Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial.

INTRODUCTION: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1-high advanced NSCLC. METHODS: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 per independent review committee and overall survival. RESULTS: Patients (N = 304) were randomized one-to-one to receive either bintrafusp alfa or pembrolizumab (n = 152 each). The median follow-up was 14.3 months (95% confidence interval [CI]: 13.1-16.0 mo) for bintrafusp alfa and 14.5 months (95% CI: 13.1-15.9 mo) for pembrolizumab. Progression-free survival by independent review committee was not significantly different between bintrafusp alfa and pembrolizumab arms (median = 7.0 mo [95% CI: 4.2 mo-not reached (NR)] versus 11.1 mo [95% CI: 8.1 mo-NR]; hazard ratio = 1.232 [95% CI: 0.885-1.714]). The median overall survival was 21.1 months (95% CI: 21.1 mo-NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 mo-NR) for pembrolizumab (hazard ratio = 1.201 [95% CI: 0.796-1.811]). Treatment-related adverse events were higher with bintrafusp alfa versus pembrolizumab; grade 3-4 treatment-related adverse events occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary end point. CONCLUSIONS: First-line treatment with bintrafusp alfa did not exhibit superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC.

ERBB2 exon 20 insertions are rare in Brazilian non-small cell lung cancer.

ERBB2 exon 20 insertions may impact the clinical management of lung cancer patients. However, the frequency of ERBB2 exon 20 insertions in lung cancer patients in Brazil is scarce. Here, we analyzed 722 Brazilian non-small cell lung cancer (NSCLC) patients from Barretos Cancer Hospital that were indicated to require routine lung cancer molecular testing. ERBB2 exon 20 insertions were evaluated by a targeted panel using next-generation sequencing (NGS). Clinicopathological and molecular data were collected from patient medical records. Among the 722 NSCLC patients, 85.2% had lung adenocarcinomas, 53.9% were male, 66.8% were quitter or current smokers, and 63.2% were diagnosed at an advanced stage of the disease. We identified 0.8% (6/722) of patients who harbored the insertion p.(Tyr772_Ala775dup) at exon 20 of the ERBB2 gene. All ERBB2 mutated patients were diagnosed with lung adenocarcinoma, were never smokers, and wild-type for EGFR, KRAS, and ALK hotspot alterations. Less than 1% of Brazilian NSCLC patients harbor ERBB2 exon 20 insertions, yet they could benefit in future from the new drugs in development.

EGFR Mutations and PD-L1 Expression in Early-Stage Non-Small Cell Lung Cancer: A Real-World Data From a Single Center in Brazil.

BACKGROUND: Targeted and immunotherapies are currently moving toward early-stage settings for patients with non-small cell lung cancer (NSCLC). Predictive biomarkers data are scarce in this scenario. We aimed to describe the frequency of EGFR mutations and PD-L1 expression levels in early-stage non-squamous patients with NSCLC from a large, single Brazilian oncology center. METHODS: We retrospectively evaluated patients with NSCLC diagnosed at an early-stage (IB to IIIA-AJCC seventh edition) at Barretos Cancer Hospital (n = 302). EGFR mutational status was assessed in FFPE tumor tissues using distinct methodologies (NGS, Cobas, or Sanger sequencing). PD-L1 expression was evaluated by immunohistochemistry (clone 22C3) and reported as Tumor Proportion Score (TPS), categorized as <1%, 1-49%, and ≥50%. We evaluated the association between EGFR mutational status and PD-L1 expression with sociodemographic and clinicopathological parameters by Fisher's test, qui-square test, and logistic regression. Survival analysis was assessed by the Kaplan-Meier method and Cox regression model. RESULTS: EGFR mutations were detected in 17.3% (n = 48) of cases and were associated with female sex, never smokers, and longer overall and event-free survival. PD-L1 positivity was observed in 36.7% (n = 69) of cases [TPS 1-49% n = 44(23.4%); TPS ≥50% n = 25(13.3%)]. PD-L1 positivity was associated with smoking, weight loss, and higher disease stages (IIB/IIIA). CONCLUSION: The frequencies of EGFR mutations and PD-L1 positivity were described for early-stage non-squamous patients with NSCLC. These results will be essential for guiding treatment strategies with the recent approvals of osimertinib and immunotherapy in the adjuvant setting.

Impact of AferBio® on quality of life and chemotherapy toxicity in advanced lung cancer patients (AFERBIO study): protocol study for a phase II randomized controlled trial.

BACKGROUND: Lung cancer patients undergoing palliative chemotherapy exhibit many symptoms related to the disease, such as adverse events and infectious complications during treatment, which impacts directly their health-related quality of life (HRQOL). Nutritional status is a relevant aspect among advanced cancer patients under palliative care and food supplementation has the potential to reduce treatment-related adverse effects and improve the nutritional status. The product named AferBio® is a fermented supplement that has been described as able to provide some benefits, including the capacity to potentiate the effects of anticancer drugs, by promoting the reduction of side effects and ultimately improving HRQOL. METHODS/DESIGN: A Phase II double-blind placebo-controlled randomized clinical trial to assess the use of food supplementation with AferBio® in Stage IIIB or IV non-small cell lung cancer (NSCLC) patients beginning a second-line palliative mono-chemotherapy. The primary goal is to compare HRQOL scores between the arms of the study over time. The ten first patients included in the present study will undergo an AferBio®toxicity-testing (non-randomized phase). If no significant toxicity is found, the study will move on to the randomized phase. All patients will be randomized in blocks at a 1:1 ratio using the online tool REDCap. ECOG-PS (0-1 versus 2) criteria will be used for stratification. All patients included in the trial will be evaluated at baseline and at each chemotherapy cycle. Each evaluation will include the following: HRQOL (EORTC QLQ-C30, LC13 and IQualiV-Lung), ECOG-PS, anthropometric measurements, clinical and laboratory toxicity assessment and response evaluation. DISCUSSION: During palliative systemic therapy in advanced cancer patients, one of the main goals is the improvement and maintenance of HRQOL, which can be negatively affected by cancer symptoms, cancer- or treatment-related psychosocial difficulties, and chemotherapy toxicity. Thus, much research has been dedicated to the development of new and more effective and/or less toxic cancer therapies. The present study is justified by the testing of a novel food supplement that may reduce some toxicities, thus, having a potential positive impact on the HRQOL of lung cancer patients. The product in question (AferBio®) is already available for sale in Brazil, but has not yet been fully tested in cancer patients. TRIAL REGISTRATION: This Trial was registered on March 19, 2018 with ClinicalTrials.gov , NCT03469063. Protocol version: 2.0 from March 26, 2018. Trial status: Patient enrollment in the study began in April, 2018.

Feasibility of concomitant cisplatin with hypofractionated radiotherapy for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The evolution of radiotherapy over recent decades has reintroduced the hypofractionation for many tumor sites with similar outcomes to those of conventional fractionated radiotherapy. The use of hypofractionation in locally advanced head and neck cancer (LAHNC) has been already used, however, its use has been restricted to only a few countries. The aim of this trial was to evaluate the safety and feasibility of moderate hypofractionated radiotherapy (HYP-RT) with concomitant cisplatin (CDDP). METHODS: This single-arm trial was designed to evaluate the safety and feasibility of HYP-RT with concomitant CDDP in LAHNC. Stage III and IV patients withnonmetastatic disease were enrolled. Patients were submitted to intensity modulatedradiation therapy, which comprised 55 Gy/20 fractions to the gross tumor and44-48 Gy/20 fractions to the areas of subclinical disease. Concomitant CDDPconsisted of 4 weekly cycles of 35 mg/m2. The primary endpoints were the treatment completion rate and acute toxicity. RESULTS: Twenty patients were enrolled from January 2015 to September 2016, and 12 (60%) were classified as unresectable. All patients completed the total dose of radiotherapy, and 19 patients (95%) received at least 3 of 4 cycles of chemotherapy. The median overall treatment time was 29 days (27-34). Grade 4 toxicity was reported twice (1 fatigue and 1 lymphopenia). The rates of grade 3 dermatitis and mucositis were 30% and 40%, respectively, with spontaneous resolution. Nasogastric tubes were offered to 15 patients (75%) during treatment; 4 patients (20%) needed feeding tubes after 2 months, and only 1 patient needed a feeding tube after 12 months. CONCLUSION: HYP-RT with concomitant CDDP was considered feasible for LAHNC, and the rate of acute toxicity was comparable to that of standard concomitant chemoradiation. A feeding tube was necessary for most patients during treatment. Further investigation of this strategy is warranted. TRIAL REGISTRATION: ClinicalTrials, NCT03194061 . Registered 21 Jun 2017 - Retrospectively registered.

Tratamento local do carcinoma hepatocelular como ponte para o transplante hepático / Local therapy for hepatocellular carcinoma as a bridge to liver transplantation

OBJETIVO: Analisar os resultados da terapia local pré-operatória em pacientes portadores de carcinoma hepatocelular submetidos a transplante hepático. MÉTODOS: . Foram analisados os prontuários dos pacientes adultos submetidos a transplante hepático cadavérico e intervivos no Hospital de Clínicas da Universidade Federal do Paraná no período entre janeiro de 2002 e agosto de 2007. Foram incluídos no estudo os portadores de cirrose hepática e carcinoma hepatocelular diagnosticado pelos critérios da EASL (European Association for the Study of the Liver). Foram analisados o número e o diâmetro dos nódulos neoplásicos antes e após a terapia local e na análise do explante, o número de sessões de terapia local e sua duração. Após o estabelecimento do diagnóstico de carcinoma hepatocelular os pacientes foram submetidos à terapia local com alcoolização. RESULTADOS: Foram analisados 22 pacientes portadores de 31 nódulos neoplásicos com diâmetro médio de 28,8±12 mm. Após as sessões de terapia local foram detectados 29 nódulos neoplásicos com diâmetro médio de 24,6±12 mm, sem diferença em relação ao observado antes do tratamento e todos dentro dos critérios de Milão. Foram realizados 17 transplantes cadavéricos e cinco transplantes intervivos. A análise do explante demonstrou seis casos fora dos critérios de Milão. Dezesseis casos estavam dentro dos critérios de Milão com 14 nódulos neoplásicos com diâmetro médio de 30±14 mm, sem diferença em relação ao observado no diagnóstico e após a terapia local. CONCLUSÃO: A terapia local para o carcinoma hepatocelular com alcoolização e quimioembolização permitiu o controle parcial da evolução da doença considerando-se os critérios de Milão em pacientes em lista de espera para transplante hepático. Ocorreram diferenças significativas em relação aos critérios de Milão entre os exames de imagem pré-operatórios e a análise do explante.

OBJECTIVE: To analyze the results of pre-operative local therapy for hepatocellular carcinoma in patients who were subjected to liver transplantation. METHODS: Cadaveric and living-related liver transplants done in cirrotic patients with hepatocellular carcinoma within the Milan criteria were included. The nodules were analyzed according to its number and diameter before and after the institution of the local therapy and on the explant evaluation. RESULTS: 22 patients with 31 nodules that measured 28.8±12 mm in diameter were included. They were subjected to 21 sessions of percutaneous ethanol injection and 29 sessions of transarterial chemoembolization. After the local therapy, 29 nodules that measured 24.6±12 mm in diameter were detected. All of them were within the Milan criteria and there was no difference compared to the diameter before the treatment. The patients were subjected to 17 cadaveric and 5 living-related liver transplantations. In six cases the tumors exceeded the Milan criteria on the explant evaluation: 4 due to its number and 2 due to its diameter. Sixteen cases were within the criteria and there were 14 neoplastic nodules with 30±14 mm in diameter. In these cases no difference was observed compared to the diameter before and after the local therapy. CONCLUSION: Local therapy for hepatocellular carcinoma with percutaneous ethanol injection and transarterial chemoembolization partially controlled tumor evolution considering the Milan criteria in patients waiting for liver transplantation. Significant differences were observed in terms of the Milan criteria on pre-operative examination compared to the explant evaluation.

[Local therapy for hepatocellular carcinoma as a bridge to liver transplantation]. / Tratamento local do carcinoma hepatocelular como ponte para o transplante hepático.

OBJECTIVE: To analyze the results of pre-operative local therapy for hepatocellular carcinoma in patients who were subjected to liver transplantation. METHODS: Cadaveric and living-related liver transplants done in cirrotic patients with hepatocellular carcinoma within the Milan criteria were included. The nodules were analyzed according to its number and diameter before and after the institution of the local therapy and on the explant evaluation. RESULTS: 22 patients with 31 nodules that measured 28.8+/-12 mm in diameter were included. They were subjected to 21 sessions of percutaneous ethanol injection and 29 sessions of transarterial chemoembolization. After the local therapy, 29 nodules that measured 24.6+/-12 mm in diameter were detected. All of them were within the Milan criteria and there was no difference compared to the diameter before the treatment. The patients were subjected to 17 cadaveric and 5 living-related liver transplantations. In six cases the tumors exceeded the Milan criteria on the explant evaluation: 4 due to its number and 2 due to its diameter. Sixteen cases were within the criteria and there were 14 neoplastic nodules with 30+/-14 mm in diameter. In these cases no difference was observed compared to the diameter before and after the local therapy. CONCLUSION: Local therapy for hepatocellular carcinoma with percutaneous ethanol injection and transarterial chemoembolization partially controlled tumor evolution considering the Milan criteria in patients waiting for liver transplantation. Significant differences were observed in terms of the Milan criteria on pre-operative examination compared to the explant evaluation.

Análise da margem cirúrgica proximal do estômago em pacientes submetidos à gastrectomia subtotal por adenocarcinoma / Proximal gastric margin analysis following subtotal gastrectomy for adenocarcinoma

RACIONAL: A gastrectomia subtotal atualmente é considerada padrão ouro no tratamento da neoplasia gástrica do terço médio e distal. No entanto, foi demonstrado que a ocorrência de neoplasia residual na margem cirúrgica proximal está associada à redução da sobrevida. OBJETIVOS: analisar a margem cirúrgica proximal no exame anátomo-patológico de pacientes submetidos à gastrectomia subtotal por adenocarcinoma gástrico e identificar os fatores relacionados com o acometimento neoplásico dessa margem. MÉTODOS: No período entre janeiro de 1998 e dezembro de 2007 foram revisados os prontuários dos pacientes submetidos à gastrectomia subtotal devido a adenocarcinoma gástrico do terço médio e distal. Os pacientes foram analisados quanto à idade, sexo, classificação de Lauren, classificação de Borrmann, maior diâmetro da lesão, localização da lesão no estômago, clínico e presença de invasão angiolinfática. Foi realizada análise univariada desses dados em relação ao acometimento da margem proximal do estômago no exame anátomo-patológico. RESULTADOS: Foram analisados 104 casos: 34 do sexo feminino e 70 do sexo masculino com idade média de 57±13 anos. Doze pacientes (12,3 por cento) apresentaram acometimento da margem proximal. A análise univariada entre os fatores analisados e o acometimento neoplásico da margem proximal demonstrou associação somente em relação à classificação de Borrmann. CONCLUSÃO: A classificação macroscópica de Borrmann, especialmente nos estágios III e IV, está relacionada à presença de acometimento da margem proximal nos casos de adenocarcinoma gástrico dos terços médio e distal submetidos a tratamento com gastrectomia subtotal.

BACKGROUND: Subtotal gastrectomy is considered the gold standard treatment for gastric neoplasms localized in the distal and medial thirds of the stomach. Nevertheless, it has been shown that residual neoplasm into the proximal margin is associated to worse prognosis. AIM: To identify factors related to residual neoplasm into the proximal margin determined on pathology examination of patients subjected(Submitted) to subtotal gastrectomy for gastric adenocarcinoma. METHODS: The charts of the patients subjected(Submitted) to subtotal gastrectomy due to gastric adenocarcinoma of the distal and medial thirds were reviewed from January 1998 to December 2007. It was recorded data referred to age, sex, Lauren and Borrmann staging, neoplasm diameter, localization inside the stomach, TNM staging and angiolymphatic invasion. These data were submitted to univariate analysis in relation to residual neoplasm into the proximal margin. RESULTS: A hundread and four cases were included: 34 females and 70 males. The median age was 57±13 years. Twelve patients (12.3 percent) presented residual neoplasm into the proximal margin. The univariate analysis showed association between only the Borrmann staging and the residual neoplasm. CONCLUSION: Borrmann staging is associated to residual neoplasm into the proximal margin in patients subjected(Submitted) to subtotal gastrectomy for medial and distal thirds gastric adenocarcinoma.

Nevirapine-induced side effects in pregnant women: experience of a brazilian university hospital

Nevirapine-based therapy is associated with increased frequency of adverse events among HIV-infected pregnant women. The aim of this article was to evaluate the incidence of adverse effects in HIV-infected women who started nevirapine during pregnancy. A retrospective study was performed in our center between January 2003 and December 2006 analyzing all women prescribed nevirapine during pregnancy. Women presenting any risk factor for hepatotoxicity were excluded from the analysis. Patients were divided into two groups according to the presence or absence of adverse effects, and a correlation to CD4 counts was performed. Liver function abnormality was graded according to the Division of AIDS toxicity guidelines. A total of 170 women initiated nevirapine during pregnancy, but only 133 were included in the study. Twenty-seven women (20.3 percent) presented adverse effects, skin rash accounting for 77.8 percent (21/27 women) and liver function abnormalities for 22.2 percent (6/27) of the cases. Baseline CD4 counts, viral loads and transaminases were similar in both groups. All nevirapine side effects were developed in less than seven weeks. Four of 31 women with CD4 counts <250 cells/µL (12.9 percent) and 23 of 102 women with CD4 counts ≥250 cells/µL (22.5 percent) developed adverse events. All patients who experienced hepatotoxicity had pretreatment CD4 counts >250cells/µL. The incidence of adverse events with nevirapine in our study was high, but most of them were cutaneous. There was no correlation between high CD4 counts and adverse events when analyzing both cutaneous and hepatic reactions; nevertheless, hepatotoxicity occurred only in pregnant women with CD4 counts ≥250cells/µL.

Nevirapine-induced side effects in pregnant women: experience of a Brazilian university hospital.

Nevirapine-based therapy is associated with increased frequency of adverse events among HIV-infected pregnant women. The aim of this article was to evaluate the incidence of adverse effects in HIV-infected women who started nevirapine during pregnancy. A retrospective study was performed in our center between January 2003 and December 2006 analyzing all women prescribed nevirapine during pregnancy. Women presenting any risk factor for hepatotoxicity were excluded from the analysis. Patients were divided into two groups according to the presence or absence of adverse effects, and a correlation to CD4 counts was performed. Liver function abnormality was graded according to the Division of AIDS toxicity guidelines. A total of 170 women initiated nevirapine during pregnancy, but only 133 were included in the study. Twenty-seven women (20.3%) presented adverse effects, skin rash accounting for 77.8% (21/27 women) and liver function abnormalities for 22.2% (6/27) of the cases. Baseline CD4 counts, viral loads and transaminases were similar in both groups. All nevirapine side effects were developed in less than seven weeks. Four of 31 women with CD4 counts <250 cells/microL (12.9%) and 23 of 102 women with CD4 counts > or = 250 cells/microL (22.5%) developed adverse events. All patients who experienced hepatotoxicity had pretreatment CD4 counts > or =250 cells/microL. The incidence of adverse events with nevirapine in our study was high, but most of them were cutaneous. There was no correlation between high CD4 counts and adverse events when analyzing both cutaneous and hepatic reactions; nevertheless, hepatotoxicity occurred only in pregnant women with CD4 counts > or =250 cells/microL.