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BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adolescente , Adulto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de DoençaRESUMO
The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.).
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Vacinas contra COVID-19/efeitos adversos , Imunoglobulinas Intravenosas , Trombocitopenia/terapia , Trombose/terapia , Idoso , ChAdOx1 nCoV-19 , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Heparina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Fator Plaquetário 4/farmacologia , Serotonina/sangue , Trombocitopenia/sangue , Trombocitopenia/etiologia , Trombose/etiologia , Trombose/imunologiaRESUMO
Clostridioides difficile is a Gram-positive opportunistic human pathogen that causes 15,000 deaths annually in the United States, prompting a need for vaccine development. In addition to the important toxins TcdA and TcdB, binary toxin (CDT) plays a significant role in the pathogenesis of certain C. difficile ribotypes by catalyzing the ADP-ribosylation of actin in host cells. However, the mechanisms of CDT neutralization by antibodies have not been studied, limiting our understanding of key epitopes for CDT antigen design. Therefore, we isolated neutralizing monoclonal antibodies against CDT and characterized their mechanisms of neutralization structurally and biochemically. Here, 2.5-Å and 2.6-Å resolution X-ray crystal structures of the antibodies BINTOXB/22 and BINTOXB/9, respectively, in complex with CDTb-the CDT subunit that forms a heptameric pore for the delivery of toxic CDTa enzyme into the host cytosol-showed that both antibodies sterically clash with adjacent protomers in the assembled heptamer. Assessment of trypsin-induced oligomerization of the purified CDTb protoxin in vitro showed that BINTOXB/22 and BINTOXB/9 prevented the assembly of di-heptamers upon prodomain cleavage. This work suggests that the CDT oligomerization process can be effectively targeted by antibodies, which will aid in the development of C. difficile vaccines and therapeutics. IMPORTANCE Clostridioides difficile strains associated with worse clinical outcomes have been found to secrete a toxin called CDT (or binary toxin). As blocking the function of this toxin could help mitigate C. difficile infections, we sought to determine the molecular basis for the inhibition of CDT by monoclonal antibodies. We isolated monoclonal antibodies targeting the B-component of CDT (CDTb) and selected two with neutralizing activity for detailed structural and biochemical characterization. High-resolution crystal structures of each antibody bound to CDTb showed that their presence would preclude the assembly of a CDTb oligomer required for activity. Oligomerization of CDTb in vitro was shown to be blocked in the presence of the neutralizing antibodies, but not a control antibody.
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Toxinas Bacterianas , Clostridioides difficile , Humanos , Toxinas Bacterianas/metabolismo , Clostridioides difficile/metabolismo , Anticorpos Neutralizantes/metabolismo , ADP Ribose Transferases , Anticorpos Antibacterianos , Anticorpos Monoclonais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismoRESUMO
BACKGROUND: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. METHODS: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. RESULTS: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. CONCLUSION: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. IMPLICATIONS FOR PRACTICE: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.
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Di-Hidrouracila Desidrogenase (NADP) , Fluoruracila , Antimetabólitos Antineoplásicos , Canadá , Capecitabina/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Genótipo , Humanos , Quebeque/epidemiologia , Estudos RetrospectivosRESUMO
Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. KEY POINTS: To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Fusão Gênica , Cadeias HLA-DRB1 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas , PirimidinasRESUMO
BACKGROUND: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. METHODS: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. RESULTS: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. CONCLUSION: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.
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INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous drug eruptions characterized by epidermal detachment. Pembrolizumab is a monoclonal antibody that binds to the programmed death-1 receptor, and it has been associated with numerous cutaneous adverse side-effects, including Stevens-Johnson syndrome. CASE REPORT: We describe a 63-year-old male with metastatic lung adenocarcinoma who developed a rapidly progressing maculopapular rash three days after a first dose of pembrolizumab. On day 16, the rash affected more than 80% of body surface area with detachment of large sheets of necrolytic epidermis in 30-40% of body surface area. However, the patient only presented with mild mucosal involvement. Histopathologic examination of a skin biopsy showed a subepidermal blister with overlying prominent full thickness epidermal keratinocytic necrosis and a superficial perivascular infiltrate of lymphocytes. A toxic epidermal necrolysis secondary to pembrolizumab was then diagnosed. Management and outcome: In addition to supportive cares, the patient received corticosteroids and cyclosporine. The patient responded rapidly to the immunosuppressant therapy, and nearly complete re-epithelialization was achieved 24 days after the start of the reaction. DISCUSSION: In our review of the literature, 15 other cases of Stevens-Johnson syndrome/toxic epidermal necrolysis were reported with programmed death-1/programmed cell death ligand-1 inhibitors. To our knowledge, this is the first case of toxic epidermal necrolysis secondary to pembrolizumab published in the literature. The American Society of Clinical Oncology guidelines suggest that cyclosporine, in addition to corticosteroids, be initiated when toxic epidermal necrolysis is suspected. Clinicians should be aware of this rare dermatological emergency with the increasing use of pembrolizumab in oncology.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Síndrome de Stevens-Johnson/diagnóstico , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/tratamento farmacológico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndrome de Stevens-Johnson/patologiaRESUMO
Nontypeable Haemophilus influenzae (NTHi) is a pathogen known for being a frequent cause of acute otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In the present study, a vaccine antigen based on the fusion of two known NTHi adhesive proteins, protein E (PE) and a pilin subunit (PilA), was developed. The quality of the combined antigen was investigated through functional, biophysical, and structural analyses. It was shown that the PE and PilA individual structures are not modified in the PE-PilA fusion and that PE-PilA assembles as a dimer in solution, reflecting PE dimerization. PE-PilA was found to bind vitronectin by enzyme-linked immunosorbent assay, as isolated PE does. Disulfide bridges were conserved and homogeneous, which was determined by peptide mapping and top-down analysis of PE, PilA, and PE-PilA molecules. Finally, the PE-PilA crystal showed a PE entity with a three-dimensional (3D) structure similar to that of the recently published isolated PE, while the structure of the PilA entity was similar to that of a 3D model elaborated from two other type 4 pilin subunits. Taken together, our observations suggest that the two tethered proteins behave independently within the chimeric molecule and display structures similar to those of the respective isolated antigens, which are important characteristics for eliciting optimal antibody-mediated immunity. PE and PilA can thus be further developed as a single fusion protein in a vaccine perspective, in the knowledge that tethering the two antigens does not perceptibly compromise the structural attributes offered by the individual antigens.
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Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Fímbrias/imunologia , Vacinas Anti-Haemophilus/imunologia , Proteínas de Bactérias/química , Cristalização , Proteínas de Fímbrias/química , Dobramento de Proteína , Vacinas Sintéticas/imunologiaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagemAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Terapia de Alvo Molecular/métodos , Receptores ErbB/antagonistas & inibidoresRESUMO
The human respiratory syncytial virus (hRSV) fusion (F) protein is considered a major target of the neutralizing antibody response to hRSV. This glycoprotein undergoes a major structural shift from the prefusion (pre-F) to the postfusion (post-F) state at the time of virus-host cell membrane fusion. Recent evidences suggest that the pre-F state is a superior target for neutralizing antibodies compared to the post-F state. Therefore, for vaccine purposes, we have designed and characterized a recombinant hRSV F protein, called Pre-F-GCN4t, stabilized in a pre-F conformation. To show that Pre-F-GCN4t does not switch to a post-F conformation, it was compared with a recombinant post-F molecule, called Post-F-XC. Pre-F-GCN4t was glycosylated and trimeric and displayed a conformational stability different from that of Post-F-XC, as shown by chemical denaturation. Electron microscopy analysis suggested that Pre-F-GCN4t adopts a lollipop-like structure. In contrast, Post-F-XC had a typical elongated conical shape. Hydrogen/deuterium exchange mass spectrometry demonstrated that the two molecules had common rigid folding core and dynamic regions and provided structural insight for their biophysical and biochemical properties and reactivity. Pre-F-GCN4t was shown to deplete hRSV-neutralizing antibodies from human serum more efficiently than Post-F-XC. Importantly, Pre-F-GCN4t was also shown to bind D25, a highly potent monoclonal antibody specific for the pre-F conformation. In conclusion, this construct presents several pre-F characteristics, does not switch to the post-F conformation, and presents antigenic features required for a protective neutralizing antibody response. Therefore, Pre-F-GCN4t can be considered a promising candidate vaccine antigen.IMPORTANCE Human respiratory syncytial virus (RSV) is a global leading cause of infant mortality and adult morbidity. The development of a safe and efficacious RSV vaccine remains an important goal. The RSV class I fusion (F) glycoprotein is considered one of the most promising vaccine candidates, and recent evidences suggest that the prefusion (pre-F) state is a superior target for neutralizing antibodies. Our study presents the physicochemical characterization of Pre-F-GCN4t, a molecule designed to be stabilized in the pre-F conformation. To confirm its pre-F conformation, Pre-F-GCN4t was analyzed in parallel with Post-F-XC, a molecule in the post-F conformation. Our results show that Pre-F-GCN4t presents characteristics of a stabilized pre-F conformation and support its use as an RSV vaccine antigen. Such an antigen may represent a significant advance in the development of an RSV vaccine.
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Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/metabolismo , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Humanos , Substâncias Macromoleculares/ultraestrutura , Espectrometria de Massas , Microscopia Eletrônica , Modelos Moleculares , Ligação Proteica , Dobramento de Proteína , Multimerização Proteica , Estabilidade Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/imunologiaRESUMO
PURPOSE OF REVIEW: Immune checkpoint inhibitors have demonstrated remarkable efficacy with durable responses in the treatment of various malignancies. This new class of therapeutic agents is associated with a toxicity profile that differs from conventional cytotoxic therapy. The present review is focused on one of these toxicities affecting the respiratory system. RECENT FINDINGS: Many types of immune-related adverse events (irAEs) have been identified since the emergence of checkpoint inhibitors including colitis, nephritis, myasthenia gravis-like syndromes, acute interstitial nephritis, pneumonitis, and endocrinopathies. Although pneumonitis is relatively less frequent than other irAEs, this toxicity is by no means inconsequential as it has led to treatment-related deaths during the initial testing phases. SUMMARY: Immune-mediated pneumonitis is a potentially serious but relatively infrequent adverse event associated with the use of immune checkpoint inhibitors. IrAEs can be challenging for oncologists who are still unfamiliar with the early presenting symptoms and subsequent management of these toxicities, especially in the context of a rapidly expanding science. A high index of suspicion for pneumonitis must be maintained in patients receiving checkpoint inhibitors and who present new onset respiratory symptoms because this type of toxicity can be severe and potentially fatal.
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Anticorpos Monoclonais/efeitos adversos , Pneumonia/induzido quimicamente , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Nivolumabe , Pneumonia/imunologiaRESUMO
BACKGROUND: Thrombopoietin receptor agonists are new treatments for patients with chronic immune thrombocytopenia (ITP). How one of these agent, romiplostim, has impacted practice patterns, especially the use of intravenous immune globulin (IVIG), has not been evaluated outside of clinical trials. STUDY DESIGN AND METHODS: This was a retrospective cohort study of adult ITP patients treated with romiplostim in four Canadian centers. Patients had primary or secondary ITP and were followed for 1 year before starting weekly romiplostim treatment. We compared IVIG use, clinical outcomes, and cost before and after romiplostim. RESULTS: Twenty-nine patients with ITP received romiplostim. Median age was 54 years (interquartile range [IQR], 45-63 years) and patients had a median of two prior ITP treatments (IQR, 1-4) including splenectomy (n = 7). Median platelet (PLT) count was 23 × 10(9) before and 124 × 10(9) after romiplostim. Median duration of romiplostim treatment was 3.7 months. Patients used a median of two IVIG infusions per year before and 0.7 per year after starting romiplostim (p = 0.16). For patients who received weekly romiplostim for at least 1 month (n = 19), IVIG infusions were three (IQR, 1-5) per year before and 0.7 (IQR, 0.4-1.6) per year after romiplostim. Results were squewed by two high IVIG users. Nineteen (66%) patients discontinued romiplostim treatment during follow-up because of lack of response (n = 8), sustained response (n = 5), toxicities (n = 4), or response to splenectomy (n = 2). Overall health care costs were similar before and after romiplostim when concomitant treatments, nursing resources, and hospitalizations were considered. CONCLUSIONS: Romiplostim was associated with improved PLT counts and fewer IVIG infusions for most ITP patients. In practice, romiplostim was generally not continued long term and was cost neutral for overall ITP management.
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Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Quinazolinonas/administração & dosagem , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Efeito Placebo , Proteínas Proto-Oncogênicas p21(ras) , Quinazolinonas/efeitos adversosRESUMO
OBJECTIVES: KRAS mutations, particularly KRASG12C, are prevalent in non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have been a frontline treatment, but recently developed KRASG12C-selective inhibitors, such as sotorasib, present new therapeutic options. We conducted a multi-center retrospective cohort study to gain insights into real-world treatment patterns and outcomes in patients with KRASG12C-positive advanced NSCLC receiving systemic therapy post-ICI treatment. METHODS: From the CAnadian CAncers With Rare Molecular Alterations-Basket Real-world Observational Study (CARMA-BROS), a cohort of 102 patients with KRASG12C-positive advanced NSCLC across 9 Canadian centers diagnosed between 2015 and 2021 was analyzed. Clinico-demographic and treatment data were obtained from electronic health records. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The patients (median age 66 years; 58 % female; 99 % current/former tobacco exposure; 59 % PD-L1 ≥ 50 %), exhibited heterogeneous treatment patterns post-ICI. Most patients received ICIs as a first-line therapy, with varying subsequent lines including chemotherapy and targeted therapy. In patients receiving systemic therapy post-ICI, median overall survival was 12.6 months, and real-world progression-free survival was 4.7 months. KRASG12C-selective targeted therapy post-ICI (n = 20) showed longer real-world progression-free survival compared to single-agent chemotherapy (aHR = 0.39, p = 0.012). CONCLUSION: This study contributes valuable real-world data on KRASG12C-positive advanced NSCLC post-ICI treatment. The absence of a standard treatment sequencing post-ICI underscores the need for further investigation and consensus-building in the evolving landscape of KRASG12C-targeted therapies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Masculino , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Idoso , Proteínas Proto-Oncogênicas p21(ras)/genética , Canadá/epidemiologia , Pessoa de Meia-Idade , Mutação , Idoso de 80 Anos ou mais , Resultado do Tratamento , AdultoRESUMO
OBJECTIVES: The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. METHODS: In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400-500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. RESULTS: Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand-foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83%) and leukopenia (83%). Pharmacokinetic data revealed no clinically significant drug-drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60%). CONCLUSIONS: With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Esquema de Medicação , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Indóis/administração & dosagem , Leucopenia/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Mesotelioma/metabolismo , Pessoa de Meia-Idade , Pemetrexede , Pirróis/administração & dosagem , Sunitinibe , Adulto JovemRESUMO
BACKGROUND: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. METHODS: Patients were randomized to larotaxel 50 mg/m(2) with cisplatin 75 mg/m(2) every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 70 mg/m(2) on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). RESULTS: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m(2) and cisplatin to 60 mg/m(2) following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. CONCLUSION: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , GencitabinaRESUMO
OBJECTIVES: Thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) are commonly used in the management of extensive-stage small-cell lung cancer (ES-SCLC); however, Phase III trials of first-line immunotherapy often excluded these options. Guidance is needed regarding appropriate use of TRT, PCI, and magnetic resonance imaging (MRI) surveillance while new data are awaited. MATERIALS AND METHODS: In two web-based meetings, a pan-Canadian expert working group of five radiation oncologists and four medical oncologists addressed eight clinical questions regarding use of radiation therapy (RT) and MRI surveillance among patients with ES-SCLC receiving immunotherapy. A targeted literature review was conducted using PubMed and conference proceedings to identify recent (January 2019-April 2022) publications in this setting. Fifteen recommendations were developed; online voting was conducted to gauge agreement with each recommendation. RESULTS: After considering recently available evidence across lung cancer populations and clinical experience, the experts recommended that all patients with a response to chemo-immunotherapy, good performance status (PS), and limited metastases be considered for consolidation TRT (e.g., 30 Gy in 10 fractions). When considered appropriate after multidisciplinary team discussion, TRT can be initiated during maintenance immunotherapy. All patients who respond to concurrent chemo-immunotherapy should undergo restaging with brain MRI to guide decision-making regarding PCI versus MRI surveillance alone. MRI surveillance should be conducted for two years after response to initial therapy. PCI (e.g., 25 Gy in 10 fractions or 20 Gy in 5 fractions) can be considered for patients without central nervous system involvement who have a response to chemo-immunotherapy and good PS. Concurrent treatment with PCI and immunotherapy or with TRT, PCI, and immunotherapy is appropriate after completion of initial therapy. All recommendations were agreed upon unanimously. CONCLUSIONS: These consensus recommendations provide practical guidance regarding appropriate use of RT and immunotherapy in ES-SCLC while awaiting new clinical trial data.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/patologia , Consenso , Canadá , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Neoplasias Encefálicas/secundário , ImunoterapiaRESUMO
The PACIFIC trial showed a survival benefit with durvalumab through five years in stage III unresectable non-small cell lung cancer (NSCLC). However, optimal use of imaging to detect disease progression remains unclearly defined for this population. An expert working group convened to consider available evidence and clinical experience and develop recommendations for follow-up imaging after concurrent chemotherapy and radiation therapy (CRT). Voting on agreement was conducted anonymously via online survey. Follow-up imaging was recommended for all suitable patients after CRT completion regardless of whether durvalumab is received. Imaging should occur every 3 months in Year 1, at least every 6 months in Year 2, and at least every 12 months in Years 3-5. Contrast computed tomography was preferred; routine brain imaging was not recommended for asymptomatic patients. The medical oncologist should follow-up during Year 1 of durvalumab therapy, with radiation oncologist involvement if pneumonitis is suspected; medical and radiation oncologists can subsequently alternate follow-up. Some patients can transition to the family physician/community primary care team at the end of Year 2. In Years 1-5, patients should receive information regarding smoking cessation, comorbidity management, vaccinations, and general follow-up care. These recommendations provide guidance on follow-up imaging for patients with stage III unresectable NSCLC whether or not they receive durvalumab consolidation therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Seguimentos , Quimiorradioterapia/métodos , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: PD-L1 expression is used to predict NSCLC response to ICIs, but its performance is suboptimal. The impact of KRAS mutations in these patients is unclear. Studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs. PATIENTS & METHODS: This is a retrospective study of patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. ORR and safety were compared using Wald method. RESULTS: From 100 patients with known KRAS status, 50 were mutated (KRASMut). Mutation in TP53, STK11 and KEAP1 were present, and their status known in, respectively, 19/40 (47.5 %), 8/39 (20.5 %) and 4/38 (10.5 %) patients. STK11Mut and KEAP1Mut were associated with shorter overall survival when compared with wild type tumors (respectively median OS of 3.3 vs 20.4, p = 0.0001 and 10.1 vs 17.7, p = 0.24). When KRAS status was compounded with STK11/KEAP1, KRASMut trended to a better prognosis in STK11+KEAP1WT tumors (median OS 21.1 vs 15.8 for KRASWT, p = 0.15), but not for STK11+/-KEAP1Mut tumors. The NLR was strongly impacted by STK11 (6.0Mutvs 3.6WT, p = 0.014) and TP53 (3.2Mutvs 4.8WT, p = 0.048), but not by KEAP1 or KRAS mutations. CONCLUSION: STK11Mut and KEAP1Mut are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11Mut but not by KEAP1Mut, suggesting differences in their resistance mechanism. In STK11-KEAP1WT tumors, KRASMut seem associated with improved survival in NSCLC patients treated with ICIs. MICROABSTRACT: Response of NSCLC to immunotherapy is not easily predictable. We conducted a retrospective study in 100 patients with NSCLC and a known KRAS status. By accounting for different co-mutations, KRAS mutation was found to be associated with a better median overall survival in STK11 and KEAP1 wild-type tumors (21.1 vs 15.8, p = 0.15). NLR was impacted by STK11, but not KEAP1 mutation, suggesting a difference in their resistance mechanism.