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Targeted therapies and immunotherapies have radically improved treatment for advanced non-small-cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting oncogenic driver mutations continue to evolve over multiple generations to enhance effectiveness and tackle drug resistance. Immune checkpoint inhibitors remain integral for the treatment of NSCLCs that do not have specific actionable genetic mutations. Antibody-drug conjugates and bispecific antibodies are being integrated into treatment guidelines, and emerging therapies include T-cell engagers, cellular therapies, cancer vaccines, and external devices. Despite these advances, challenges remain in identifying predictive biomarkers to individually tailor treatments, abrogate resistance, reduce costs, and ensure optimal cancer treatment accessibility.
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BACKGROUND: Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. METHODS: This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786. FINDINGS: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2]; stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). INTERPRETATION: First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. FUNDING: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Platina/uso terapêutico , Qualidade de Vida , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
INTRODUCTION: The aim of this study was to analyze real-life data from a cohort of adult patients receiving atezolizumab in combination with carboplatin and etoposide for first-line treatment of ES-SCLC, in order to assess relative dose intensity (RDI), time-to-treatment discontinuation (TTD), time-to-treatment failure (TTF), progression-free survival (PFS), overall survival (OS) of treatments as well as the correlation between these outcomes. METHODS: An observational retrospective study was conducted. All patients treated with atezolizumab combined with carboplatin and etoposide for first-line treatment of ES-SCLC were included. Median TTD, TTF, PFS and OS were calculated in our cohort of patient by the Kaplan Meier method. RESULTS: The curves obtained with the Kaplan Meier method of TTF and TTD are substantially similar, indicating a good concordance of the information extracted by the two different data sources. This tendency was confirmed also when the TTD versus PFS curves were compared. The median OS registered was 11.8 months. Patients with no liver metastases showed a longer median time of OS than patients with liver metastases. The mean value of RDI for the entire cohort was 87.4%. CONCLUSIONS: Our study showed that TTD, calculated from the administration data is a useful proxy of TTF as registered in the clinical chart. TTD is a real-world outcome that can be used to demonstrate the efficacy of drugs used for administered therapies. It can be used as an end point for RWE studies, where the evaluation is less structured and standardized.
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BACKGROUND: Monotherapy immune checkpoint inhibitor (ICI) used in second- or later-line settings has been reported to induce hyperprogression. This study evaluated hyperprogression risk with ICI (atezolizumab) in the first-, second-, or later-line treatment of advanced non-small cell lung cancer (NSCLC), and provides insights into hyperprogression risk with contemporary first-line ICI treatment. METHODS: Hyperprogression was identified using Response Evaluation Criteria in Solid Tumours (RECIST)-based criteria in a dataset of pooled individual-participant level data from BIRCH, FIR, IMpower130, IMpower131, IMpower150, OAK, and POPLAR trials. Odds ratios were computed to compare hyperprogression risks between groups. Landmark Cox proportional-hazard regression was used to evaluate the association between hyperprogression and progression-free survival/overall survival. Secondarily, putative risk factors for hyperprogression among second- or later-line atezolizumab-treated patients were evaluated using univariate logistic regression models. RESULTS: Of the included 4644 patients, 119 of the atezolizumab-treated patients (n = 3129) experienced hyperprogression. Hyperprogression risk was markedly lower with first-line atezolizumab-either chemoimmunotherapy or monotherapy-compared to second/later-line atezolizumab monotherapy (0.7% vs. 8.8%, OR = 0.07, 95% CI, 0.04-0.13). Further, there was no statistically significant difference in hyperprogression risk with first-line atezolizumab-chemoimmunotherapy versus chemotherapy alone (0.6% vs. 1.0%, OR = 0.55, 95% CI, 0.22-1.36). Sensitivity analyses using an extended RECIST-based criteria including early death supported these findings. Hyperprogression was associated with worsened overall survival (HR = 3.4, 95% CI, 2.7-4.2, P < .001); elevated neutrophil-to-lymphocyte ratio was the strongest risk factor for hyperprogression (C-statistic = 0.62, P < .001). CONCLUSIONS: This study presents first evidence for a markedly lower hyperprogression risk in advanced NSCLC patients treated with first-line ICI, particularly with chemoimmunotherapy, as compared to second- or later-line ICI treatment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options. METHODS: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines. RESULTS: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006). CONCLUSIONS: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments.
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Neoplasias , Estados Unidos , Humanos , National Cancer Institute (U.S.) , Estudos Retrospectivos , Mutação , Neoplasias/genética , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biomarcadores Tumorais/genéticaRESUMO
Pembrolizumab monotherapy is a standard first-line treatment for PD-L1-high advanced non-small-cell lung cancer (NSCLC) without actionable genomic alterations (AGA). However, few patients experience long-term disease control, highlighting the need for more effective therapies. Datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2-directed antibody-drug conjugate, showed encouraging safety and antitumor activity with pembrolizumab in advanced NSCLC. We describe the rationale and design of TROPION-Lung08, a phase III study evaluating safety and efficacy of first-line Dato-DXd plus pembrolizumab versus pembrolizumab monotherapy in patients with advanced/metastatic NSCLC without AGAs and with PD-L1 tumor proportion score ≥50%. Primary end points are progression-free survival and overall survival; secondary end points include objective response rate, duration of response, safety and presence of antidrug antibodies. Clinical trial registration: NCT05215340 (ClinicalTrials.gov).
More than half of patients with non-small-cell lung cancer (NSCLC) are diagnosed when their tumor is advanced (unlikely to be cured with currently available treatments) or metastatic (spread to other parts of the body). These patients have poor survival outcomes. NSCLCs can grow by using a protein called PD-L1 to escape from the immune system. Pembrolizumab is an immunotherapy that targets PD-1, the protein on immune cells that detects PD-L1. Because of this, pembrolizumab prevents the tumor from escaping the immune system by blocking the interaction of PD-L1 with PD-1. Patients whose NSCLC tumors express PD-L1 often respond to pembrolizumab at first but, for most of these patients, their cancer eventually comes back. An investigational drug called datopotamab deruxtecan (Dato-DXd) is a type of therapy called an antibodydrug conjugate that delivers chemotherapy to tumors using an antibody. The antibody in Dato-DXd is directed against a protein called TROP2, which is commonly expressed by tumor cells. Results from early studies show that combining pembrolizumab with Dato-DXd may work well for patients with solid tumors, including NSCLC. This study will look at the benefits and side effects of Dato-DXd added to pembrolizumab compared with pembrolizumab alone as a first treatment option for patients with advanced NSCLC and high levels of PD-L1.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Antígeno B7-H1/genética , Antineoplásicos/uso terapêutico , Imunoconjugados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase III como AssuntoRESUMO
Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 (ClinicalTrials.gov).
Patients with lung cancer that has spread to other parts of the body are usually treated with a combination of chemotherapy and drugs that stimulate the immune system to kill cancer cells, which is referred to as immunotherapy. If after receiving these drugs the cancer still gets worse, patients have only a few treatment options left and are usually treated with chemotherapy only. Researchers will study if a new medicine called Tedopi®, a vaccine that specifically attacks cancer cells, used together with chemotherapy or immunotherapy, will work better then chemotherapy alone for these patients. The study will monitor how long patients will live after treatment, for how long they will live without their disease getting worse and how many patients will improve after treatment. Moreover, researchers will study if patients present specific features, such as certain molecules in their tumor cells or blood cells, that may indicate that they respond better to certain treatments.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Docetaxel/uso terapêutico , Nivolumabe , Neoplasias Pulmonares/patologia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
KRAS is the most frequently mutated oncogene identified in human cancers. Despite the numerous efforts to develop effective specific inhibitors against KRAS, this molecule has remained "undruggable" for decades. The development of direct KRAS inhibitors, such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, was made possible with the discovery of a small pocket in the binding switch II region of KRAS G12C. However, a new challenge is represented by the necessity to overcome resistance mechanisms to KRAS inhibitors. Another area to be explored is the potential role of co-mutations in the selection of the treatment strategy, particularly in the setting of immune checkpoint inhibitors. The aim of this review was to analyze the state-of-the-art of KRAS mutations in non-small-cell lung cancer by describing the biological structure of KRAS and exploring the clinical relevance of KRAS as a prognostic and predictive biomarker. We reviewed the different treatment approaches, focusing on the novel therapeutic strategies for the treatment of KRAS-mutant lung cancers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acetonitrilas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Piperazinas , Proteínas Proto-Oncogênicas p21(ras)/genética , PirimidinasRESUMO
New evidence on the impact of dysregulation of the CDK4/6 pathway on breast cancer (BC) cell proliferation has led to the development of selective CDK4/6 inhibitors, which have radically changed the management of advanced BC. Despite the improved outcomes obtained by CDK4/6 inhibitors, approximately 10% of tumors show primary resistance, whereas acquired resistance appears to be an almost ubiquitous occurrence, leading to treatment failure. The identification of differentially expressed genes or genomic mutational signatures able to predict sensitivity or resistance to CDK4/6 inhibitors is critical for medical decision making and for avoiding or counteracting primary or acquired resistance against CDK4/6 inhibitors. In this review, we summarize the main mechanisms of resistance to CDK4/6 inhibitors, focusing on those associated with potentially relevant biomarkers that could predict patients' response/resistance to treatment. Recent advances in biomarker identification are discussed, including the potential use of liquid biopsy for BC management and the role of multiple microRNAs as molecular predictors of cancer cell sensitivity and resistance to CDK4/6 inhibitors.
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Neoplasias da Mama , MicroRNAs , Inibidores de Proteínas Quinases , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Biópsia Líquida , MicroRNAs/genética , MicroRNAs/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/farmacologiaRESUMO
BACKGROUND: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma. METHODS: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36. FINDINGS: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths. INTERPRETATION: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting. FUNDING: Eli Lilly Italy. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.
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Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Mesotelioma Maligno/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Itália , Masculino , Mesotelioma Maligno/diagnóstico , Mesotelioma Maligno/mortalidade , Pessoa de Meia-Idade , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/mortalidade , Intervalo Livre de Progressão , Fatores de Tempo , Gencitabina , RamucirumabRESUMO
BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Quinase do Linfoma Anaplásico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Receptores Proteína Tirosina Quinases/genética , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Substantial changes in the management of cancer patients have been required worldwide in response to the COVID-19 pandemic. Beyond the due details on the primitive cancer site and setting at diagnosis, these latter adaptions are most commonly exemplified by a significant reduction in the screening of asymptomatic subjects, delays in elective surgery and radiotherapy for primary tumors, and dose reductions and/or delays in systemic therapy administration. Advanced breast cancer patients with hormonal receptor positive, HER2 negative tumors are usually treated with endocrine therapy combined with CDK 4/6 inhibitors as first- and second-line treatment. During the pandemic, experts' recommendations have suggested the omission or delay of CDK 4/6 inhibitors delivery, or a careful evaluation of their real need due to the hypothesized increased risk of SARS-Cov-2 infection and disease possibly related to neutropenia. The inherent literature is sparse and inconsistent. We herein present data on the use of CDK 4/6 inhibitors during the pandemic. The evidence reported punctually reflects the experience matured at our Institution, a comprehensive cancer centre, on the topic of interest.
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Neoplasias da Mama , COVID-19/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Pandemias , Fatores de RiscoRESUMO
BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
Aim: To assess the measures applied to reduce the spread of coronavirus disease (COVID-19) and the timing of their application in medical oncology departments. Materials & methods: We surveyed all medical oncology departments from the Italian Emilia Romagna region via a multidomain questionnaire. The questions covered items on patients, healthcare workers, risk reduction measure and clinical trials. Results: A total of 12 centers involving 861 healthcare members joined the survey. The measures applied to patients and health workers partially converged in all the departments while major divergences were found in the clinical trials domain. High rate of COVID-19 infection occurred among medical doctors (21/208, 10.1%) and social care workers (13/110, 11.8%). Rate of infection among nurses was 5.7% (24/418). Conclusion: All measures able to reduce risk of COVID-19 infection must be applied in medical oncology departments. Early introduction of risk reduction measures may be a critical issue.
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Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/métodos , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Betacoronavirus , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Humanos , Itália/epidemiologia , Neoplasias/tratamento farmacológico , Enfermeiras e Enfermeiros/estatística & dados numéricos , Médicos/estatística & dados numéricos , Pneumonia Viral/tratamento farmacológico , SARS-CoV-2 , Assistentes Sociais/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. METHODS: IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. FINDINGS: Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group. INTERPRETATION: IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. FUNDING: F. Hoffmann-La Roche.
Assuntos
Albuminas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Humanos , Neoplasias Pulmonares/patologia , MasculinoRESUMO
BACKGROUND: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. METHODS: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Nivolumabe/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. PATIENTS AND METHODS: Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. RESULTS: The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2-9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3-4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. CONCLUSION: To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. IMPLICATIONS FOR PRACTICE: Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.
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Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Ensaios de Uso Compassivo , Esquema de Medicação , Feminino , Humanos , Imunoterapia , Itália , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Segurança , Resultado do TratamentoRESUMO
OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , não Fumantes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
AIM: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010. MATERIALS & METHODS: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials. RESULTS: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4 months. Among 1141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected. CONCLUSION: Time to treatment failure durations and objective response rates were encouraging.