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Afatinib vs erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung.

ABSTRACT: Background:The global Phase III LUX-Lung 8 trial (ClinicalTrials.gov: NCT01523587) identified significant improvements in progression-free survival (PFS), overall survival (OS), and patient-reported outcomes (PROs) with second-line afatinib vs erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung. Materials and methods:We conducted a post hoc analysis of data for patients in LUX-Lung 8 from mainland China (n=67). Compared with erlotinib, afatinib reduced the risk of disease progression or death (PFS) in the Chinese subgroup by 30% (HR=0.70; 95% CI: 0.38-1.27). Results:The risk of death was reduced by 31% (HR=0.69; 95% CI: 0.39-1.21). The proportion of Chinese patients with improvements in PROs also favored afatinib vs erlotinib (global health status/quality of life [QoL], 52.8% vs 29.6%, P=0.072; dyspnea, 47% vs 26%, P=0.091; "dyspnea walked", 44% vs 15%, P=0.017; QoL rate, 53% vs 26%, P=0.037). Discussion:While this analysis was not powered to demonstrate differences compared to the overall trial population (OTP), and there were some differences in baseline characteristics (eg, the proportion of patients aged ?65 years old), the benefits of afatinib treatment in Chinese patients with SCC of the lung appeared to be at least comparable to that observed in LUX-Lung 8. As with the OTP, the most common adverse events (AEs) with afatinib in the Chinese subgroup were diarrhea and rash/acne, and the incidence and type of the most frequently occurring AEs were similar. Conclusion:The results suggest that afatinib represents a feasible treatment option for Chinese patients with advanced SCC of the lung following progression on platinum-based chemotherapy.

SUBMITTER: Lu S

PROVIDER: S-EPMC6292388 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Afatinib vs erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung.

Lu Shun S Li Wei W Zhou Caicun C Hu Cheng-Ping CP Qin Shukui S Cheng Gang G Feng Jifeng J Wang Jie J Cseh Agnieszka A Peil Barbara B Gibson Neil N Ehrnrooth Eva E Zhang Li L

OncoTargets and therapy 20181130

<h4>Background</h4>The global Phase III LUX-Lung 8 trial (ClinicalTrials.gov: NCT01523587) identified significant improvements in progression-free survival (PFS), overall survival (OS), and patient-reported outcomes (PROs) with second-line afatinib vs erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung.<h4>Materials and methods</h4>We conducted a post hoc analysis of data for patients in LUX-Lung 8 from mainland China (n=67). Compared with erlotinib, afatinib reduced th ...[more]

PMID: 30573970

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Project description:BackgroundLUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months' treatment).MethodsLUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted.Findings795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73-0·97; p = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, ERBB family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%).InterpretationAfatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with ERBB family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated.

Project description:BackgroundThe level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) versus ASC alone in aESCC.MethodsWe conducted a tri-center retrospective cohort study (n = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC (n = 92, 55%) versus ASC alone (n = 74, 45%).ResultsThe most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35-0.69, p < 0.0001]. However, patients in the second-line + ASC group were characterized by more favorable baseline features including a better Eastern Cooperative Oncology Group (ECOG) performance status, a longer first-line treatment duration and lower C-reactive protein levels. After rigorous adjusting for baseline confounders by re-weighting the data with the IPTW the favorable association between second-line and longer OS weakened but prevailed. The median OS was 6.1 months in the second-line + ASC group and 3.2 months in the ASC group, respectively (IPTW-adjusted HR = 0.40, 95% CI: 0.24-0.69, p = 0.001). Importantly, the benefit of second-line was consistent across several clinical subgroups, including patients with ECOG performance status ⩾1 and age ⩾65 years. The most common grade 3 or 4 adverse events associated with palliative second-line therapy were hematological toxicities.ConclusionThis real-world study supports the concept that systemic second-line therapy prolongs survival in patients with aESCC.

Project description:BACKGROUND:Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS:In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4? isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS:The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS:Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).

Project description:Importance:Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers. Objective:To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens. Design, Setting, and Participants:Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017. Interventions:Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397). Main Outcomes and Measures:Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression. Results:Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome. Conclusions and Relevance:Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation. Trial Registration:ClinicalTrials.gov Identifier: NCT01523587.

Dataset Information

Afatinib vs erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung.

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Afatinib vs erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung.

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