Correlation of ERCC1 expression on circulating tumor cells with progression-free survival in metastatic non-small cell lung cancer patients treated with platinum-based chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10574-10574
Author(s):  
Jonathan Riess ◽  
Millie Snigdha Das ◽  
Paul Henry Frankel ◽  
Erich Schwartz ◽  
Robyn Bennis ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Free Survival ◽  
Metastatic Nsclc ◽  
Log Rank Test ◽  
Platinum Based Chemotherapy ◽  
Ercc1 Expression ◽  
Platinum Chemotherapy

10574 Background: Biomarkers predicting efficacy of chemotherapy are highly desirable. Fiber array scanning technology (FAST) is a novel method of detecting circulating tumor cells (CTCs) that does not employ an EpCam enrichment step. The purpose of this study was to use FAST to evaluate ERCC1 expression on CTCs to determine whether ERCC1 expression correlates with progression-free survival (PFS) in patients who received platinum-based chemotherapy for metastatic non-small-cell lung cancer (NSCLC). Methods: Peripheral blood from one hundred enrolled patients with metastatic NSCLC was collected by two institutions (Stanford Cancer Institute and Billings Clinic Cancer Center). FAST was used to identify individual CTCs on immunofluorescence by pancytokeratin antibodies. Nuclear localization of ERCC1 expression by immunofluorescence was quantified on individual CTCs. Total patient ERCC1 levels were determined from the average expression of all the CTCs in each patient sample. Fifty-seven of the one hundred patients enrolled received platinum chemotherapy. Seventeen of those fifty-seven patients (30%) had ≥ 2 evaluable intact CTCs and were analyzed retrospectively. Linear regression (F-test) was used to evaluate the correlation between ERCC1 expression and PFS. Kaplan-Meier survival analysis (log-rank test) was used to compare PFS in patients with CTCs with no detectable ERCC1 expression versus patients with CTCs that expressed any level of ERCC1. Results: PFS decreased with increasing ERCC1 expression (P<0.04 F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days vs. 172 days, log-rank test P<0.02). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p<0.02, log-rank test). Conclusions: In this small study, using FAST to isolate CTCs, low expression of ERCC1 on evaluable CTCs correlated with increased PFS in patients with metastatic NSCLC who received platinum chemotherapy. A larger, prospective study to validate these retrospective results is warranted.

scholarly journals Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater

2019 ◽  
Vol 37 (7) ◽  
pp. 537-546 ◽  
Author(s):  
Martin Reck ◽  
Delvys Rodríguez–Abreu ◽  
Andrew G. Robinson ◽  
Rina Hui ◽  
Tibor Csőszi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Failure Time ◽  
Progression Free Survival ◽  
Small Cell ◽  
Structural Failure ◽  
Small Cell Lung ◽  
Free Survival ◽  
Inverse Probability ◽  
Platinum Based Chemotherapy

Purpose In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. Patients and Methods Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator’s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. Results Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). Conclusion With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Clinical significance of ERCC2 haplotype-tagging single nucleotide polymorphisms in patients with unresectable non-small cell lung cancer treated with first-line platinum-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19156-e19156
Author(s):  
Seok-Hyun Kim ◽  
Gyeong-won Lee ◽  
Yi Yeong Jeong ◽  
Ho-Cheol Kim ◽  
Jong Deog Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell ◽  
Rank Test ◽  
Nucleotide Polymorphisms ◽  
Small Cell Lung ◽  
First Line ◽  
Single Nucleotide ◽  
Log Rank Test ◽  
Platinum Based Chemotherapy ◽  
Grade 3

e19156 Background: DNA repair pathway is a crucial molecular mechanism potentially involved in resistance to platinum-based chemotherapy in the unresectable non-small cell lung cancer. Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes. Methods: We genotyped 8 ERCC2 htSNPs for 129 unresectable NSCLC (stage IIIA, 12; stage III, 36; stage IV, 82) cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of htSNPs in patient response, survival, and chemotherapy-related adverse events were analyzed according to each ERCC2 htSNP using chi-square test, Kaplan-Meier method, and Cox proportional hazard model. Results: No differences were observed in patient or disease characteristics and response according to ERCC2 htSNPs. In a survival analysis, rs50872 was significantly related to overall survival (OS) (log-rank test, p=0.014). The median survival duration of rs50872 G/G, A/G, and A/A genotypes was 35.75 (95% confidence interval [CI] 21.05-50.45), 36.07 (hazard ratio[HR] 1.02, 95% CI 25.20-46.94), and 16.75 (HR 3.49, 95% CI 5.73-27.77) months, respectively. A significant association was observed between grade 3-4 infections and poor survival: OS in patients with a grade 0-2 infection: 35.75 months (95% CI 28.15-43.35); OS in patients with a grade 3-4 infection: 12.86 months (95% CI 8.99-16.72, HR 3.57) (log-rank test, p<0.001). In a subgroup analysis, rs238405 genotype was significantly related to OS in the taxane-based group. However, rs238416 genotype was significantly associated with OS in the gemcitabine-based group. Conclusions: ERCC2 htSNPs rs50872 (overall), rs238405 (taxane-based group), and rs238416 (gemcitabine-based group) and infection related to first-line chemotherapy were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. However, additional large prospective studies focusing on the role of ERCC2 htSNPs in unresectable NSCLC are needed.

scholarly journals Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study

2021 ◽  
pp. JCO.20.03579 ◽  
Author(s):  
Michael Boyer ◽  
Mehmet A. N. Şendur ◽  
Delvys Rodríguez-Abreu ◽  
Keunchil Park ◽  
Dae Ho Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
First Line ◽  
Double Blind ◽  
Free Survival ◽  
Metastatic Nsclc

PURPOSE Pembrolizumab monotherapy is standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234 ), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy

2000 ◽  
Vol 18 (10) ◽  
pp. 2095-2103 ◽  
Author(s):  
Frances A. Shepherd ◽  
Janet Dancey ◽  
Rodryg Ramlau ◽  
Karin Mattson ◽  
Richard Gralla ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Supportive Care ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Best Supportive Care ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Log Rank Test ◽  
Platinum Based Chemotherapy

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non–small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non–small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m 2 . Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20700-e20700
Author(s):  
Andre Deeke Sasse ◽  
Fernanda Proa Ferreira ◽  
Adolfo Jose de Oliveira Scherr ◽  
David Pinheiro Cunha ◽  
Vivian Castro Antunes Vasconcelos ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Metastatic Nsclc

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Therapy of Advanced Non–Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan

2017 ◽  
Vol 35 (24) ◽  
pp. 2790-2797 ◽  
Author(s):  
Rebecca Suk Heist ◽  
Michael J. Guarino ◽  
Gregory Masters ◽  
W. Thomas Purcell ◽  
Alexander N. Starodub ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
End Points ◽  
Free Survival ◽  
Metastatic Nsclc

Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non–small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2–expressing tumors.

scholarly journals Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%

2021 ◽  
pp. JCO.21.00174
Author(s):  
Martin Reck ◽  
Delvys Rodríguez-Abreu ◽  
Andrew G. Robinson ◽  
Rina Hui ◽  
Tibor Csőszi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Free Survival ◽  
Chemotherapy Group ◽  
Platinum Based Chemotherapy

PURPOSE We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non–small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738 ) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS). METHODS Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point. RESULTS Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti–PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3-40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48-0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure. CONCLUSION Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

scholarly journals Comparison of efficiency and toxicity of two chemotherapy protocols in treatment of advanced non-small cell lung cancer

2011 ◽  
Vol 64 (7-8) ◽  
pp. 368-372 ◽  
Author(s):  
Alma Mekic-Abazovic ◽  
Ibrahim Sisic ◽  
Vladimir Kovcin ◽  
Hakija Beculic ◽  
Senad Dervisevic ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumour Response ◽  
Progression Free Survival ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Free Survival ◽  
Significant Difference

Introduction. This study was aimed at comparing the efficiency and tolerability of two reference protocols Cisplatin and Etoposide and Cisplatin and Vinorelbine in advanced Non-Small Cell Lung Cancer. Material and Methods. A total of 60 patients (two groups consisting of 30 patients) were treated for advanced Non-Small Cell Lung Cancer during the period from January to December 2005 according to the reference protocols (Cisplatin 100mg/m2 D1; Vinorelbine 30 mg/m2 D1, D8 on 4 weeks) and (Cisplatin 100 mg/m2 D1; Etoposide 100 mg/m2 D1, D3, D5 on 4 weeks) at the Department of Oncology of KBC ?Bezanijska kosa?. All patients were analyzed for tumour response, progression free survival as well as for toxicity. X2 test, Kaplan Meiers curves and Log rank test were used for statistical analysis. Results. Although the recorded response rates were a bit lower than in previously published trials, they were not significantly different p=0.485. No statistically significant difference was recorded in either progression free survival or overall survival. The chemotherapeutical Cisplatin/Etoposide protocol proved to be more toxic both in hematologic (3% vs. 10%) and total toxicities (p=0.047). Conclusion. Our study proved both protocols to have equivalent efficacy. However, the Cisplatin, Vinorelbine protocol could be recommended because of its less expressed toxic effects.

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