scholarly journals Clinical outcomes of patients with HER2-mutant advanced lung cancer: chemotherapies versusHER2-directed therapies

2020 ◽  
Vol 12 ◽  
pp. 175883592093609
Author(s):  
Jiebai Zhou ◽  
Ning Ding ◽  
Xiaobo Xu ◽  
Yong Zhang ◽  
Maosong Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Clinical Outcomes ◽  
Disease Diagnosis ◽  
Advanced Lung Cancer ◽  
Insertion Mutation ◽  
Targeted Agents ◽  
First Line ◽  
Line Therapy ◽  
Exon 20

Background: Lung cancer is now the leading cause of cancer mortality worldwide for both men and women. In non-small cell lung cancer (NSCLC), matching a specifically targeted drug to the identified driver mutation in each patient resulted in dramatically improved therapeutic efficacy, often in conjunction with decreased toxicity. Mutations in HER2 have been identified as an oncogenic driver gene for NSCLC. This retrospective study was conducted to better understand the clinical outcomes of advanced lung cancer patients harboring HER2 mutations treated with chemotherapies and HER2-targeted agents, as well as the optimal clinical choice. Methods: Patients who were diagnosed with advanced lung cancer (stage IIIB/IV) and had undergone molecular testing at Zhongshan Hospital, Fudan University, Shanghai, China from April 2016 to December 2018 were reviewed. For patients that had HER2 mutant advanced lung cancer, we analyzed their clinical and molecular features and clinical outcomes, including overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR). Results: We identified 44 patients harboring HER2 mutations. Their median age was 56 years, with the majority being women ( n = 24), never smokers ( n = 32), and having the adenocarcinoma genotype ( n = 42). Amongst the HER2 mutations present, a 12 base pair in-frame insertion in exon 20 with p.771insAYVM was the most common subtype in patients with known detail variants of HER2 mutation (9/27). The median OS from the date of advanced disease diagnosis was 9.9 months with 24 deaths, and a median follow-up of 12.7 months for survivors. For patients with a known HER2 exon 20 insertion mutation, OS tended to be superior (though not statistically) in the first-line HER2-TKI group to that in the group receiving chemotherapy (10.8 versus 9.8 months, p = 0.40). However, patients that received first-line chemotherapy had a median PFS of 5.9 months, numerically longer than that of the HER2-TKI group (4.6 months, p = 0.63). Patients who received HER2-targeted therapy as first-line therapy had an improved OS (10.8 versus 10.1 months, p = 0.30) and PFS (4.6 versus 2.8 months, p = 0.36) relative to those who received HER2-targeted therapy as subsequent-line therapy, although they did not meet the threshold for statistical significance. Furthermore, patients with AYVM mutation were associated with poor clinical outcomes. Conclusion: Pemetrexed-based chemotherapy remains an important component of care for patients with HER2-mutant NSCLC. HER2-TKI given as an initial therapy may bring more clinical benefits than when given as a subsequent-line therapy. Refining the patient population based on patterns of HER2 variants may help improve the efficacy of anti- HER2 treatment in lung cancer. Developing highly effective and tolerable HER2-targeted agents is urgently needed for this population.

Clinical Outcomes In Patients with Chronic Myelogenous Leukemia (CML) and the BCR-ABL 35 Base Pair (bp) Intron 8 Insertion Mutation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3408-3408 ◽  
Author(s):  
Ellin Berman ◽  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Thomas O'Hare ◽  
Christopher Eide ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Research Funding ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Insertion Mutation ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Abl Kinase ◽  
Line Therapy

Abstract Abstract 3408 More than 80% of patients (pts) with CML who are treated with imatinib as first line therapy achieve a complete cytogenetic response (CCR), although approximately 20% of these pts may ultimately progress. The most common mechanism for loss of response is acquired resistance to imatinib due to the development of a point mutation in the ABL kinase domain of BCR-ABL that interferes with optimal imatinib binding. An alternatively spliced BCR-ABL mRNA with a 35 bp insertion between exons 8 and 9 was first described in 2008 (Laudadio, 2008: Lee, 2008); this results in a BCR-ABL protein with 10 novel amino acids inserted after amino acid 474 within the C- terminus of the kinase domain followed by a stop codon. However, clinical responses to imatinib, dasatinib, or nilotinib have not been previously described in patients with this mutation. We retrospectively identified 40 pts who had this mutation detected and describe their clinical outcomes. Of the 40 patients, 24 were male, and the median age was 50, (range 16–70). Six patients had received treatment prior to 2001, and all 40 patients began initial therapy with imatinib. Twenty nine pts had mutation testing done because of either disease progression or lack of response to imatinib and in 9 pts, the mutation was detected during retrospective analysis. Two pts had the mutation detected at the time of diagnosis (one is still on imatinib). Six pts had additional mutations detected simultaneously: E255V, E355G, E450G, T315I with F416L, T315I with E255K, and one with another insertion between exons 4 and 5. The median time from start of imatinib to insertion mutation detection was 36 months (range 0–189). Thirty of the 40 pts (75%) either did not tolerate (n=2) or progressed while on therapy with imatinib (n=28). Eleven pts remain on imatinib, although 5 are on doses of 600 mg/day or higher. Eighteen of the 30 pts (60%) who failed imatinib were changed to dasatinib as second line therapy; 10 of these (56%) did not respond and were changed to nilotinib as third line therapy. Ten of the 30 pts (30%) who did not respond to imatinib were changed to nilotinib as second line therapy; 3 pts achieved an MCR. In summary, this report provides the first clinical summary of pts with CML who have the 35 bp intron 8 insertion mutation. Although it is not clear whether this insertion mutation directly leads to imatinib resistance, given that 75% of pts progressed on standard dose imatinib, other alternative therapies should be considered once this mutation is detected. However, given the small numbers of pts treated with dasatinib or nilotinib as second line therapy, it is difficult to determine whether either has a superior effect. Results of biochemical and cellular studies comparing the relative sensitivity of the BCR-ABL 35 bp intron 8 insertion mutation to several ABL kinase inhibitors will be presented. Table 1. Response summary for patients with BCR-ABL 35 bp intron 8 insertion mutation. Number of patients (%) Failure or progression on first-line imatinib 30/40 (75%) Failure or progression on second-line dasatinib 10/18 (56%) Failure or progression on second-line nilotinib 7/10 (70%) Kinase domain mutation concurrently detected with 35 bp insertion mutation 6/40 (15%) Received non-TKI treatment prior to front-line imatinib 6/40 (15%) Disclosures: Berman: Novartis Inc: Research Funding. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding. Druker:Molecular MD: Equity Ownership.

Anlotinib, a multitarget tyrosine kinase inhibitor, for advanced lung cancer patients: Efficacy in real-world study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15652-e15652
Author(s):  
Jifeng Feng ◽  
Lei Qian
Keyword(s):  
Lung Cancer ◽  
Real World ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Advanced Lung Cancer ◽  
Line Treatment ◽  
First Line ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line

e15652 Background: Anlotinib is an novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced NSCLC by CFDA in May 2018, and also approved as third-line therapy for patients with advanced SCLC in China in 2019. The objective of this study was to assess the efficacy of Anlotinib for patients with advanced lung cancer in the real world. Methods: We reviewed the patients who were diagnosed as advanced lung cancer and had received anlotinib in Jiangsu Caner Hospital from May 2018 to Sep 2019. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 465 patients were included in our study, containing 384 cases of NSCLC and 81 cases of SCLC. Among patients with NSCLC, 85 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment, whereas 299 cases received anlotinib alone or anlotinib based therapy as third-line or later treatment. There were no significant differences in PFS, ORR and DCR between cohort of 1st /2nd line treatment and those with 3rd /later treatment. However, patients received combination therapy (including anlotinib combined with PD1 inhibitors such as Nivolumab, pembrolizumab, or chemotherapy such as platinum, docetaxel, pemetrexed, paclitaxel, tegafur, etc.) showed a significant longer PFS and higher ORR and DCR (P < 0.001, table). In patients with SCLC, 44 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment. There were no significant differences in PFS, ORR and DCR between cohort of anlotinib monotherapy and other combination therapies (P > 0.05, table). No additional safety profile was observed. Conclusions: Anlotinib shows similar effect in patients with NSCLC and SCLC in real world. Anlotinib provides more significant benefits when combining with PD1 inhibitor or chemotherapy comparing with monotherapy in patients with advanced NSCLC. [Table: see text]

scholarly journals Clinical Characteristics of Advanced Non-Small Cell Lung Cancer with EGFR Exon 20 Insertions

2021 ◽  
Author(s):  
Chie Morita ◽  
Tatsuya Yoshida ◽  
Masayuki Shirasawa ◽  
Ken Masuda ◽  
Yuji Matsumoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Clinical Characteristics ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Line Therapy ◽  
Exon 20 ◽  
Insertion Mutations

Abstract Background: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 4%–10% of all EGFR mutations in patients with non-small cell lung cancer (NSCLC). However, data on the differences in clinical characteristics between patients with EGFR exon 20 insertion mutations and major mutations (exon 19 deletion and L858R) are limited. Methods: We retrospectively reviewed advanced NSCLC patients with EGFR mutations, including EGFR exon 20 insertions and major mutations, who were treated with systemic therapy between January 2011 and December 2019.Results: We identified 23 patients with EGFR exon 20 insertions and 534 patients with EGFR mutations. Among patients with exon 20 insertion, the median age was 60 years (range: 27–88 years), and females and never smokers were predominant. The clinical characteristics of patients with exon 20 insertions were similar to those with major EGFR mutations. Regarding the clinical outcomes in patients with exon 20 insertions, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9%. Additionally, eight patients received anti-PD-1 antibodies and seven patients received EGFR-tyrosine kinase inhibitors (TKIs) in any-line therapy, and their ORR and mPFS were 0%, 25% and 2.2, 3.1 months, respectively. Overall survival was significantly shorter in patients with exon 20 insertions than in those with EGFR major mutations (29.3 vs. 43.4 months, p=0.04). Conclusions: The clinical outcomes in patients with exon 20 insertions were not satisfactory compared to those in patients with major EGFR mutations.

scholarly journals LGG-03. LONG-TERM FOLLOW UP OF TARGETED THERAPY IN PEDIATRIC LOW-GRADE GLIOMAS: THE DANA-FARBER/BOSTON CHILDREN’S EXPERIENCE

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i31-i31
Author(s):  
Jessica Tsai ◽  
Jayne Vogelzang ◽  
Cecilia Sousa ◽  
Kee Kiat Yeo ◽  
Keith Ligon ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Natural History ◽  
Low Grade ◽  
Targeted Agents ◽  
First Line ◽  
Therapy Initiation ◽  
Line Therapy ◽  
History Of ◽  
Targeted Agent

Abstract Background Pediatric low grade gliomas (pLGGs) are the most common central nervous system (CNS) tumor in children and characterized by alterations in the MAPK pathway. Standard of care is not well defined, and treatment has evolved over the last decade to include molecular targeted therapies. The impact of targeted agents on the natural history of pLGGs remains unknown. We present a retrospective review of patients receiving targeted agents integrated with molecular profiling. Methods We performed an IRB-approved, retrospective chart review of pLGGs treated with off-label use of dabrafenib, vemurafenib, everolimus, and trametinib at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Results Forty-nine patients were identified (dabrafenib n=9, everolimus n=27, trametinib n=10, and vemurafenib n=3). All patients receiving BRAF inhibitors harbored BRAF V600E mutation. Targeted agent was used as first-line therapy for 25% of patients, while for 31% of patients, targeted agent was second-line therapy. The median time from diagnosis to targeted therapy initiation was 4.76 years (0.10 – 23.77), median duration of targeted therapy was 0.79 years (0.01 – 4.87), median time to subsequent therapy post first-line targeted therapy was 0.2 years (0.01 – 3.33), and overall median follow-up for the entire cohort was 3.09 years (0.36 – 11.87). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation was 58.0%, 32.2%, and 26.9%, respectively. Survival analyses by molecular subgroup and agent were performed. Reasons for cessation of targeted therapy included toxicities, progression, and/or planned end of therapy. Conclusions Further efforts are ongoing to perform volumetric analysis of growth rates before, during, and after treatment. While targeted molecular therapies show great promise, it will be critical to understand how these agents alter the natural history of pLGGs, particularly in the context of genomic profiling.

Demonstrating the value of liquid biopsy for lung cancer in a public health care system.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3546-3546
Author(s):  
Rosalyn A. Juergens ◽  
Doreen Anuli Ezeife ◽  
Janessa J. Laskin ◽  
Jason Scott Agulnik ◽  
Desiree Hao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Liquid Biopsy ◽  
Checkpoint Inhibitors ◽  
Molecular Profiling ◽  
Public Health Care ◽  
Smoking History ◽  
Advanced Lung Cancer ◽  
First Line ◽  
Treatment Naïve

3546 Background: Given the challenges of molecular profiling in patients with advanced lung cancer, this prospective study examines clinical outcomes and utility of liquid biopsy in treatment naive stage IV lung adenocarcinoma patients (Cohort 1) and in the setting of resistance to targeted therapy (Cohort 2; not reported here). Methods: This study is being conducted at 6 Canadian centres (NCT03576937) using Guardant 360 (G360), a validated cell-free DNA next-generation sequencing assay that identifies variants in 74 cancer-associated genes, including fusions and copy number gain. Cohort 1 (N = 150) includes patients with treatment-naïve advanced non-squamous lung carcinoma, ≤10 pack-year smoking history, and measurable disease. Patients received standard of care tumour tissue (TT) molecular profiling ( EGFR, ALK +/- ROS1) and liquid biopsy (LB). The primary endpoint was response rate to first-line therapy (RECIST 1.1); secondary endpoints include incremental targetable alterations identified through G360 ( EGFR, ALK, BRAF, ERBB2, KRAS (G12C), NTRK, MET (amplification, exon 14 skipping), RET, ROS1), turn-around time (TAT) and successful molecular profiling rates. Results: To date, 84 eligible patients with clinical data have been accrued to Cohort 1. Median age is 64 (range 23-91), 64% are female, 85% never smokers, 96% have adenocarcinoma. Actionable targets have been identified in 55% of patients using G360 ( EGFR/ALK in 37%), 39% using standard TT profiling. Eight EGFR/ALK aberrations were identified in TT but not LB, while 6 were identified in LB but not TT. TT profiling for EGFR/ALK was unsuccessful in 8% of patients (insufficient tissue, failed biopsy). Fourteen patients (17%) had no ctDNA alterations detected by G360 (low disease burden vs. non-shedding). Of 75 patients receiving first-line treatment, 57% received targeted therapy, 28% chemotherapy combinations, 11% checkpoint inhibitors and 4% were observed. Treatment decisions were informed by G360 alone in 37% and by G360+TT results in 27% (by physician report). Among 46 evaluable patients, ORR was 54% (25/46). Using G360, ORR was 75% (15/20) in those with actionable alterations and 38.5% (10/26) in those without. Using TT, ORR was 67% (14/21) in those with actionable alterations and 44% (11/25) in those without. Mean TAT was 7.9 days (SD+/-1.7) for LB vs 19.9 days (SD+/- 9.8) for TT. Conclusions: Liquid biopsy using G360 identifies actionable targets beyond tissue profiling alone in newly diagnosed lung cancer patients, has faster TAT and yields similar outcomes with targeted and non-targeted therapy. Clinical trial information: NCT03576937 .

P50.06 First-Line Therapy in NSCLC harbouring EGFR or HER2 Exon 20 Insertion Mutation. Hunting for the Best Candidate

2021 ◽  
Vol 16 (10) ◽  
pp. S1116-S1117
Author(s):  
A. Prelaj ◽  
A. Bottiglieri ◽  
G. Lo Russo ◽  
R. Ferrara ◽  
G. Galli ◽  
...  
Keyword(s):  
Insertion Mutation ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Exon 20
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