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Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.

ABSTRACT: Axitinib is an orally active and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. This phase II study assessed the efficacy and safety of axitinib combined with cisplatin/gemcitabine in chemotherapy-naïve patients with advanced/metastatic (stage IIIB/IV) squamous non-small-cell lung cancer (NSCLC).Axitinib (starting dose 5 mg twice daily [bid]; titrated up or down to 2-10 mg bid) was administered orally on a continuous schedule with cisplatin (80 mg/m(2) intravenously [i.v.] every 3 weeks) and gemcitabine (1,250 mg/m(2) i.v. on days 1 and 8 of each 3-week cycle), and was continued as monotherapy after completion of six cycles (maximum) of chemotherapy. The primary study endpoint was objective response rate, as defined by Response Evaluation Criteria in Solid Tumours.Of the 38 patients treated, one (2.6%) patient achieved a complete response and 14 (36.8%) patients had a partial response; nine (23.7%) patients showed stable disease and three (7.9%) patients had disease progression. Median progression-free survival was 6.2 months, and median overall survival was 14.2 months. The estimated probability of survival at 12 months and 24 months was 63.2% and 30.8%, respectively. The most frequent grade ?3 toxicities were neutropaenia and hypertension (13.2% each). Three (7.9%) patients experienced haemoptysis, of which one case (2.6%) was fatal.Treatment with the combination of axitinib and cisplatin/gemcitabine demonstrated anti-tumour activity in patients with advanced/metastatic squamous NSCLC and the fatal haemoptysis rate was low. However, without a reference arm (cisplatin/gemcitabine alone), it is not conclusive whether the combination is better than chemotherapy alone. This study was registered at ClinicalTrials.gov, registration # NCT00735904, on August 13, 2008.

SUBMITTER: Bondarenko IM

PROVIDER: S-EPMC4424571 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.

Bondarenko Igor M IM Ingrosso Antonella A Bycott Paul P Kim Sinil S Cebotaru Cristina L CL

BMC cancer 20150501

<h4>Background</h4>Axitinib is an orally active and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. This phase II study assessed the efficacy and safety of axitinib combined with cisplatin/gemcitabine in chemotherapy-naïve patients with advanced/metastatic (stage IIIB/IV) squamous non-small-cell lung cancer (NSCLC).<h4>Methods</h4>Axitinib (starting dose 5 mg twice daily [bid]; titrated up or down to 2-10 mg bid) was administered orally on a continuou ...[more]

PMID: 25929582

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Project description:We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004-2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers.

Project description:PurposeNivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC).Patients and methodsPatients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression.ResultsNo dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression.ConclusionThe safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

Project description:BackgroundAtezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes.MethodsThis phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m2) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%.ResultsThe HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 vs. 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively.ConclusionsCisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted.Trial registrationUniversity hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).

Project description:ImportanceThis study demonstrates that tislelizumab in combination with chemotherapy is associated with improved progression-free survival (PFS) in patients with advanced squamous non-small-cell lung cancer (sq-NSCLC).ObjectiveTo assess the efficacy and safety/tolerability of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for patients with advanced sq-NSCLC.Design, setting, and participantsThis open-label, randomized phase 3 clinical trial was conducted at 46 sites in China between July 2018 and June 2019 and included patients with treatment-naive, histologically confirmed stage IIIB/IV sq-NSCLC. The data cutoff for these analyses was December 6, 2019; data extraction occurred on January 7, 2020.InterventionsPatients were randomized (1:1:1) to receive 1 of the following regimens intravenously on a 21-day cycle: tislelizumab (200 mg, day 1) plus paclitaxel (175 mg/m2, day 1) and carboplatin (area under the concentration of 5, day 1) (arm A); tislelizumab plus nab-paclitaxel (100 mg/m2, days 1, 8, and 15) and carboplatin (arm B); and paclitaxel and carboplatin (arm C). Patients were stratified by disease stage and tumor programmed cell death 1 ligand 1 (PD-L1) expression (<1% vs 1%-49% vs ≥50%).Main outcomes and measuresThe primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary end points included overall survival, investigator-assessed (INV) PFS, IRC-assessed objective response rate (ORR), and IRC-assessed duration of response, as well as the incidence and severity of adverse events (AEs).ResultsOverall, 355 patients (median [range] age, 62 [34-74] years; 330 men [91.7%]) with sq-NSCLC received treatment. After a median study follow-up of 8.6 months (95% CI, 8.1-9.0 months), IRC-assessed PFS was significantly improved with tislelizumab plus chemotherapy (arm A, 7.6 months; arm B, 7.6 months) vs chemotherapy alone (arm C, 5.5 months; hazard ratios were 0.524 (95% CI, 0.370-0.742; P < .001 [A vs C]) and 0.478 (95% CI, 0.336-0.679; P < .001 [B vs C]). Higher IRC-assessed ORR and longer IRC-assessed duration of response were observed in arms A (72.5%; 8.2 months) and B (74.8%; 8.6 months) vs C (49.6%; 4.2 months). No association was observed between PD-L1 expression and IRC-assessed PFS or ORR. Discontinuation of any treatment because of AEs was reported in 15 (12.5%; arm A), 35 (29.7%; arm B), and 18 (15.4%; arm C) patients. In each arm, the most common grade of 3 or greater AE was decreased neutrophil levels, which aligned with known chemotherapy toxic effects. Six treatment-related AEs leading to death occurred; however, no deaths were solely attributed to tislelizumab.Conclusions and relevanceIn this phase 3 randomized clinical trial, adding tislelizumab to chemotherapy was associated with significantly prolonged IRC-assessed PFS, higher IRC-assessed ORRs, and a manageable safety/tolerability profile in patients with advanced sq-NSCLC, regardless of PD-L1 expression.Trial registrationClinicalTrials.gov Identifier: NCT03594747.

Project description:Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting.Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0-1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m(2) every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients' quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011.This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design requires unusual methodology and specific logistics to address outcomes relevant to the home-delivery approach. This article presents a study design that offers a novel and reproducible model for home-based chemotherapy, and provides an up-to-date overview of the literature regarding this type of treatment.ClinicalTrials.gov: NCT01473563.

Dataset Information

Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.

Publications

Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer.

Similar Datasets

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