrast to those patients with a dominant monosomy 7 clone. Progression to higher grade MDS or AML is associated with the acquisition of additional somatic mutations including mutations in SETBP1, KRAS and RUNX1. The recognition of these germline mutations has had an immediate impact on the clinical management of children with MDS, including their family members, and ongoing clinical work in the pediatric MDS community is aimed at establishing guidelines for the pathologic diagnosis, clinical monitoring and treatment for these patients. In addition to these ongoing clinical pursuits, there is significant research interest in these genes, the function of their proteins in hematopoietic cells and how the germline mutations alter the function of the wild-type protein. The SAMD9 and SAMD9L proteins are largely uncharacterized and have been shown to be important in endocytosis, growth factor signaling and to have antiviral properties. Intriguingly, SAMD9 and SAMD9L are both induced by inflammatory signals, including interferons, suggesting a link between inflammatory stress and the disease phenotype. Ongoing studies are aimed at developing models, including in vitro and in vivo models, to understand the mechanisms by which these germline mutations can ultimately lead to the development of pediatric MDS and related disorders. Disclosures No relevant conflicts of interest to declare.

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

scholarly journals IncreasedHOXA5expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma

2018 ◽  
Vol 32 (7-8) ◽  
pp. 512-523 ◽  
Author(s):  
Patrick J. Cimino ◽  
Youngmi Kim ◽  
Hua-Jun Wu ◽  
Jes Alexander ◽  
Hans-Georg Wirsching ◽  
...  
Keyword(s):  
Selective Advantage ◽  
Chromosome 7 ◽  
Wild Type

A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of nonsquamous NSCLC patients with wild-type EGFR (CTONG0806).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8042-8042 ◽  
Author(s):  
Jinji Yang ◽  
Ying Cheng ◽  
Mingfang Zhao ◽  
Qing Zhou ◽  
Hong hong Yan ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
Free Survival ◽  
Line Setting ◽  
Nsclc Patients

8042 Background: Pemetrexed or gefitinib is one of the standard second-line treatments for advanced non-squamousNSCLC in East Asia. The CTONG 0806 a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as the second-line treatment in advanced NSCLC patients without EGFR mutation. Methods: The patients with locally advanced or metastatic, non-squamous NSCLC previously treated with platinum-based chemotherapy and no EGFR mutation in exons 18-21 were enrolled. Patients were 1:1 randomized to receive either gefitinib 250 mg per oral every day (G arm) or pemetrexed 500 mg/m2 iv day 1 with vitamin B12 and folic acid supplement every 21 days (P arm) until disease progression, unacceptable toxicity, or discontinuation of treatment due to other reason. The primary endpoint was progression-free survival (PFS). The secondary endpoints were 4-month and 6-month progression-free survival rate, overall survival (OS), objective response rate (ORR), quality of life using the FACT-L questionnaire and safety, EGFR and K-ras mutation status were evaluated and correlated with outcomes. Results: From Feb. 2009 to Aug. 2012, 157 evaluable patients were randomized (81 cases in G arm and 76 in P arm). Baseline age, gender, and ECOG performance status were balanced between arms. The primary endpoint of PFS was met with 1.6 months for G arm versus 4.8 months for P arm, the HR is 0.51 (95% CI 0.36~0.73, P<0.001). Overall response rates were 14.7 % and 13.3 % (P=0.814) and DCR were 32.0% and 61.3% (P<0.001) for G arm and P arm, respectively. OS data were not yet mature. More skin rash and diarrhoea were seen in G arm, but more fatigue and ALT increased in P arm. CTCAE grade 3 or 4 of AEs was 12.3% in G arm and 32.9% in P arm (p=0.002). The further analyses of efficacy evaluated by IRR and biomarkers analysis will be presented on the ground. Conclusions: CTONG0806 is the first trial to show significant improvements in PFS and DCR with pemetrexed compared with gefitinib in second-line setting for advanced NSCLC with EGFR wild type. Patients with EGFR wild type did not benefit from EGFR TKI gefitinb in second-line setting. Clinical trial information: NCT00891579.

scholarly journals Efficacy and Safety of Docetaxel and Sodium Cantharidinate Combination vs. Either Agent Alone as Second-Line Treatment for Advanced/Metastatic NSCLC With Wild-Type or Unknown EGFR Status: An Open-Label, Randomized Controlled, Prospective, Multi-Center Phase III Trial (Cando-L1)

2021 ◽  
Vol 11 ◽  
Author(s):  
Lin Wu ◽  
Chao Deng ◽  
Hui Zhang ◽  
Jie Weng ◽  
Youhua Wu ◽  
...  
Keyword(s):  
Single Agent ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
Efficacy And Safety ◽  
Wild Type ◽  
Open Label ◽  
Metastatic Nsclc ◽  
Significant Difference ◽  
Nsclc Patients

Second-line treatment options for advanced/metastatic non-small cell lung cancer (NSCLC) patients are limited. We aimed to evaluate the efficacy and safety of docetaxel/sodium cantharidinate combination vs. either agent alone as second-line treatment for advanced/metastatic NSCLC patients with wild-type or unknown EGFR status. A randomized, open-label, phase III study was performed at 12 institutions. Patients with failure of first-line platinum regimens were randomized to receive either single-agent sodium cantharivsdinate (SCA) or single-agent docetaxel (DOX) or docetaxel/sodium cantharidinate combination (CON). The primary endpoints were centrally confirmed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. A total of 148 patients were enrolled in our study between October 2016 and March 2020. After a median follow-up time of 8.02 months, no significant difference was observed among the three groups in ORR (SCA vs. DOX vs. CON: 6.00% vs. 8.33% vs. 10.00%, respectively; p=0.814) and DCR (74.00% vs. 52.00% vs. 62.50%, respectively; p=0.080). In additional, the mOS was significantly higher in the CON group, compared with the single-agent groups (7.27 vs. 5.03 vs. 9.83 months, respectively; p=0.035), while no significant differences were observed in terms of PFS (2.7 vs. 2.9 vs. 3.1 months, respectively; p=0.740). There was no significant difference in the baseline QoL scores between the three groups (p&gt;0.05); after treatment, life quality in SCA and CON group was significantly better than that in the DOX group (p&lt;0.05). Furthermore, the incidence of adverse events (AEs) in the SCA group was significantly lower (46.00 vs. 79.17 vs. 25.00%, respectively; p=0.038) and the incidence of grade ≥3 AEs was also significantly lower in the SCA group compared with the DOX and CON groups (10.00 vs. 82.00 vs. 30.00%, respectively; p=0.042). Single-agent SCA and single-agent DOX has similar therapeutic efficacy in the second-line treatment of advanced/metastatic NSCLC with wild-type or unknown EGFR status, but single-agent SCA has fewer AEs and better QoL. Also, SCA plus DOX can significantly improve OS and exerted a significant synergistic effect, with good safety and tolerance profile.

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