Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial

Afatinib; Segunda linea; Carcinoma de pulmón de células escamosasAfatinib; Segona línia; Carcinoma de pulmó de cèl·lules escamosesAfatinib; Second-line; Squamous cell lung carcinomaBackground LUX-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). Methods LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 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. Findings 795 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%). Interpretation Afatinib 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.Boehringer Ingelheim

P.025 Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in participants with late-onset Pompe disease (LOPD)

Background: Phase 3 COMET trial (NCT02782741) compares avalglucosidase alfa (n=51) with alglucosidase alfa (n=49) in treatment-naïve LOPD. Methods: Primary objective: determine avalglucosidase alfa effect on respiratory muscle function. Secondary/other objectives include: avalglucosidase alfa effect on functional endurance, inspiratory/expiratory muscle strength, lower/upper extremity muscle strength, motor function, health-related quality of life, safety. Results: At Week 49, change (LSmean±SE) from baseline in upright forced vital capacity %predicted was greater with avalglucosidase alfa (2.89%±0.88%) versus alglucosidase alfa (0.46%±0.93%)(absolute difference+2.43%). The primary objective, achieving statistical non-inferiority (p=0.0074), was met. Superiority testing was borderline significant (p=0.0626). Week 49 change from baseline in 6-minute walk test was 30.01-meters greater for avalglucosidase alfa (32.21±9.93m) versus alglucosidase alfa (2.19±10.40m). Positive results for avalglucosidase alfa were seen for all secondary/other efficacy endpoints. Treatment-emergent adverse events (AEs) occurred in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five participants withdrew, 4 for AEs, all on alglucosidase alfa. Serious AEs occurred in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants. IgG antidrug antibody responses were similar in both. High titers and neutralizing antibodies were more common for alglucosidase alfa. Conclusions: Results demonstrate improvements in clinically meaningful outcome measures and a more favorable safety profile with avalglucosidase alfa versus alglucosidase alfa. Funding: Sanofi Genzym

Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial

41st Annual Meeting of the American-Society-of-Clinical-Oncology -- MAY 13-17, 2005 -- Orlando, FLWOS: 000268881000007PubMed ID: 19568958The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented. Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling. A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm. There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.Amer Soc Clin Onco

Anticancer effects of imidazole nucleus in hepatocellular carcinoma cell lines via the inhibition of AKT and ERK1/2 signaling pathways

Background Imidazole nucleus has been used efficiently in the development of many drug molecules due to its therapeutic effects. Many derivatives of it have been produced particularly for use in cancer treatment. However, the anti-cancer effects of imidazole nucleus in liver cancer cells are as yet unclear. In this study, we aimed to investigate the anti-cancer effects of imidazole nucleus in hepatocellular carcinoma (HCC) cell lines. Methods and results Anti-cancer effect of imidazole nucleus was investigated using cell viability assay, apoptosis analysis, cell migration analysis, cell morphology analysis, colony formation assay and 3D cell culture techniques in HuH-7 and Mahlavu cell lines. Also, effect of imidazole on AKT and ERK1/2 pathways were determined using by western blot analysis. Imidazole decreased cell viability in both HCC cell lines in a dose and time-dependent manner and also suppressed the colony forming ability of the cells (p 0.05). Imidazole increased the cleaved caspase 3 protein levels and thus induced apoptosis (p 0.05). Imidazole induced morphological alterations and autophagy by increasing intracellular vacuolization. Also, imidazole decreased the viability and dimensions of HCC cell tumor spheroids produced in 3D cell cultures (p 0.05). Moreover, it was observed that all of these effects, are defined above, appeared in parallel with suppression of AKT and ERK1/2 signaling pathways by imidazole nucleus. Conclusions The findings of this present study established the anti-cancer effects of imidazole nucleus in HCC cell lines and showed that it could be a potential molecule in the treatment of HCC via inhibition of AKT and ERK1/2 signaling pathways.We would like to thank Academic Oncology Association from Turkey for funding support. We thank Professor Dr. Nee Atabey for providing us with the HCC cell lines.Academic Oncology Association from Turke

Algorithms for scheduling of chemotherapy plans

WOS: 000329413800014PubMed ID: 24290927Chemotherapy is used to control and cure cancer by using drugs to destroy cancer cells. Treatment schedules for chemotherapy may vary depending on the type of cancer, the goals of treatment, the type of chemotherapy and the patient's state of health. Chemotherapy is usually given in cycles of a treatment-period followed by a rest-period. An oncologist decides the choice of a particular regimen; however, modifications to drug dose and schedule are often necessary because of variabilities in the health of an individual patient. Therefore an orderly execution of chemotherapy regimens requires management, scheduling and allocation of the resources available. Chemotherapy scheduling is an optimization problem. In this paper, a two-phase approach has been adopted to deal with the problem. An adaptive negative-feedback scheduling algorithm is proposed for the first phase to control the load on the system. Two heuristics based on the 'Multiple Knapsack Problem' have been evaluated for the second phase to assign patients to specific infusion seats. The overall design has been put to test at a local chemotherapy center and has yielded good results for patient waiting times, orderly execution of chemotherapy regimen and utilization of infusion chairs. (C) 2013 Elsevier Ltd. All rights reserved

Leptomeningeal carcinomatosis of gastric adenocarcinoma

WOS: 000292752300014PubMed ID: 21796558Gastric cancer is the third most common malignancy among gastrointestinal malignancies. With the advance of new treatments, overall survival in gastric cancer is extending, and metastasis to atypical sites is seen more commonly. Leptomeningeal metastasis is one such atypical metastasis for gastric cancer. We report a case of gastric adenocarcinoma with leptomeningeal metastasis as an atypical involvement. A 39-year-old female, presenting with headache, vertigo, horizontal gaze palsy, visual disturbances, and seizures, was admitted to our hospital in August 2009. The funduscopic examination revealed the presence of bilateral papilledema. Magnetic resonance imaging of the brain showed diffuse leptomeningeal enhancement and biventricular dilatation. Cytological examination of the cerebrospinal fluid revealed malignant cells. These findings were consistent with leptomeningeal carcinomatosis. Six months before, she was diagnosed as having gastric cancer by upper gastrointestinal tract endoscopy, which was performed as a part of the diagnostic work-up to clarify the cause of her abdominal ascites. She received six cycles of docetaxel-cisplatin-5-fluorouracil for metastatic gastric cancer, and she developed the above-mentioned symptoms under chemotherapy. She was included in a craniospinal radiotherapy program and received intrathecal methotrexate treatment. We present this case report since leptomeningeal carcinomatosis of gastric cancers is a rare clinical entity, and treatment strategies remain challenging for clinicians

Real-life comparison of afatinib and erlotinib in non-small cell lung cancer with rare EGFR exon 18 and exon 20 mutations: a Turkish Oncology Group (TOG) study

Objectives To compare the survival of first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with rare EGFR exon 18 and exon 20 mutation-positive non-small cell lung cancer (NSCLC). Materials and methods We retrospectively evaluated survival characteristics of 125 patients with EGFR exon 18 and exon 20 mutated NSCLC who received erlotinib or afatinib as first line treatment between 2012 and 2021 from 34 oncology centres. Since exon 20 insertion is associated with TKI resistance, these 18 patients were excluded from the study. Results EGFR exon 18 mutations were seen in 60%, exon 20 mutations in 16%, and complex mutations in 24% of the patients with NSCLC who were evaluated for the study. There were 75 patients in erlotinib treated arm and 50 patients in afatinib arm. Patients treated with erlotinib had progression-free survival time (PFS) of 8.0 months and PFS was 7.0 months in the afatinib arm (p = 0.869), while overall survival time (OS) was 20.0 vs 24.8 months, respectively (p = 0.190). PFS of exon 18 mutated arm was 7.0 months, exon 20 mutated arm was 4.3 months, and complex mutation positive group was 17.3 months, and this was statistically significant (p = 0.036). The longest OS was 32.5 months, seen in the complex mutations group, which was not statistically different than exon 18 and in exon 20 mutated groups (21.0 and 21.2 months, respectively) (p = 0.323). Conclusion In this patient group, especially patients with complex mutations are as sensitive to EGFR TKI treatment similar to classical mutations, and in patients with rare exon 18 and exon 20 EGFR mutation both first- and second-generation EGFR-TKIs should be considered, especially as first- and second-line options

Single-agent irinotecan for recurrent/metastatic colorectal cancer: A retrospective analysis

WOS: 000242846500008PubMed ID: 16763396Objective: To evaluate the efficacy, toxicity and factors affecting the survival rate of patients treated with irinotecan. Subjects and Methods: Data from the medical records of 74 patients who had recurrent/metastatic colorectal cancer treated with single-agent irinotecan were analyzed. Results: The mean age for all the patients was 56 years (range 19-77). Forty-one (55%) and 33 (45%) patients had recurrent and/or metastatic colon cancer, respectively. All the patients were treated with irinotecan 350 mg/m(2) every 21 days. Grade 3-4 emesis, grade 3-4 diarrhea, grade 3-4 neutropenia and severe early cholinergic events developed in 7, 15, 7 and 1.3% of patients, respectively. One patient died due to acute renal failure. The overall response rate was 14% (complete response 5%, partial response 9%); 61% had stable response while another 25% had progressive disease. Patients with multiple metastatic foci, patients <= 50 years of age and patients with peritonitis carcinomatosa were shown to have worse outcomes than others. The median duration of response was 16.7 months. The median progression-free survival and overall survival were 4 and 14 months, respectively. Conclusion: The data show that irinotecan was useful in the treatment of recurrent/metastatic colorectal cancer with acceptable toxicity. Copyright (C) 2006 S. Karger AG, Basel