Molecular analysis of cell-free DNA to identify distinct molecular mutational burden and its effect on first-line chemotherapy in patients with NSCLC from a phase III trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20660-e20660
Author(s):  
Caicun Zhou ◽  
Xuefei Li ◽  
Tao Jiang ◽  
Shengxiang Ren ◽  
ChunXia Su ◽  
...  
Keyword(s):  
Phase Iii ◽  
First Line ◽  
Cell Free Dna ◽  
Phase Iii Trial ◽  
Free Dna ◽  
Mutational Burden ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Nsclc Patients ◽  
Line Chemotherapy

e20660 Background: To investigate the predictive significance of molecular mutational burden via genetic analysis of circulating cell-free DNA (cfDNA) in NSCLC patients treated with first-line platinum-based chemotherapy. Methods: Eligible patients were enrolled in a phase III trial (NCT01560195). Blood samples were collected at baseline, every two cycles of chemotherapy and at disease progression. Both cfDNA fragment and genomic DNA were isolated and subjected to enrichment for a 1.15M size panel covering exon regions from 1,086 genes. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: Forty-eight patients were enrolled. 17 genes alterations were frequently found from 15 patients (training set). Patients with partial response (PR, n = 3) had significantly lower total mutational burden of these genes than that with stable disease (SD, n = 9) and progression disease (PD, n = 3) (P < 0.05). Based on these results, we further developed a predictive model including 6 genes ( PIK3CA, KIF5B, CD74, XRCC1, MTHFR and KRAS) in the validation set (n = 33). The results showed that the mutational burden of 6-genes panel had the promising predictive yield in patients with PR (n = 7) vs. SD+PD (n = 25) (AUC = 0.962, P = 0.000), PR vs. SD (n = 18) (AUC = 0.960, P = 0.000) and SD vs. PD (n = 8) (AUC = 0.964, P = 0.003). Notably, there was no significant difference in the baseline cfDNA concentration among patients with PR, SD and PD (P > 0.05). Patients with PR experienced a reduction of molecular mutational burden of cfDNA while patients with SD or PD experienced no change or increased molecular mutational burden of cfDNA after two or four cycles of chemotherapy. However, it did not reach the statistically significant difference. Conclusions: The current study demonstrated that molecular characteristics of cfDNA was significantly associated with the effect of first-line platinum-based chemotherapy in patients with NSCLC. The mutational burden of six-genes panel had the promising predictive value in NSCLC patients treated with first-line chemotherapy.

A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21703-e21703
Author(s):  
Lin Wu ◽  
Zhijun Wu ◽  
Zemin Xiao ◽  
Jie Weng ◽  
Zhongsha Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Phase Iii ◽  
Wild Type ◽  
First Line ◽  
End Points ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy ◽  
Group A ◽  
Group B ◽  
Nsclc Patients

e21703 Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.

scholarly journals PD-L1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer in PD-L1 Positive Patients: A Safety Data Network Meta-Analysis

2021 ◽  
Vol 10 (19) ◽  
pp. 4583
Author(s):  
María Rosario García Campelo ◽  
Edurne Arriola ◽  
Begoña Campos Balea ◽  
Marta López-Brea ◽  
José Fuentes-Pradera ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Meta Analysis ◽  
Safety Data ◽  
Phase Iii ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Safety Outcomes ◽  
Using Data ◽  
Nsclc Patients

This network meta-analysis (NMA) evaluates the safety of first-line programmed death-ligand 1 (PD-L1) inhibitor monotherapy in advanced NSCLC patients compared to platinum-based chemotherapy. We also compared the risk of adverse events (AEs) according to programmed cell death-1 receptor (PD-1) or PD-L1 inhibitors therapy. To that end, we conducted a series of metanalyses (MAs) using data from six phase III clinical trials, including 4053 patients. Our results show a reduced risk of any grade treatment-related AEs (risk ratio (RR) = 0.722 95% CI: 0.667–0.783, p = 0.002), and grade 3–5 AEs (RR = 0.406 95% CI: 0.340–0.485, p = 0.023) in immunotherapy as compared to chemotherapy. In contrast, a higher risk of immune-related AEs (irAEs) was estimated for immunotherapy versus chemotherapy. The subgroup MAs comparing PD-L1 to PD-1 inhibitors, determined a lower risk of AEs leading to treatment discontinuation in the anti-PD-L1 subgroup (RR = 0.47 95% CI: 0.29–0.75, p = 0.001); however, this statistically significant difference between anti-PD-L1 and anti-PD-1 subgroups was not reached for other safety outcomes analyzed. In conclusion, our findings show that PD-L1 inhibitor monotherapy improves safety outcomes in the 1L treatment of advanced NSCLC patients as compared to chemotherapy except for irAEs.

Circulating Endothelial Cells for Evaluation of Tumor Response in Non-Small Cell lung cancer patients receiving first-line chemotherapy

2015 ◽  
Vol 30 (4) ◽  
pp. 374-381
Author(s):  
Fadi Najjar ◽  
Ghassan Al-Massarani ◽  
Israa Banat ◽  
Moosheer Alammar
Keyword(s):  
Advanced Nsclc ◽  
Tumor Response ◽  
Small Cell ◽  
Percentage Change ◽  
Circulating Endothelial Cells ◽  
Small Cell Lung ◽  
First Line ◽  
Significant Difference ◽  
Nsclc Patients ◽  
Line Chemotherapy

Background Circulating endothelial cells (CECs) reflect the neovascularization in the tumor mass. We therefore investigated the potential role of CEC kinetics after first-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Peripheral blood samples were obtained from 45 healthy subjects and 51 naïve patients with advanced NSCLC. Quantification of CD146+ CECs was performed using immunomagnetic separation (IMS). Results Pretreatment and posttreatment CEC levels in NSCLC patients were significantly higher than in healthy subjects (p<0.0001). An objective response was achieved after chemotherapy with partial response (PR) or stable disease (SD) in 26 patients, whereas the remaining 25 patients had progressive disease (PD). Baseline CEC levels were significantly higher in PR/SD patients than in PD patients (p = 0.039). After chemotherapy, CEC count significantly decreased in PR/SD patients (p = 0.014) and increased in patients with PD (p = 0.019). Moreover, there was a significant difference in the percentage change of CEC counts between the 2 groups (p = 0.0016). No significant difference in the median progression-free survival and overall survival (OS) was observed between patients with high baseline CEC counts and those with low baseline CEC levels. However, patients with high percentage change in CEC count had longer OS than those with low percentage change after chemotherapy (p = 0.05). Conclusions Changes in CEC counts after chemotherapy reflect tumor response in advanced NSCLC patients. Moreover, high percentage changes in CEC counts after chemotherapy may predict longer OS in advanced NSCLC. High baseline CEC levels might be an indicator of tumor response in advanced NSCLC patients after first-line chemotherapy.

scholarly journals Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome

2019 ◽  
Vol 37 (14) ◽  
pp. 1217-1227 ◽  
Author(s):  
Federico Innocenti ◽  
Fang-Shu Ou ◽  
Xueping Qu ◽  
Tyler J. Zemla ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Mutational Analysis ◽  
Gene Mutations ◽  
Phase Iii ◽  
First Line ◽  
Mutational Burden ◽  
Significant Difference ◽  
Tumor Mutational Burden

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

Impact of gemcitabine (G) on the activity of first-line chemotherapy in non-small cell lung cancer (NSCLC): A meta-analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7138-7138
Author(s):  
G. L. Pappagallo ◽  
O. Belvedere ◽  
O. Vinante ◽  
F. Grossi
Keyword(s):  
Meta Analysis ◽  
Performance Status ◽  
Objective Response ◽  
Response To Treatment ◽  
Third Generation ◽  
First Line ◽  
Significant Difference ◽  
Nsclc Patients ◽  
The Impact ◽  
Line Chemotherapy

7138 Background: A two-drug platinum-based regimen in which cisplatin or carboplatin is combined with a third-generation agent (i.e. paclitaxel, vinorelbine, docetaxel, or G) is the standard first-line treatment for NSCLC patients with good performance status. Encouraging results have recently been reported for nonplatinum regimens composed of two third-generation drugs. Methods: To assess the impact of G on the activity of first-line chemotherapy in NSCLC, we carried out a meta-analysis on data from 4,362 NSCLC patients who were enrolled in 11 randomized trials comparing a G-containing vs. G-free new generation regimens. We constructed 2x2 tables using response to treatment data. For trials with more than one eligible G-free comparator arm, individual comparisons between the G-based treatment arms and each of the comparator arms were analyzed. A general variance-based method was used to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). We assessed for heterogeneity among the trials based on standard methods. Results: Sixteen comparisons contributed to this analysis. G-containing regimens included: G+cisplatin (894), G+docetaxel (565), G+paclitaxel (200 patients), G+vinorelbine (157), G+carboplatin (49). G-free regimens included: vinorelbine+cisplatin (866), carboplatin+paclitaxel (539), docetaxel+cisplatin (494), cisplatin+paclitaxel (439), vinorelbine+carboplatin (159). Comparing G-containing vs. G-free regimens, the OR for progression was 0.867 (CI 95% 0.770–0.977; p = 0.019), with heterogeneity chi-square 11.639 (p = 0.71). No significant difference was observed for complete (OR 0.909, CI 95% 0.556–1.487; P = 0.707) and overall (complete + partial) response (OR 0.987, CI 95% 0.881–1.106; P = 0.819). Conclusions: These data demonstrate that the progression of disease is more likely in patients treated with G-free doublets. Further analyses are required to address whether disease control (objective response + stable disease) is associated with a survival benefit and may therefore be used as a surrogate end point for survival in chemotherapy trials of NSCLC. No significant financial relationships to disclose.

BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. LBA516-LBA516 ◽  
Author(s):  
J. F. Forbes ◽  
T. Pienkowski ◽  
V. Valero ◽  
W. Eiermann ◽  
G. Von Minckwitz ◽  
...  
Keyword(s):  
Metastatic Breast ◽  
Phase Iii ◽  
First Line ◽  
Her2 Positive ◽  
Phase Iii Trial ◽  
Efficacy Analysis ◽  
Significant Difference ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Taxane Chemotherapy

LBA516 Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial for women with HER2+ MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH, (H with T 100 mg/m2) or TCH, (H with T 75 mg/m2 and C AUC=6). Chemo was given q3 wks for 8 cycles with wkly H at 2 mg/kg (loading dose of 4 mg/kg), followed by H q3 wks at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was TTP with 80% power (0.05 significance) to detect a 50% improvement in median TTP between the 2 arms. Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm. Pt characteristics were well balanced in both groups. Importantly, only 52% of pts received C at the protocol specified dose (RDI > 0.9). Efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p = 0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). The most common gr 3/4 toxicities were: infection (44% vs 30%), neutropenic infection (22% vs 12%), thrombocytopenia (2% vs 15%), febrile neutropenia (12% vs 13%) asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 9%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline > 15% were seen in 5.5% vs 6.7% of pts. One pt (0.8%) had a symptomatic CHF in TH arm Conclusions: The already effective TH regimen does not benefit from the addition of C, when the T dose in TH is 100 mg/m2 and 75 mg/m2 in TCH, in women with HER2+ MBC. No significant financial relationships to disclose.

Carboplatin (C) plus paclitaxel (P) versus carboplatin plus pegylated liposomal doxorubicin (PLD) in patients with advanced ovarian cancer (AOC): Final analysis of the MITO-2 randomized multicenter trial.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA5033-LBA5033 ◽  
Author(s):  
S. Pignata ◽  
G. Scambia ◽  
A. Savarese ◽  
R. Sorio ◽  
E. Breda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rate ◽  
Multivariable Analysis ◽  
Advanced Ovarian Cancer ◽  
Final Analysis ◽  
Phase Iii ◽  
P Value ◽  
First Line ◽  
Significant Difference ◽  
Line Chemotherapy

LBA5033 Background: CP is standard first-line chemotherapy for AOC. MITO-2 (Multicentre Italian Trials in Ovarian Cancer) is an academic multicenter randomized phase III study, testing whether C-PLD is more effective than CP. Methods: AOC chemo-naïve patients (pts), stage IC-IV, aged≤75, ECOG PS≤2, were randomized to CP (C AUC5 + P 175 mg/m2,d1q3w) or to C-PLD (C AUC5 + PLD 30 mg/m2,d1q3w), both for 6 cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, toxicity and quality of life (QoL). To have 80% power in detecting a 0.80 HR in PFS, with 2-sided α error 0.05, 632 events were needed and 820 pts were planned. Response rate and toxicity have been reported at ASCO 2009 (abs #LBA5508). All analyses are based on intention to treat. Results: From Jan ’03 to Nov ’07, 820 pts were randomized, 410 to each arm. Median age was 57 yrs (range 21-77). Stage III (60%) and IV (21%) were prevalent. A plateau in PFS events was reached before obtaining the planned number. Thus, following an IDMC recommendation, the final analysis was done with 556 events occurred as of December 31, 2009. This size is consistent with HR to be detected equal to 0.79, with 80% power. With a median follow-up of 40.2 months, median PFS was 19.0 and 16.8 months with C-PLD and CP, respectively (HR 0.95, 95%CI 0.81-1.13, log-rank p value=0.58). Lack of significant difference was confirmed (HR 0.96, 95%CI 0.81-1.14) at multivariable analysis adjusted by stage, PS, residual disease, age and size of the institution. There was no heterogeneity of treatment effect among major subgroups. With 313 deaths recorded, median OS was 61.6 and 53.2 months with C-PLD and CP, respectively (HR 0.89, 95%CI 0.72-1.12, log-rank p value=0.32). QoL data will be presented at the meeting. Conclusions: In the MITO-2 trial, C-PLD was not found to be superior to CP, which remains the standard first-line chemotherapy for AOC.However, given the observed confidence interval and the different toxicity profile, C-PLD could be considered an alternative to standard therapy. Study was partially supported by Schering-Plough. [Table: see text]

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients with metastatic colorectal cancer (mCRC): Efficacy and safety results of the international GERCOR DREAM phase III trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. LBA3500-LBA3500
Author(s):  
Christophe Tournigand ◽  
Benoit Samson ◽  
Werner Scheithauer ◽  
Gérard Lledo ◽  
Frédéric Viret ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
First Line ◽  
Daily News ◽  
Phase Iii Trial ◽  
Online Supplement ◽  
Final Text ◽  
Line Chemotherapy

LBA3500^ The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

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