Search

Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination.The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

Introduction: Adjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA. Methods: Patients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB-IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage. Results: Overall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10-0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13-0.40), regardless of disease stage. Conclusions: These findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Background Team debriefing is an important teamwork development intervention for improving team outputs in healthcare. Debriefing is a key component of experiential team training teamwork development interventions such as simulation-based training. Improving the quality of debriefing of healthcare teams, therefore, has multiple benefits. We investigated whether the quality of student-led debriefing improved using a shortened guide. Methods Senior medical students, nurse anesthesia students, and senior undergraduate nursing students participated in student operating room team training at a health sciences center in the southeastern United States. Student teams participated in a dual-scenario simulation-based training session with immediate after-action debriefings after each scenario. In 2018, student teams conducted the second debriefing using as a guide the teamwork assessment scale, an 11-item, 3-subscale, 6-point Likert-type instrument. In 2019, they used a shortened, revised, 5-item version of the teamwork assessment scale, the quick teamwork assessment scale. Trained observers rated the quality of the student-led debriefings using the Objective Structured Assessment of Debriefing, an 8-item, 5-point instrument. The Wilcoxon-Mann-Whitney test was used to compare the teamwork assessment scale-guided and the quick teamwork assessment scale-guided mean item debriefing scores. Results Two observers rated 3 student-led team debriefings using the teamwork assessment scales as a guide in 2018, and 6 such debriefings happened using the quick teamwork assessment scale as a guide in 2019. For each debriefing, observer scores were averaged for each Objective Structured Assessment of Debriefing item; these mean scores were then averaged with other mean scores for each year. The use of the quick teamwork assessment scale resulted in a statistically significant higher mean score for the Analysis Objective Structured Assessment of Debriefing item compared with the use of the teamwork assessment scale (4.92 [standard deviation 0.20] versus 3.83 [standard deviation 0.76], P = .023). Conclusion The use of a shortened teamwork assessment instrument as a debriefing guide for student teams in student operating room team training was more effective in analysis of actions than the original, longer tool. Next steps include determining the efficacy of the quick teamwork assessment scale in an actual clinical setting.

Background Molecular characterization of non–small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting. Patients and Methods We collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups. Results Eighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations. Conclusion Our study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations.

Fluid resuscitation in the management of patients with sepsis and severe sepsis has been considered the standard of care for almost 2 decades. The rationale for fluid resuscitation is related to improvement in cardiac output and organ perfusion. Recent research evidence challenges the use of fluid resuscitation in patients diagnosed with sepsis. Research is needed to determine the timing of fluid administration, as well as the volume and type of fluid to achieve positive patient outcomes. This article discusses the pros and cons of early fluid administration in the management of patients with sepsis.

Risk of brain metastases (BM) affects a remarkable number of non-small cell lung cancer (NSCLC) patients, impacting on their quality of life (QoL) and prognosis. While tyrosine-kinase inhibitors (TKIs) showed interesting intracranial control rates in oncogene-addicted NSCLC, BM still represent an unmet need for the counterpart without driver gene mutations. For these patients, new treatment options include anti-angiogenic drugs and immune-checkpoint inhibitors, possibly combined with standard chemotherapy, even though the benefit on BM has not been clearly defined. A multidisciplinary team including neurosurgeons, medical and radiation oncologists is needed in order to integrate systemic and loco-regional strategies at the right time point. Ad-hoc designed clinical trials are slowly emerging for previously treated patients with uncontrolled BM. The aim of this review is to offer a detailed and updated picture of possible approaches for non oncogene-addicted NSCLC patients having BM, in order to support clinicians in their daily practice.

Treatment of locally advanced NSCLC (LA-NSCLC) is focused on multimodal strategy, including chemotherapy and radiotherapy (in combination or as alternative treatments), followed by surgery in selected cases. Recently, durvalumab consolidation after definitive chemo-radiation has shown a meaningful overall survival benefit. However, it is important to note that elderly patients represent a high proportion of NSCLC population and frailty and comorbidities can significantly limit treatment options. Indeed, elderly patients are under-represented in clinical trials and data to drive treatment selection in this category of patients are scanty. Available data, main issues and controversies on multimodal treatment in elderly LA-NSCLC patients will be reviewed in this paper.

Immune checkpoint inhibitors (ICIs) have emerged as one of the main new therapeutic options for advanced non-small cell lung cancer (NSCLC) patients. Even though they demonstrated superiority towards standard chemotherapy in different disease settings, the response rates do not exceed 45% in highly molecularly selected patients. This is related to known limitations of the available biomarkers, as well to the complex and dynamic nature of tumor microenvironment. The study of the different strategies adopted by tumor cells to escape the immune system lays the basis of the new combination strategies. This review focuses on analyzing the biological rationale and early clinical data available concerning therapeutic strategies combining ICIs together, ICIs with different regimens and schedules of standard chemotherapy, ICIs with tyrosine kinase inhibitors, ICIs with antiangiogenic agents and ICs with radiotherapy.

Objectives Data supporting the prognostic role of chemotherapy induced haematological toxicity suggest that toxicity-adjusted-dosing (TAD) of chemotherapy might improve treatment efficacy. We tested whether TAD of the cisplatin-etoposide combination might improve the response rate, in previously untreated extensive stage disease (ED)-SCLC patients, as compared with standard fixed-dosing (FD). Methods Patients with ED-SCLC were randomized to receive either TAD or FD of cisplatin-etoposide as first-line treatment. Primary endpoint was the objective response rate (ORR) according to the RECIST 1.0 criteria, secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity. Results Hundred-fifty-eight patients were randomized. Most patients were male, with ECOG-PS 1, without brain metastases and had not received radiotherapy before study entry. Response rate was 54.4 (95%CI: 43.5–64.9%) and 58.2 (95%CI: 47.2–68.5%) in the control and experimental arms, respectively (P = 0.75). No significant differences were found in terms of PFS (HR 1.04; 95%CI: 0.74–1.44, P = 0.84) and OS (HR1.01; 95%CI 0.71–1.42, p = 0.97). Seven patients died on treatment, one in the standard arm and 6 in the experimental arm. The most frequent cause of death was neutropenia with infection and, apart in one, death was not related to dose modification. Severe toxicity was more frequent in the experimental arm (91% vs 60%). Conclusions In our population of chemonaive ED SCLC patients, TAD failed to improve the ORR, PFS and OS over the FD of cisplatin-etoposide as first line chemotherapy and was associated with increased toxicity.

Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.

Background Treatment landscape for patients with advanced NSCLC is rapidly evolving, with recent randomized phase III trials demonstrating superiority of chemo-immuno combinations versus chemotherapy alone. Role of chemo-free combinations, including NI, is under investigation with limited available data. Aim of the present trial is to investigate outcome of SqCLC patients when treated with NI or CN. Trial design SQUINT (NCT03823625) is an open-label, randomized, parallel, non-comparative phase II study designed to assess the efficacy of NI (Arm A) or CN (Arm B) in patients with advanced, metastatic SqCLC. Eligibility requires age ≥ 18 years, histologically confirmed stage IV or recurrent stage IIIB SqCLC, p63+/p40+ and TTF- tumour tissue, availability of PD-L1 status, no prior systemic therapy, ECOG performance status 0-1, adequate organ functions. Key exclusion criteria include concomitant radiotherapy or chemotherapy, prior treatment with immune checkpoint inhibitors, untreated brain metastases, other serious illness or medical condition potentially interfering with the study or with NI administration. Patients are randomly assigned 1:1 to receive N 360 mg Q3W plus I 1 mg/kg Q6W (Arm A) or plus platinum-based chemotherapy up to 6 cycles plus nivolumab 360 mg Q3W (Arm B), and stratified by PD-L1 expression ( Clinical trial identification EudraCT: 2016-004003-31. Legal entity responsible for the study Fondazione Ricerca Traslazionale. Funding Has not received any funding. Disclosure L. Landi: Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck SharpD Advisory / Consultancy: Boehringer Ingelheim. A. Delmonte: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD. M.R. Migliorino: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck SharpD Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. F. Cappuzzo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Aim: Locally advanced NSCLCs are not primarily resectable due to local invasion of vital structure or to the degree of nodal involvement. Intensive chemotherapy induction treatment could improve the response rate and potentially the rate of patients able to undergo radical intent local treatment. The present study aims to assess the response rate and the feasibility of induction chemotherapy with carboplatin, paclitaxel and gemcitabine followed by surgery and postoperative radiotherapy. Methods: We retrospectively collected clinical data and radiological imaging from locally-advanced NSCLCs treated with carboplatin (AUC 6 d1), paclitaxel (200 mg/m2, d 1) and gemcitabine (1000 mg/m2 d1,8) for 3/4 courses, followed by surgery and/or radical intent radiotherapy. We analyzed the radiological response to chemotherapy according to RECIST v1.1 criteria as primary end-point. We collected the data about toxicity. Median Progression-free survival (PFS) and Overall survival (OS) of the study population have been estimated and correlated to radiological response, surgery and clinical features. Results: 58 locally advanced NSCLCs were included in the study: 41 were radiologically staged as stage IIIA, 17 as stage III B according to the 7th TNM classification. After chemotherapy, 37 (64%) patients underwent surgery followed by adjuvant radiotherapy, one patient received radical intent radiotherapy. Median delayed time to surgery was 2 weeks. Partial response was observed in 36 (62%, 95%CI: 48%-74%) cases, progression in 6 (10%) cases. 36 (62%) patients experienced grade 3-4 hematological toxicity. Main non hematological toxicities were grade 1-2 nausea and arthralgia. One patient was hospitalized for febrile neutropenia. The median PFS and OS of the study population were 10 and 26 months respectively. One-year PFS and OS rate were 44% and 76%. Objective response and surgery were significantly associated both with PFS (p Conclusions: The intensive chemotherapy induction treatment was feasible and associated with a considerable radiological response rate. We are planning prospective validation of the proposed multimodality treatment. Disclosure: All authors have declared no conflicts of interest.

Background Preclinical and clinical data have shown that low BRCA1 expression increases sensitivity to platinum. However, the complexity of DNA repair pathways suggests that the BRCA1 function could be modulated by several proteins. MDC1, the protein initiating the response to DNA double strand breaks, activates two parallel pathways: 53BP1 and BRCA1. We hypothesized that the mRNA expression of components involved in the 53BP1 pathway could influence the predictive value of BRCA1. Methods mRNA expression levels of BRCA1, MDC1, UBC13, RNF8, 53BP1, PIAS4, MMSET and UBC9 were assessed by real-time PCR analysis in 115 paraffin-embedded tumor samples collected from advanced NSCLC p treated with first-line platinum-based chemotherapy without taxanes. Results Expression levels of BRCA1 were correlated with MDC1 (r = 0.47, P Conclusions Advanced NSCLC p with low levels of both BRCA1 and 53BP1 showed significantly improved outcome to first-line platinum-based chemotherapy. The assessment of BRCA1 and 53BP1 can be useful for customizing chemotherapy. Disclosure All authors have declared no conflicts of interest.