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Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer: Experiences in ALTER-0303.

ABSTRACT: BACKGROUND:Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial. METHODS:Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and managed by investigators. Key strategies for preventing and managing the most common adverse events included patient education, supportive care, and dose modification. RESULTS:Between February 2015 and August 2016, 294 patients received anlotinib. A total of 170 (57.8%) patients received antihypertensive medications for hypertension, 53 (18.0%) patients received levothyroxine for hypothyroidism, 24 (8.2%) patients received fibrates for hypertriglyceridemia, 11 (3.7%) patients took cortisone cream for hand-foot syndrome, and 38 (12.9%) patients received anti-diarrheal medications for diarrhea. Dose reduction and drug discontinuation were required in 24 (8.16%) and 31 (10.54%) patients in the anlotinib group, respectively. CONCLUSION:Anlotinb-related adverse events could be controlled by patient education, prophylactic measures, early and active intervention, and dose modification.

SUBMITTER: Si X

PROVIDER: S-EPMC6397894 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer: Experiences in ALTER-0303.

Si Xiaoyan X Zhang Li L Wang Hanping H Zhang Xiaotong X Wang Mengzhao M Han Baohui B Li Kai K Wang Qiming Q Shi Jianhua J Wang Zhehai Z Cheng Ying Y Shi Yuankai Y Chen Weiqiang W Wang Xiuwen X Luo Yi Y Nan Kejun K Jin Faguang F

Thoracic cancer 20190121 3

<h4>Background</h4>Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth ...[more]

PMID: 30666799

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Project description:ImportanceAnlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC).ObjectiveTo investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment.Design, setting, and participantsThe ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle.Main outcomes and measuresThe primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety.ResultsIn total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia.Conclusions and relevanceAmong the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC.Trial registrationClinicalTrials.gov identifier: NCT02388919.

Project description:Adverse events (AEs) related to medical treatments in non-small cell lung cancer (NSCLC) are frequent and need an appropriate costing in health economic models. Nevertheless, data on costs associated with AEs in NSCLC are scarce, particularly since the development of immunotherapy with specific immune-related AEs.To estimate the costs of grades 3 and 4 AEs related to NSCLC treatments including immunotherapy in France.Grades 3 and 4 AEs related to treatment and reported in at least 1% of patients in Phase III clinical trials for erlotinib, ramucirumab plus docetaxel, docetaxel, pemetrexed plus carboplatin plus bevacizumab, platinum-based chemotherapies, nivolumab and pembrolizumab were identified. When no cost evaluation was reported in literature, estimates on standard treatments and medical resource use for each AE were obtained thanks to an expert panel. Total cost per AE was calculated from a French national health insurance perspective and updated in 2017 Euros. Hospital stay costs were estimated based on public and private weighted tariffs and data from the French Medical Information System (Programme de Médicalisation des Systèmes d'Information). Costs of tests, consultations and treatments were calculated based on national reimbursement tariffs.Overall, costs of grades 3 and 4 AEs related to treatment ranged from €46 per event to €7,742 per year. Fourteen out of 24 AEs identified had a mean estimated cost over €2,000. The highest mean costs were related to type 1 diabetes (€7,742 per year) followed by pneumonitis (€5,786 per event), anemia (€5,752 per event), dehydration (€5,207 per event) and anorexia (€4,349 per event). Costs were mostly driven by hospitalization costs.Among the AEs identified, a majority appeared to have an important economic impact, with a management cost of at least €2,000 per event mainly driven by hospitalization costs. This study may be of interest for economic evaluations of new interventions in NSCLC.

Project description:IntroductionPD-(L)1 inhibitors have improved prognosis of non-small-cell lung cancer (NSCLC), but can also cause immune-related adverse events (irAEs) that complicate management.MethodsWe analyzed NSCLC patients receiving PD-(L)1 inhibitors from 2012 to 2020 in a German academic center.ResultsIrAE showed comparable frequencies in stage IV (198/894 or 22%) vs. III (14/45 or 31%, p = 0.15), after anti-PD-(L)1 monotherapy vs. chemoimmunotherapy (139/483 vs. 58/213, p = 0.75), and across treatment lines. In stage IV, irAE occurred after 3.1 months in median, affected multiple organs (median 2) in 27/894 patients and were associated with PD-L1 positivity (25 vs. 14%, p = 0.003), lower neutrophil-to-lymphocyte ratios (29 vs. 17%, p < 0.001 for NLR dichotomized at 5), better ECOG status (26 vs. 18% for 0 vs. 1, p = 0.004), but not related to age, sex, smoking and palliative radiotherapy. Two hundred thirty two irAEs occurred mostly in endocrine glands (4.9%), lungs (4.4%), the musculoskeletal system (4.2%), colon (4.1%), liver (3.7%), and skin (2.6%), while pneumonitis was most frequent with durvalumab following definitive chemoradiation (16% or 7/45, p < 0.01). IrAE severity was grade 1 in 11%, 2 in 41%, 3 in 36%, and 4 in 11% events, while two were lethal (<1%, myocarditis and pneumonitis). Therapy was suspended in 72%, while steroids were initiated in 66% and complemented by other immunosuppressants in 6%, with longest treatment duration for rheumatic events (mean >3 months), and average cumulative prednisone doses >700 mg for all organs, except for skin. Patients developing irAE had longer progression-free (PFS) and overall survival (OS) in multivariable 12/14-week landmark analyses including ECOG status, treatment line, treatment type, PD-L1 TPS, and NLR (median PFS 17 vs. 10 months, HR = 0.68, p = 0.009; median OS 37 vs. 15 months, HR = 0.40, p < 0.001), regardless of grade. OS was longest with skin (95% at 2 years) and shortest with pneumonitis, hepatitis, neurologic, and cardiologic irAE (38, 37, 28, and 0% at 2 years, p < 0.001).ConclusionsApproximately one-fourth of immunotherapy-treated NSCLC patients develop irAEs, most of which necessitate treatment suspension and steroids. Despite more frequent occurrence with PD-L1 positive tumors, lower NLR, and better ECOG PS, irAEs are independently associated with longer survival, especially when affecting the skin. Lethality is below 1%.

Dataset Information

Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer: Experiences in ALTER-0303.

Publications

Management of anlotinib-related adverse events in patients with advanced non-small cell lung cancer: Experiences in ALTER-0303.

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