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

Paz‐Ares, Luis; Mezger, J.; Ciuleanu, Tudor; Fischer, Jürgen R.; Pawel, Joachim von; Provencio, Mariano; Każarnowicz, Andrzej; Losonczy, György; Castro, Gilberto de; Szczęsna, Aleksandra; Crinò, Lucio; Reck, Martin; Ramlau, Rodryg; Ulsperger, Ernst; Schümann, Christian; Miziara, Juliana Muniz; Lessa, Álvaro Edson Ramos; Dediu, Mircea; Bálint, Beatrix; Depenbrock, H.; Soldatenkova, Victoria; Kurek, Raffael; Hirsch, Fred R.; Thatcher, Nick; Socinski, Mark A.

doi:10.1016/s1470-2045(15)70046-x

Cited by 123 publications

(95 citation statements)

References 34 publications

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“…Covariate analysis did not indicate any patient factors such as gender, age, race, disease status, renal function, hepatic status, or baseline tumor load, while weight had a small contribution, all in concordance with previous findings of IgG‐type mAbs in oncology 8, 10. The interindividual variability in distribution and elimination was relatively high, leading to a wide distribution of steady‐state serum levels observed in the phase III trials 11, 12…”

supporting

confidence: 86%

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Cosson

Wallin³

2017

CPT Pharmacometrics Syst. Pharmacol.

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We sought to describe the exposure–response relationship of necitumumab efficacy in squamous non‐small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first‐order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.

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supporting

confidence: 86%

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Cosson

Wallin³

2017

CPT Pharmacometrics Syst. Pharmacol.

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“…Meta-analyses regarding the use of TKIs in a population with mixed EGFR-activating mutations have only reported PFS and relative risk (RR) benefits, and no OS benefit (13)(14)(15). Previous studies have demonstrated the benefits of afatinib on patient OS using pooled data from the LUX-lung 3 and 6 clinical trials (11,12,18). Afatinib is hypothetically more effective at inhibiting EGFR signaling than reversible TKIs, due it forming stable covalent bonds and irreversibly inhibiting ATP from binding to the tyrosine kinase domain of EGFR (19); however, no randomized clinical trial or meta-analysis has demonstrated that afatinib is superior to erlotinib or gefitinib regarding OS.…”

Section: Discussionmentioning

confidence: 99%

“…EGFR is overexpressed in >60% of NSCLC cases (9). In combination with monoclonal antibodies against EGFR, including cetuximab and necitumumab, first-line chemotherapy has resulted in improved survival rates in patients with advanced-stage disease (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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Abstract. Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

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“…Two randomized controlled trials, iNspiRE and sQUiRE, indicated that necitumumab with gemcitabine and cisplatin as a first-line therapy improved os in treatment-naïve patients with advanced sqNscLc (11.5 vs. 9.9 months; p=0.01) but not in non-sqNscLc treated with necitumumab with pemetrexed and cisplatin (49,50). combination therapy of necitumumab and pembrolizumab is currently being studied for safety and efficacy in patients with advanced sqNscLc and non-sqNscLc in a phase i study (51).…”

Section: Combination With Targeted Therapymentioning

confidence: 99%

Immune-based Therapies for Non-small Cell Lung Cancer

Rafei

El-Bahesh

Finianos³

et al. 2017

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Lung cancer is the leading cause of cancer-related death in males, and the second leading cause of death in females worldwide (1). Non-small cell lung cancer (NscLc) accounts for 85% to 90% of all lung cancer. There are different subtypes of NscLc that are grouped together because, until recently, the approach to treatment as well as prognosis was often similar. These subtypes are squamous cell carcinoma (sqNscLc), adenocarcinoma, large cell carcinoma and more poorly differentiated variants (2). squamous cell carcinoma constitutes about 25-30% of all lung cancer. it originates from the bronchial lining, and is often linked to a history of smoking. Adenocarcinoma represents around 40% of lung cancer. it emerges from mucus-secreting cells. While this type of cancer occurs mainly in current and former smokers, it is the most common type of lung cancer occurring in non-smokers. Large-cell carcinoma accounts for about 10% to 15% of lung cancer and tends to grow and spread quickly (1).Treatment options for NscLc have evolved tremendously over the past 15 years, especially with the advent of genetic and molecular techniques to characterize the driver mutations at the cellular level. overall survival (os) rates from lung cancer have been increasing slowly over the past decade for both men and women. This is mainly due to reduction in smoking over the past 50 years, although the decline in the rates of lung cancer in men started significantly before that in women (3). several treatment modalities are being used including surgery, radiation therapy, chemotherapy, targeted therapy, laser therapy, photodynamic therapy, radiofrequency ablation, cryosurgery, electrocautery, and watchful waiting. New modalities are being tested in clinical trials and they include immunotherapy, combination therapies and chemoprevention (4). To date, there are no studies that evaluate the best sequence of available therapies, and as such, the choice of therapy is highly personalized and likely depends on the setting in which available drugs were investigated, stage of disease, cytogenetic or molecular profile, performance status, toxicities, and medical comorbidities.For a long time, lung cancer has been considered to be non-immunogenic. However, after the success of immunotherapies in melanoma (5), there has been great interest and investigation in the immune checkpoint inhibitors in NscLc. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination 377Τhis article is freely accessible online.Correspondence to: imad Tabbara, MD,

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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

Cited by 123 publications

References 34 publications

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Immune-based Therapies for Non-small Cell Lung Cancer

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