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Nick Thatcher - One of the best experts on this subject based on the ideXlab platform.
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EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2017Co-Authors: Carlo Genova, Nick Thatcher, Raffael Kurek, Mark A. Socinski, Luis Paz-ares, Rebecca R. Hozak, Javad Shahidi, Christopher J. Rivard, Marileila Varella GarciaAbstract:Abstract Introduction Necitumumab is a monoclonal antibody targeting EGFR. In the SQUIRE trial, the addition of Necitumumab to chemotherapy for squamous cell lung cancer significantly improved overall survival (OS) (hazard ratio [HR] = 0.84); in a post hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend toward improved OS (HR = 0.70) and progression-free survival (PFS) (HR = 0.71) with the addition of Necitumumab. We present the analysis of granular EGFR FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification, as both were included in the FISH-positive category. Methods Available specimens from SQUIRE underwent FISH analysis in a central laboratory, and each sample was evaluated by using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed. Results Samples were available for 557 of 1093 patients; 208 patients (37.3%) were FISH-positive, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of Necitumumab resulted in a statistically significant increase in PFS (6.08 versus 5.13 months [p = 0.044]) and nonstatistically significant increase in OS (12.6 versus 9.5 months [p = 0.133]); among patients with gene amplification, the addition of Necitumumab did not significantly improve PFS (7.4 versus 5.6 months; [p = 0.334]) but did improve OS (14.8 versus 7.6 months; [p = 0.033]). Conclusions EGFR copy number gain by FISH might have a role as a predictive biomarker for Necitumumab in squamous cell lung cancer. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker.
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Necitumumab plus Gemcitabine and Cisplatin as First-Line Therapy in Patients with Stage IV EGFR- Expressing Squamous Non-Small-Cell Lung Cancer: German Subgroup Data from an Open-Label, Randomized Controlled Phase 3 Study (SQUIRE).
Oncology research and treatment, 2016Co-Authors: Martin Reck, Mark A. Socinski, Henrik Depenbrock, Victoria Soldatenkova, Mike Thomas, Cornelia Kropf-sanchen, Joerg Mezger, Jacqueline Brown, Thomas Krause, Nick ThatcherAbstract:Background: In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody Necitumumab to first-line gemcitabine and cisplatin (GC + N
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correlation of egfr expression with safety and efficacy outcomes in squire a randomized multicenter open label phase iii study of gemcitabine cisplatin plus Necitumumab versus gemcitabine cisplatin alone in the first line treatment of patients with s
Annals of Oncology, 2016Co-Authors: Luis Pazares, Nick Thatcher, Raffael Kurek, Mark A. Socinski, Rebecca R. Hozak, Javad Shahidi, Victoria Soldatenkova, Marileila Varellagarcia, Fred R HirschAbstract:Background SQUIRE demonstrated addition of Necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.
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Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first line therapy in patients with stage iv squamous non small cell lung cancer squire an open label randomised controlled phase 3 trial
Lancet Oncology, 2015Co-Authors: Nick Thatcher, Alexander V Luft, Mircea Dediu, Reiner Ramlau, Rinat Galiulin, Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Fred R Hirsch, Gyorgy LosonczyAbstract:Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without Necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive Necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the Necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the Necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the Necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the Necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of Necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
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Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study.
Journal of Clinical Oncology, 2015Co-Authors: Martin Reck, Mark A. Socinski, Richard J. Gralla, Coleman K Obasaju, Javad Shahidi, Victoria Soldatenkova, Jacqueline Brown, Philip Bonomi, Patrick Peterson, Nick ThatcherAbstract:8099 Background: SQUIRE, a randomized, phase III study (N = 1093) demonstrated that the addition of Necitumumab (N) to gemcitabine-cisplatin (GC) improved OS in patients with stage IV squamous NSCLC. We further analyzed the results by baseline MSS and other cofactors that preliminary models suggested were prognostic for OS in this study. Methods: This post-hoc analysis defined the MSS for each patient as the worst (highest) score of any individual LCSS item at baseline. MSS was evaluated as a prognostic and predictive factor for OS and progression-free survival (PFS) using Cox and Kaplan-Meier methods. Cox models included baseline ECOG performance status, sum of target lesions, number of metastatic sites, body mass index, platelets, hemoglobin, and leukocytes. Results: As a continuous variable, MSS was prognostic for OS (p < 0.001) with a statistically significant interaction (p = 0.006) with treatment effect. These results manifested as subgroup differences shown in the table below. Results for PFS and O...
Mark A. Socinski - One of the best experts on this subject based on the ideXlab platform.
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A phase II study of nab-paclitaxel and carboplatin chemotherapy plus Necitumumab in the first-line treatment of patients with stage IV squamous non-small cell lung cancer.
Lung cancer (Amsterdam Netherlands), 2019Co-Authors: Liza C. Villaruz, Manuel Cobo, Konstantinos N. Syrigos, Dimitrios Mavroudis, Wei Zhang, Jong Seok Kim, Mark A. SocinskiAbstract:Abstract Objectives Necitumumab is a second-generation, recombinant, human IgG1-type monoclonal antibody directed against EGFR approved for adult patients with metastatic squamous non-small cell lung cancer (NSCLC) in combination with gemcitabine and cisplatin. This study assessed the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) and carboplatin in combination with Necitumumab as first-line therapy in patients with stage IV squamous NSCLC. Materials and methods The treatment regimen comprised triplet induction with Necitumumab (800 mg) with nab-paclitaxel (100 mg/m2) and carboplatin (AUC 6 mg*min/mL) for 4 cycles, followed by doublet maintenance with Necitumumab and nab-paclitaxel with a 3-weekly schedule until progressive disease or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR). Results Fifty-four patients were enrolled. Median age was 65 years (range, 47–80 years). The majority of the patients were male (n = 42 [77.8%]) with an ECOG PS of 1 (n = 42 [77.8%]). The ORR was 51% (n = 26/54), and the disease control rate was 78.4% (n = 40/54). Median overall survival (OS) was 15.5 months (95% confidence interval [CI]: 10.18–not calculable), and the OS rate at 12 months was 50.4% (95% CI: 29.0–68.4). Median progression-free survival was 5.6 months (95% CI: 4.24–7.69)]. The most frequently reported treatment-emergent adverse events were anemia (57.4%), fatigue (55.6%), neutrophil count decreased (55.6%), hypomagnesemia (44.4%), and rash (38.9%). Conclusion Necitumumab/nab-paclitaxel/carboplatin first-line therapy produced favorable efficacy outcomes with manageable toxicity in patients with stage IV squamous NSCLC. The safety profile was fairly comparable with previous Necitumumab combination studies in lung cancer.
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Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2017Co-Authors: Mark A. Socinski, Fred R Hirsch, Coleman K Obasaju, Ronald B. Natale, David R. Gandara, Philip Bonomi, Paul A. Bunn, Edward S. Kim, Corey J. Langer, Silvia NovelloAbstract:Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including Necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.
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EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2017Co-Authors: Carlo Genova, Nick Thatcher, Raffael Kurek, Mark A. Socinski, Luis Paz-ares, Rebecca R. Hozak, Javad Shahidi, Christopher J. Rivard, Marileila Varella GarciaAbstract:Abstract Introduction Necitumumab is a monoclonal antibody targeting EGFR. In the SQUIRE trial, the addition of Necitumumab to chemotherapy for squamous cell lung cancer significantly improved overall survival (OS) (hazard ratio [HR] = 0.84); in a post hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend toward improved OS (HR = 0.70) and progression-free survival (PFS) (HR = 0.71) with the addition of Necitumumab. We present the analysis of granular EGFR FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification, as both were included in the FISH-positive category. Methods Available specimens from SQUIRE underwent FISH analysis in a central laboratory, and each sample was evaluated by using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed. Results Samples were available for 557 of 1093 patients; 208 patients (37.3%) were FISH-positive, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of Necitumumab resulted in a statistically significant increase in PFS (6.08 versus 5.13 months [p = 0.044]) and nonstatistically significant increase in OS (12.6 versus 9.5 months [p = 0.133]); among patients with gene amplification, the addition of Necitumumab did not significantly improve PFS (7.4 versus 5.6 months; [p = 0.334]) but did improve OS (14.8 versus 7.6 months; [p = 0.033]). Conclusions EGFR copy number gain by FISH might have a role as a predictive biomarker for Necitumumab in squamous cell lung cancer. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker.
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efficacy and safety of Necitumumab continuation therapy in the phase iii squire study of patients with stage iv squamous non small cell lung cancer
Clinical Lung Cancer, 2017Co-Authors: Tudor Ciuleanu, Reiner Ramlau, Aleksandra Szczesna, Beatrix Balint, Mark A. Socinski, Olivier Molinier, Coleman K Obasaju, A Luft, Wojciech Szafranski, Henrik DepenbrockAbstract:Abstract Introduction In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent Necitumumab continuation therapy in patients with stage IV squamous non–small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. Patients and Methods Patients were randomized 1:1 for ≤ 6 cycles of gemcitabine and cisplatin either with or without Necitumumab. Patients who received Necitumumab continued receiving single-agent Necitumumab until progressive disease (Necitumumab continuation). Tissue collection was mandatory in SQUIRE. EGFR protein expression was assessed using immunohistochemistry in a central lab. In this subgroup analysis we compared patients treated with Necitumumab monotherapy after completion of ≥ 4 cycles of chemotherapy with those in the chemotherapy arm who were progression-free and did not discontinue because of adverse events (AEs) after completion of ≥ 4 cycles of chemotherapy (gemcitabine-cisplatin nonprogressors). The same analysis was done for the subgroup of EGFR-expressing patients (EGFR > 0). Results Baseline characteristics and chemotherapy exposure were well balanced between the Necitumumab continuation (n = 261) and gemcitabine-cisplatin nonprogressor (n = 215) arms and in the EGFR-expressing population. Median overall survival (OS) from randomization in the Necitumumab with gemcitabine-cisplatin versus gemcitabine-cisplatin nonprogressor arm was 15.9 versus 15.0 months (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.05) and median progression-free survival (PFS) from randomization was 7.4 versus 6.9 months (HR, 0.86; 95% CI, 0.70-1.06). OS and PFS benefits were similar when assessed from the postinduction period and in EGFR-expressing patients. No new safety findings emerged. Conclusion There was a consistent treatment effect in favor of Necitumumab continuation versus that in gemcitabine-cisplatin nonprogressors, with no unexpected increases in AEs in intention-to-treat as well as EGFR-expressing populations.
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Necitumumab plus Gemcitabine and Cisplatin as First-Line Therapy in Patients with Stage IV EGFR- Expressing Squamous Non-Small-Cell Lung Cancer: German Subgroup Data from an Open-Label, Randomized Controlled Phase 3 Study (SQUIRE).
Oncology research and treatment, 2016Co-Authors: Martin Reck, Mark A. Socinski, Henrik Depenbrock, Victoria Soldatenkova, Mike Thomas, Cornelia Kropf-sanchen, Joerg Mezger, Jacqueline Brown, Thomas Krause, Nick ThatcherAbstract:Background: In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody Necitumumab to first-line gemcitabine and cisplatin (GC + N
Aleksandra Szczesna - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Necitumumab continuation therapy in the phase iii squire study of patients with stage iv squamous non small cell lung cancer
Clinical Lung Cancer, 2017Co-Authors: Tudor Ciuleanu, Reiner Ramlau, Aleksandra Szczesna, Beatrix Balint, Mark A. Socinski, Olivier Molinier, Coleman K Obasaju, A Luft, Wojciech Szafranski, Henrik DepenbrockAbstract:Abstract Introduction In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent Necitumumab continuation therapy in patients with stage IV squamous non–small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. Patients and Methods Patients were randomized 1:1 for ≤ 6 cycles of gemcitabine and cisplatin either with or without Necitumumab. Patients who received Necitumumab continued receiving single-agent Necitumumab until progressive disease (Necitumumab continuation). Tissue collection was mandatory in SQUIRE. EGFR protein expression was assessed using immunohistochemistry in a central lab. In this subgroup analysis we compared patients treated with Necitumumab monotherapy after completion of ≥ 4 cycles of chemotherapy with those in the chemotherapy arm who were progression-free and did not discontinue because of adverse events (AEs) after completion of ≥ 4 cycles of chemotherapy (gemcitabine-cisplatin nonprogressors). The same analysis was done for the subgroup of EGFR-expressing patients (EGFR > 0). Results Baseline characteristics and chemotherapy exposure were well balanced between the Necitumumab continuation (n = 261) and gemcitabine-cisplatin nonprogressor (n = 215) arms and in the EGFR-expressing population. Median overall survival (OS) from randomization in the Necitumumab with gemcitabine-cisplatin versus gemcitabine-cisplatin nonprogressor arm was 15.9 versus 15.0 months (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.05) and median progression-free survival (PFS) from randomization was 7.4 versus 6.9 months (HR, 0.86; 95% CI, 0.70-1.06). OS and PFS benefits were similar when assessed from the postinduction period and in EGFR-expressing patients. No new safety findings emerged. Conclusion There was a consistent treatment effect in favor of Necitumumab continuation versus that in gemcitabine-cisplatin nonprogressors, with no unexpected increases in AEs in intention-to-treat as well as EGFR-expressing populations.
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The Effect of Necitumumab in Combination with Gemcitabine plus Cisplatin on Tolerability and on Quality of Life: Results from the Phase 3 SQUIRE Trial
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2016Co-Authors: Martin Reck, Mircea Dediu, Reiner Ramlau, Gyorgy Losonczy, Aleksandra Szczesna, Mark A. Socinski, Alexander Luft, Olivier Molinier, Christian Schumann, Richard J. GrallaAbstract:Abstract Introduction Necitumumab, a second-generation, recombinant human immunoglobulin G1 epidermal growth factor receptor antibody in the phase 3 SQUIRE trial (NCT00981058), increased survival benefit for patients randomized to receive Necitumumab plus gemcitabine-cisplatin compared with those who received gemcitabine-cisplatin. Here we characterize health-related quality of life (HRQoL) and tolerability results. Methods A total of 1093 patients with stage IV squamous non–small cell lung cancer were randomized 1:1 to receive Necitumumab (800 mg absolute dose intravenously [IV]) plus gemcitabine-cisplatin (gemcitabine = 1250 mg/m 2 IV on days 1 and 8; cisplatin = 75 mg/m 2 IV on day 1) or gemcitabine-cisplatin alone (every 21 days) for up to six cycles. Patients receiving Necitumumab plus gemcitabine-cisplatin without disease progression continued Necitumumab until progression. HRQoL was measured by Eastern Cooperative Oncology Group performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five-Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Hospitalization rates were collected. Results Most patients in both study arms similarly maintained Eastern Cooperative Oncology Group performance status and comparable LCSS and European Quality of Life Five-Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the Necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the Necitumumab plus gemcitabine-cisplatin arm continued on single-agent Necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the Necitumumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin arms, respectively. Hospitalizations were slightly higher with Necitumumab plus gemcitabine-cisplatin (36.4%) than with gemcitabine-cisplatin (34.0%). Conclusions The addition of Necitumumab to gemcitabine-cisplatin was well tolerated, did not negatively affect HRQoL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower HRQoL.
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Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first line therapy in patients with stage iv squamous non small cell lung cancer squire an open label randomised controlled phase 3 trial
Lancet Oncology, 2015Co-Authors: Nick Thatcher, Alexander V Luft, Mircea Dediu, Reiner Ramlau, Rinat Galiulin, Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Fred R Hirsch, Gyorgy LosonczyAbstract:Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without Necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive Necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the Necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the Necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the Necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the Necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of Necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
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safety and efficacy of Necitumumab continuation therapy subgroup analysis of phase 3 squire study
Journal of Clinical Oncology, 2015Co-Authors: Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Andrzej Kazarnowicz, Mark A. Socinski, Coleman K Obasaju, A Luft, Wojciech Szafranski, Rodryg Ramlau, Olivier MolinierAbstract:e19024 Background: The SQUIRE study demonstrated that the addition of Necitumumab (N) to gemcitabine-cisplatin (GC) improved survival in patients (pts) with stage IV sq-NSCLC. This retrospective analysis compares safety and efficacy outcomes for patients who received N single agent as continuation therapy after completion of chemotherapy treatment (CT) to the continuation therapy-eligible population of the GC arm. Methods: Pts were randomized 1:1 to GC (G = 1250 mg/m² iv, days 1 and 8; C = 75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8) (GC+N arm), or GC alone (GC arm) every 21 days up to 6 cycles. Pts in GC+N with no progression continued on N alone until progressive disease or intolerable toxicity. We present overall survival (OS), progression-free survival (PFS), and safety (TEAEs) for pts in the GC+N arm who were alive and progression free at the start of N alone and pts in GC arm who were alive and progression free at the completion of CT. This analysis included pts in both arms who received at ...
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Necitumumab plus pemetrexed and cisplatin as first line therapy in patients with stage iv non squamous non small cell lung cancer inspire an open label randomised controlled phase 3 study
Lancet Oncology, 2015Co-Authors: Luis Pazares, Gyorgy Losonczy, Tudor Ciuleanu, J Mezger, Jurgen R Fischer, Joachim Von Pawel, Mariano Provencio, Andrzej Kazarnowicz, Gilberto De Castro, Aleksandra SzczesnaAbstract:Summary Background Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare Necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). Methods We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with Necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. Findings Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either Necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the Necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84–1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the Necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the Necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the Necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the Necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 [15%] of 304 vs one [ vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. Interpretation Our findings show no evidence to suggest that the addition of Necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, Necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Funding Eli Lilly and Company.
Amelie Forest - One of the best experts on this subject based on the ideXlab platform.
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abstract 3632 combination of egfr antibody with pd 1 pathway inhibitors improves anti tumor efficacy and enhances intra tumor immune response in preclinical mouse tumor models
Cancer Research, 2018Co-Authors: Veena Kandaswamy, Amelie Forest, Thompson N Doman, David Surguladze, Marianne Deroose, David Schaer, Ting Chen, Shengwu Liu, Yungmae Yao, Gerald HallAbstract:Necitumumab (EGFR inhibitor) in combination with chemotherapy provides a modest, yet a significant improvement in overall survival over chemotherapy alone in patients with advanced squamous non-small cell lung carcinoma (NSCLC). However, combination therapies targeting EGFR and PD-1 pathway blockers may represent a better way to extend clinical benefit to more cancer patients given that PD-(L)1 antibodies have emerged as a standard of care in NSCLC. Antibodies targeting EGFR have the potential to promote an inflamed tumor microenvironment through engagement of Fc-gamma receptors (FcγR) on innate immune cells resulting in an improved antigen presentation and T cell priming. Therefore, the present study was initiated to understand the combinatorial effect of immune checkpoint (PD-(L)1) inhibitors with Necitumumab. Preclinical modeling of EGFR/PD-(L)1 mAb combination in mice is challenging due to the lack of cross-reactivity of Necitumumab with mouse EGFR. Syngeneic mouse tumor models widely used to study effects of immunomodulatory agents express low or no EGFR. To overcome this limitation, we used two immunocompetent model systems to study the combination effect of EGFR mAb with PD-1 (RMP1-14) or PD-L1 (178G7) mAbs: 1) genetically engineered mouse model of lung adenocarcinoma (TD model) driven by mutant forms of human EGFR (exon 19 deletion and T790M mutation) and 2) CT26 syngeneic mouse tumor model with ectopic expression of human EGFR (CT26-hEGFR). To engage mouse immune cells more efficiently, a murinized version of Necitumumab was generated through antibody engineering, with human EGFR binding Fabs and a mouse Fc backbone. Intratumor immune response was evaluated by immunohistochemistry and a custom-made immune profiling Quantigene Plex (QGP) gene expression panel. In both models, targeting EGFR and PD-1 pathway resulted in the combinatorial antitumor efficacy exemplified by decreased tumor burden compared to the monotherapy groups. QGP analysis of CT26-hEGFR tumor tissue revealed that the combination treatment enhanced intra-tumor immune response exemplified by an upregulation of immune-related genes indicative of T cell infiltration (Cd3e, Cd4, Cd8b1), T cell activation (Ifng, Cd274, Pdcd1lg2, Icos, Tnfrsf4, Tnfrsf18, Cd69, Ido1, Havcr2, Lag3), myeloid cell infiltration (Cd86, Timd4, Vista, Cd68, Mpo, Nos2). Histopathological analysis confirmed an increase in T cell infiltration indicating an improved immune response in the combination therapy group. Taken together, these results provide a rationale for further evaluation of EGFR and PD-(L)1 mAbs in clinical setting. Citation Format: Veena Kandaswamy, Amelie Forest, Marianne Deroose, David A. Schaer, Ting Chen, Shengwu Liu, David Surguladze, Yung-mae Yao, Thompson Doman, Gerald Hall, Kwok-Kin Wong, Michael Kalos, Ruslan D. Novosiadly. Combination of EGFR antibody with PD-1 pathway inhibitors improves anti-tumor efficacy and enhances intra-tumor immune response in preclinical mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3632.
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abstract a160 combination of Necitumumab with second or third generation egfr tyrosine kinase inhibitors downregulates dna repair mechanisms and induces durable tumor remissions in xenograft nsclc models with egfr mutations
Molecular Cancer Therapeutics, 2018Co-Authors: Amelie Forest, Erik R Rasmussen, Thompson N Doman, Michael Amatulli, Gerald Hall, Jason Manro, David Surguladze, Manisha Brahmachary, Rajiv Bassi, Yungmae M YaoAbstract:First- , second- , and third-generation EGFR tyrosine kinase inhibitors (TKIs) demonstrate profound tumor responses in EGFR mutation-positive NSCLC. Nevertheless, most patients invariably develop acquired resistance. The objective of the present study was to evaluate the effects of dual EGFR blockade using a ligand-blocking antibody (Necitumumab) and second- or third-generation TKIs (afatinib or osimertinib) in preclinical NSCLC models with EGFR mutations. Afatinib and osimertinib (AZD9291), second- and third-generation EGFR TKIs, respectively, are irreversible covalent inhibitors of the EGFR tyrosine kinase, with the latter specifically targeting a mutant form of the receptor (EGFR-T790M). We sought to investigate whether combination of Necitumumab (LY3012211) with afatinib and osimertinib would provide any benefit over the monotherapies in preclinical mouse models of lung cancer. Using PC-9 and NCI-H1975 xenograft models of NSCLC that harbor EGFR mutations, we observed that dual EGFR blockade of ligand binding and receptor tyrosine kinase activity improved the antitumor efficacy and, more importantly, resulted in durable tumor remissions compared to either single-agent therapy. Additionally, we explored two dosing schedules of Necitumumab/osimertinib combination treatment (concurrent versus phased). Concurrent administration of both agents for four weeks was significantly more efficacious compared to the phased schedule (e.g., administration of osimertinib for one week followed by Necitumumab and osimertinib combination for additional three weeks). To provide mechanistic insights into the combinatorial activity observed, we employed high-content gene expression analysis using nCounter Pan-Cancer Pathways assay. Pathway analysis of the combination and single-agent treatment groups identified multiple shared and treatment-specific pathway alterations. Genes implicated in FGFR, PI3K pathways and extracellular remodeling appeared to be upregulated by combination and monotherapies and suggested potential common mechanisms of acquired resistance to EGFR inhibitors, whereas compromised DNA repair mechanisms were identified in PC-9 and NCI-H1975 tumors upon treatment with both combinations. In conclusion, these data demonstrate that combination of Necitumumab with second- or third-generation EGFR TKIs results in an improved antitumor efficacy compared to the respective monotherapies; a more profound inhibition of EGFR pathway and compromised DNA repair mechanisms may underlie this effect. A phase I clinical trial of Necitumumab and osimertinib in EGFR mutation-positive stage IV or recurrent NSCLC who have progressed on a previous EGFR TKI is currently ongoing (NCT02496663). Citation Format: Amelie Forest, Erik R. Rasmussen, Thompson N. Doman, Michael Amatulli, Rajiv Bassi, Gerald E. Hall, Jason R. Manro, Manisha Brahmachary, David Surguladze, Yung-mae M. Yao, Michael D. Kalos, Ruslan D. Novosiadly. Combination of Necitumumab with second- or third-generation EGFR tyrosine kinase inhibitors downregulates DNA repair mechanisms and induces durable tumor remissions in xenograft NSCLC models with EGFR mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A160.
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abstract a160 combination of Necitumumab with second or third generation egfr tyrosine kinase inhibitors downregulates dna repair mechanisms and induces durable tumor remissions in xenograft nsclc models with egfr mutations
Molecular Cancer Therapeutics, 2018Co-Authors: Amelie Forest, Erik R Rasmussen, Thompson N Doman, Michael Amatulli, Gerald Hall, Jason Manro, David Surguladze, Manisha Brahmachary, Rajiv Bassi, Yungmae M YaoAbstract:First- , second- , and third-generation EGFR tyrosine kinase inhibitors (TKIs) demonstrate profound tumor responses in EGFR mutation-positive NSCLC. Nevertheless, most patients invariably develop acquired resistance. The objective of the present study was to evaluate the effects of dual EGFR blockade using a ligand-blocking antibody (Necitumumab) and second- or third-generation TKIs (afatinib or osimertinib) in preclinical NSCLC models with EGFR mutations. Afatinib and osimertinib (AZD9291), second- and third-generation EGFR TKIs, respectively, are irreversible covalent inhibitors of the EGFR tyrosine kinase, with the latter specifically targeting a mutant form of the receptor (EGFR-T790M). We sought to investigate whether combination of Necitumumab (LY3012211) with afatinib and osimertinib would provide any benefit over the monotherapies in preclinical mouse models of lung cancer. Using PC-9 and NCI-H1975 xenograft models of NSCLC that harbor EGFR mutations, we observed that dual EGFR blockade of ligand binding and receptor tyrosine kinase activity improved the antitumor efficacy and, more importantly, resulted in durable tumor remissions compared to either single-agent therapy. Additionally, we explored two dosing schedules of Necitumumab/osimertinib combination treatment (concurrent versus phased). Concurrent administration of both agents for four weeks was significantly more efficacious compared to the phased schedule (e.g., administration of osimertinib for one week followed by Necitumumab and osimertinib combination for additional three weeks). To provide mechanistic insights into the combinatorial activity observed, we employed high-content gene expression analysis using nCounter Pan-Cancer Pathways assay. Pathway analysis of the combination and single-agent treatment groups identified multiple shared and treatment-specific pathway alterations. Genes implicated in FGFR, PI3K pathways and extracellular remodeling appeared to be upregulated by combination and monotherapies and suggested potential common mechanisms of acquired resistance to EGFR inhibitors, whereas compromised DNA repair mechanisms were identified in PC-9 and NCI-H1975 tumors upon treatment with both combinations. In conclusion, these data demonstrate that combination of Necitumumab with second- or third-generation EGFR TKIs results in an improved antitumor efficacy compared to the respective monotherapies; a more profound inhibition of EGFR pathway and compromised DNA repair mechanisms may underlie this effect. A phase I clinical trial of Necitumumab and osimertinib in EGFR mutation-positive stage IV or recurrent NSCLC who have progressed on a previous EGFR TKI is currently ongoing (NCT02496663). Citation Format: Amelie Forest, Erik R. Rasmussen, Thompson N. Doman, Michael Amatulli, Rajiv Bassi, Gerald E. Hall, Jason R. Manro, Manisha Brahmachary, David Surguladze, Yung-mae M. Yao, Michael D. Kalos, Ruslan D. Novosiadly. Combination of Necitumumab with second- or third-generation EGFR tyrosine kinase inhibitors downregulates DNA repair mechanisms and induces durable tumor remissions in xenograft NSCLC models with EGFR mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A160.
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Molecular basis for Necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance.
Molecular cancer therapeutics, 2017Co-Authors: Atrish Bagchi, Amelie Forest, Jaafar N. Haidar, Scott W. Eastman, Michal Vieth, Michael Topper, Michelle D. Iacolina, Jason M. Walker, Yang Shen, Ruslan D. NovosiadlyAbstract:Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that Necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 A resolution of the Necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the Necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that Necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether Necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that Necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. Mol Cancer Ther; 17(2); 521-31. ©2017 AACR.
Tudor Ciuleanu - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Necitumumab continuation therapy in the phase iii squire study of patients with stage iv squamous non small cell lung cancer
Clinical Lung Cancer, 2017Co-Authors: Tudor Ciuleanu, Reiner Ramlau, Aleksandra Szczesna, Beatrix Balint, Mark A. Socinski, Olivier Molinier, Coleman K Obasaju, A Luft, Wojciech Szafranski, Henrik DepenbrockAbstract:Abstract Introduction In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent Necitumumab continuation therapy in patients with stage IV squamous non–small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. Patients and Methods Patients were randomized 1:1 for ≤ 6 cycles of gemcitabine and cisplatin either with or without Necitumumab. Patients who received Necitumumab continued receiving single-agent Necitumumab until progressive disease (Necitumumab continuation). Tissue collection was mandatory in SQUIRE. EGFR protein expression was assessed using immunohistochemistry in a central lab. In this subgroup analysis we compared patients treated with Necitumumab monotherapy after completion of ≥ 4 cycles of chemotherapy with those in the chemotherapy arm who were progression-free and did not discontinue because of adverse events (AEs) after completion of ≥ 4 cycles of chemotherapy (gemcitabine-cisplatin nonprogressors). The same analysis was done for the subgroup of EGFR-expressing patients (EGFR > 0). Results Baseline characteristics and chemotherapy exposure were well balanced between the Necitumumab continuation (n = 261) and gemcitabine-cisplatin nonprogressor (n = 215) arms and in the EGFR-expressing population. Median overall survival (OS) from randomization in the Necitumumab with gemcitabine-cisplatin versus gemcitabine-cisplatin nonprogressor arm was 15.9 versus 15.0 months (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.05) and median progression-free survival (PFS) from randomization was 7.4 versus 6.9 months (HR, 0.86; 95% CI, 0.70-1.06). OS and PFS benefits were similar when assessed from the postinduction period and in EGFR-expressing patients. No new safety findings emerged. Conclusion There was a consistent treatment effect in favor of Necitumumab continuation versus that in gemcitabine-cisplatin nonprogressors, with no unexpected increases in AEs in intention-to-treat as well as EGFR-expressing populations.
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Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first line therapy in patients with stage iv squamous non small cell lung cancer squire an open label randomised controlled phase 3 trial
Lancet Oncology, 2015Co-Authors: Nick Thatcher, Alexander V Luft, Mircea Dediu, Reiner Ramlau, Rinat Galiulin, Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Fred R Hirsch, Gyorgy LosonczyAbstract:Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without Necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive Necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the Necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the Necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the Necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the Necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of Necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
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safety and efficacy of Necitumumab continuation therapy subgroup analysis of phase 3 squire study
Journal of Clinical Oncology, 2015Co-Authors: Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Andrzej Kazarnowicz, Mark A. Socinski, Coleman K Obasaju, A Luft, Wojciech Szafranski, Rodryg Ramlau, Olivier MolinierAbstract:e19024 Background: The SQUIRE study demonstrated that the addition of Necitumumab (N) to gemcitabine-cisplatin (GC) improved survival in patients (pts) with stage IV sq-NSCLC. This retrospective analysis compares safety and efficacy outcomes for patients who received N single agent as continuation therapy after completion of chemotherapy treatment (CT) to the continuation therapy-eligible population of the GC arm. Methods: Pts were randomized 1:1 to GC (G = 1250 mg/m² iv, days 1 and 8; C = 75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8) (GC+N arm), or GC alone (GC arm) every 21 days up to 6 cycles. Pts in GC+N with no progression continued on N alone until progressive disease or intolerable toxicity. We present overall survival (OS), progression-free survival (PFS), and safety (TEAEs) for pts in the GC+N arm who were alive and progression free at the start of N alone and pts in GC arm who were alive and progression free at the completion of CT. This analysis included pts in both arms who received at ...
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Necitumumab plus pemetrexed and cisplatin as first line therapy in patients with stage iv non squamous non small cell lung cancer inspire an open label randomised controlled phase 3 study
Lancet Oncology, 2015Co-Authors: Luis Pazares, Gyorgy Losonczy, Tudor Ciuleanu, J Mezger, Jurgen R Fischer, Joachim Von Pawel, Mariano Provencio, Andrzej Kazarnowicz, Gilberto De Castro, Aleksandra SzczesnaAbstract:Summary Background Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare Necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). Methods We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with Necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. Findings Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either Necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the Necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84–1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the Necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the Necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the Necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the Necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 [15%] of 304 vs one [ vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. Interpretation Our findings show no evidence to suggest that the addition of Necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, Necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Funding Eli Lilly and Company.
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A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus Necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (s
Journal of Clinical Oncology, 2014Co-Authors: Nick Thatcher, Mircea Dediu, Rinat Galiulin, Tudor Ciuleanu, Aleksandra Szczesna, Beatrix Balint, Fred R Hirsch, Wojciech Szafranski, Rodryg Ramlau, Gyorgy LosonczyAbstract:8008^ Background: Necitumumab (N), a human IgG1 anti-EGFR monoclonal antibody, inhibits ligand-binding and receptor activation. EGFR is detectable in the vast majority of advanced sq-NSCLC tumors. ...
