ABSTRACT
BACKGROUND: COVID-19 has had wide-reaching effects on healthcare services beyond the direct treatment of the pandemic. Most current studies have reported changes in realised service usage, but the dynamics of how patients engage with healthcare services are less well understood. We analysed the effects of COVID-19 on healthcare bookings and cancellations for various service channels between January 2020 and July 2021. METHODS: Our data includes 7.3 million bookings, 11.0 million available appointments, and 405.1 thousand cancellations by 900.6 thousand individual patients between the ages of 18 and 65 years. The data were collected from electronic health record data, including laboratory and imaging services as well as inpatient stays, between January 2017 and July 2021. The patients were Finnish private and occupational healthcare customers in the capital region of Finland. We fitted an autoregressive moving average (ARIMA) model on data between 2017 and 2019 to predict the expected numbers of bookings, available appointments, and cancellations, which were compared to observed time series data between 2020 and 2021. RESULTS: Utilisation of physical, in-person primary care physician appointments decreased by up to 50% during the first 18 months of the pandemic. At the same time, digital care channels experienced a rapid, multi-fold increase in service usage. Simultaneously, the number of bookings for laboratory and imaging services decreased by 50% below the pre-pandemic projections. The number of specialist and hospital service bookings remained at the predicted level during the study period. Cancellations for most health services increased sharply by up to three times the pre-COVID levels during the first weeks of the pandemic but returned to the pre-pandemic levels for the rest of the study period. CONCLUSIONS: The reduction in in-person appointments and the increase in the utilisation of digital services was likely a contributing factor in the decrease of the utilisation of diagnostic and imaging services throughout the study period. Utilisation of specialist care and hospital services were not affected. Cancellations contributed to the changes in service utilisation only during the first weeks of the pandemic.
Subject(s)
COVID-19 , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Finland/epidemiology , Time Factors , COVID-19/epidemiology , Patient Acceptance of Health Care , Health FacilitiesABSTRACT
Immune checkpoint inhibitors (ICI) show substantially greater efficacy in inflamed tumors characterized by preexisting T-cell infiltration and IFN signaling than in noninflamed "cold" tumors, which often remain immunotherapy resistant. The cancer immunotherapy bexmarilimab, which inhibits the scavenger receptor Clever-1 to release macrophage immunosuppression and activate adaptive immunity, has shown treatment benefit in subsets of patients with advanced solid malignancies. However, the mechanisms that determine bexmarilimab therapy outcome in individual patients are unknown. Here we characterized bexmarilimab response in ovarian cancer ascites macrophages ex vivo using single-cell RNA sequencing and demonstrated increased IFN signaling and CXCL10 secretion following bexmarilimab treatment. We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to ICIs.
Subject(s)
Interferons , Ovarian Neoplasms , Female , Humans , Tumor-Associated Macrophages/pathology , Immunotherapy/methods , Ovarian Neoplasms/pathology , Adaptive Immunity , Tumor MicroenvironmentABSTRACT
Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.
Subject(s)
Antibodies, Monoclonal, Humanized , Neoplasms , Humans , Antibodies, Monoclonal, Humanized/pharmacology , Macrophage Activation , Neoplasms/therapyABSTRACT
BACKGROUND: In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. METHODS: Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. RESULTS: All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. CONCLUSIONS: Long-term darolutamide treatment was well tolerated; no new safety signals observed. In patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide.
ABSTRACT
BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαß-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.
Subject(s)
Antineoplastic Agents , Melanoma , Humans , Programmed Cell Death 1 Receptor , Melanoma/drug therapy , Melanoma/genetics , Nivolumab/therapeutic use , Antineoplastic Agents/pharmacology , CD8-Positive T-Lymphocytes , Receptors, Antigen, T-Cell/metabolism , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: There is an ongoing need to identify biomarkers for correct patient selection for immune-oncology treatments in metastatic renal cell carcinoma (mRCC). The aim of our study was to evaluate the prognostic role of elevated C-reactive protein (CRP) values and immune-related adverse events (irAEs) to indicate immune checkpoint inhibitors' (ICIs) efficacy in nivolumab-treated mRCC patients. MATERIALS AND METHODS: Data from 96 mRCC patients treated with nivolumab at Comprehensive Cancer Center, Helsinki University Hospital in a real-life setting were collected between 2006 and 2020 retrospectively. Patients' baseline CRP, on-treatment (<12 weeks) CRP, and reported irAE association to median survival and outcome were analyzed using Kaplan-Meier and Cox regression. RESULTS: Patients with elevated baseline CRP were associated with worse overall survival (OS) and progression-free survival (PFS) when compared with normal baseline CRP. This significant correlation was also observed with patients with elevated on-treatment CRP. In multivariate survival analyses both elevated baseline and on-treatment CRP had shorter OS and PFS than patients with normal CRP: hazard ratio (HR) 2.84 (95% CI 1.48-5.42), HR 3.68 (95% CI 1.92-7.03) and PFS: HR 1.77 (95% CI 1.06-2.97), HR 2.88 (95% CI 1.75-4.73), respectively. A significant difference in OS was also seen between patients without irAE and with irAE during treatment. In multivariate survival analyses, patients without irAE had shorter OS HR 1.93 (95% CI 1.03-3.62) compared with patients with reported irAE. CONCLUSIONS: Elevated baseline CRP, on-treatment CRP, and absence of irAE correlate with poor outcome in nivolumb-treated mRCC patients. These results suggest that monitoring CRP values as well as potential irAEs during treatment may be of use in clinical decision making.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Nivolumab/adverse effects , Immune Checkpoint Inhibitors/adverse effects , C-Reactive Protein/analysis , Prognosis , Kidney Neoplasms/pathology , Retrospective StudiesABSTRACT
OBJECTIVE: To evaluate the trajectories of acute upper respiratory tract infections (URTIs), COVID-19, and the use of antibiotics in Finland during the COVID-19 epidemic. DESIGN: Population-based cohort study. SETTING: Electronic medical records from a nationwide healthcare chain in Finland. PARTICIPANTS: 833 444 patients from a cohort of 1 970 013 Finns who had used medical services between 2017 and 2020. MAIN OUTCOME MEASURES: Number of weekly patients of acute URTIs, COVID-19, and the prescribed number of antibiotics in Finland between 6 January 2020 and 21 June 2020. We estimated the respective expected numbers from 1 March 2020 onward using autoregressive integrated moving average model from 1 January 2017 to 1 March 2020. We assessed the public interest in COVID-19 by collecting Google search trend frequencies. RESULTS: There was a rapid increase in COVID-related internet searches between weeks 10 and 12. At the same time, there was a 106% increase in diagnoses of acute URTIs, from 410 per 100 000 inhabitants to 845 per 100 000. The first COVID-19 cases were diagnosed on week 11. Prescriptions for URTI-related antibiotics declined by 71% (403 per 100 000 to 117 per 100 000) between weeks 11 and 15 while no relevant change took place in prescriptions of antibiotics for urinary tract infections. CONCLUSIONS: At the beginning of the epidemic, many people contacted healthcare professionals with relatively mild symptoms, as indicated by the reduced rate of URTI-antibiotics prescriptions. Our findings indicate that health service providers should be prepared for rapid variations in service demand. Securing access of true COVID-19 patients to proper diagnostics, care and isolation measures may help in preventing the spread of the disease.
Subject(s)
COVID-19 , Respiratory Tract Infections , Anti-Bacterial Agents/therapeutic use , Cohort Studies , Finland/epidemiology , Humans , Incidence , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/epidemiology , SARS-CoV-2 , Time FactorsABSTRACT
PURPOSE: Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer. METHODS: The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients. RESULTS: The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF. CONCLUSION: Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.
Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/administration & dosage , Chemotherapy, Adjuvant/methods , Cyclophosphamide/administration & dosage , Disease-Free Survival , Docetaxel/administration & dosage , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , HumansABSTRACT
While the abundance and phenotype of tumor-infiltrating lymphocytes are linked with clinical survival, their spatial coordination and its clinical significance remain unclear. Here, we investigated the immune profile of intratumoral and peritumoral tissue of clear cell renal cell carcinoma patients (n = 64). We trained a cell classifier to detect lymphocytes from hematoxylin and eosin stained tissue slides. Using unsupervised classification, patients were further classified into immune cold, hot and excluded topographies reflecting lymphocyte abundance and localization. The immune topography distribution was further validated with The Cancer Genome Atlas digital image dataset. We showed association between PBRM1 mutation and immune cold topography, STAG1 mutation and immune hot topography and BAP1 mutation and immune excluded topography. With quantitative multiplex immunohistochemistry we analyzed the expression of 23 lymphocyte markers in intratumoral and peritumoral tissue regions. To study spatial interactions, we developed an algorithm quantifying the proportion of adjacent immune cell pairs and their immunophenotypes. Immune excluded tumors were associated with superior overall survival (HR 0.19, p = 0.02) and less extensive metastasis. Intratumoral T cells were characterized with pronounced expression of immunological activation and exhaustion markers such as granzyme B, PD1, and LAG3. Immune cell interaction occurred most frequently in the intratumoral region and correlated with CD45RO expression. Moreover, high proportion of peritumoral CD45RO+ T cells predicted poor overall survival. In summary, intratumoral and peritumoral tissue regions represent distinct immunospatial profiles and are associated with clinicopathologic characteristics.
Subject(s)
Algorithms , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/immunology , Decision Support Techniques , Immunohistochemistry , Immunophenotyping , Kidney Neoplasms/immunology , Leukocyte Common Antigens/analysis , Lymphocytes, Tumor-Infiltrating/immunology , T-Lymphocytes/immunology , Tumor Microenvironment/immunology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/therapy , DNA-Binding Proteins/genetics , Female , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/mortality , Kidney Neoplasms/therapy , Male , Middle Aged , Mutation , Nuclear Proteins/genetics , Phenotype , Predictive Value of Tests , Prognosis , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/geneticsABSTRACT
PURPOSE: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. PATIENTS AND METHODS: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. RESULTS: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. CONCLUSIONS: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.
Subject(s)
Cell Adhesion Molecules, Neuronal , Lymphocyte Activation , Neoplasms , Receptors, Lymphocyte Homing , Humans , CD8-Positive T-Lymphocytes/immunology , Cell Adhesion Molecules, Neuronal/antagonists & inhibitors , Down-Regulation , Lymphocyte Activation/drug effects , Neoplasms/drug therapy , Neoplasms/immunology , Receptors, Lymphocyte Homing/antagonists & inhibitorsABSTRACT
The modulation of subpopulations of pro-angiogenic monocytes (VEGFR-1+CD14 and Tie2+CD14) was analyzed in an ancillary study from the prospective PazopanIb versus Sunitinib patient preferenCE Study (PISCES) (NCT01064310), where metastatic renal cell carcinoma (mRCC) patients were treated with two anti-angiogenic drugs, either sunitinib or pazopanib. Blood samples from 86 patients were collected prospectively at baseline (T1), and at 10 weeks (T2) and 20 weeks (T3) after starting anti-angiogenic therapy. Various subpopulations of myeloid cells (monocytes, VEGFR-1+CD14 and Tie2+CD14 cells) decreased during treatment. When patients were divided into two subgroups with a decrease (defined as a >20% reduction from baseline value) (group 1) or not (group 2) at T3 for VEGFR-1+CD14 cells, group 1 patients presented a median PFS and OS of 24 months and 37 months, respectively, compared with a median PFS of 9 months (p = 0.032) and a median OS of 16 months (p = 0.033) in group 2 patients. The reduction in Tie2+CD14 at T3 predicted a benefit in OS at 18 months after therapy (p = 0.04). In conclusion, in this prospective clinical trial, a significant decrease in subpopulations of pro-angiogenic monocytes was associated with clinical response to anti-angiogenic drugs in patients with mRCC.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/blood supply , Kidney Neoplasms/drug therapy , Monocytes/pathology , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/pharmacology , Animals , Antigens, CD/metabolism , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/pathology , Disease Models, Animal , Humans , Kidney Neoplasms/blood , Kidney Neoplasms/pathology , Mice, Inbred BALB C , Myeloid Cells/drug effects , Myeloid Cells/pathology , Neoplasm Metastasis , Sunitinib/pharmacology , Sunitinib/therapeutic use , Treatment Outcome , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
BACKGROUND: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. METHODS: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. RESULTS: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. CONCLUSION: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed. TRIAL REGISTRATION NUMBER: NCT02264418.
Subject(s)
Neoplasms , Vascular Endothelial Growth Factor A , Aged , Angiogenesis Inhibitors/therapeutic use , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Fibroblast Growth Factor/therapeutic use , Vascular Endothelial Growth Factor A/therapeutic useABSTRACT
BACKGROUND: Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. METHODS: This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. RESULTS: Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed. CONCLUSIONS: ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT03035591.
Subject(s)
Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Oxazoles/administration & dosage , Proteins/antagonists & inhibitors , Pyridines/administration & dosage , Quinolines/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biological Availability , Blood Platelets/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Drug Administration Schedule , Fatigue/chemically induced , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/metabolism , Male , Maximum Tolerated Dose , Melanoma/drug therapy , Melanoma/metabolism , Middle Aged , Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Oxazoles/adverse effects , Oxazoles/pharmacokinetics , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyridines/adverse effects , Pyridines/pharmacokinetics , Quinolines/adverse effects , Quinolines/pharmacokinetics , Sarcoma/drug therapy , Sarcoma/metabolism , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/metabolism , Young AdultABSTRACT
BACKGROUND: Most prostate cancer patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy treatment. CRPC growth is mediated mostly by androgen receptor signalling driven by primary androgens synthesised largely by the CYP17A1 enzyme. OBJECTIVE: To evaluate the safety profile and dose-limiting toxicities of ODM-204. DESIGN, SETTING, AND PARTICIPANTS: In this open, uncontrolled, nonrandomised, multicentre, tolerability and pharmacokinetic first-in-man phase I dose escalation study, patients with metastatic CRPC were randomised to receive ODM-204 in sequential cohorts of five dose levels (ie, 50, 100, 200, 300, and 500mg twice daily) concomitantly with prednisone. INTERVENTION: ODM-204, a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed. RESULTS AND LIMITATIONS: Of the 23 patients enrolled into the study, 60.9% experienced mild adverse effects considered to be related to the study treatment, which were fatigue, increased/decreased appetite, nausea, asthenia, diarrhoea, and weight decrease. ODM-204 area under the curve (AUC0-12) values increased dose dependently until the 300mg dose. The AUC was lower on day 8 after repeated dosing compared with day 1 from the 200mg dose upwards. Decreases in testosterone levels were seen with ODM-204 treatment confirming androgen deprivation. Of the patients, 13% also demonstrated a >50% decrease in PSA at week 12 and continued ODM-204 treatment for over a year. CONCLUSIONS: ODM-204 was well tolerated up to the highest evaluated dose. There were decreases in both testosterone and PSA levels, suggesting preliminary antitumour activity in the treatment of CRPC. The pharmacokinetic properties of the molecule, however, prevent further development. PATIENT SUMMARY: This study looked at the safety of ODM-204, a novel dual inhibitor of CYP17A1 and the androgen receptor, in castration-resistant prostate cancer patients. ODM-204 treatment was found to be well tolerated, and it also reduced both serum testosterone and prostate-specific antigen levels, but the properties of the molecule prevent further development.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Imidazoles/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Aged , Aged, 80 and over , Androgen Receptor Antagonists/adverse effects , Humans , Imidazoles/adverse effects , Imidazoles/pharmacology , Male , Middle Aged , Time Factors , Treatment OutcomeSubject(s)
Ambulatory Care/psychology , Hematology/statistics & numerical data , Oncology Nursing/statistics & numerical data , Outpatients/psychology , Patient Preference/psychology , Patient Preference/statistics & numerical data , Adult , Aged , Aged, 80 and over , Ambulatory Care/statistics & numerical data , Female , Finland , Humans , Male , Middle Aged , Outpatients/statistics & numerical dataABSTRACT
INTRODUCTION: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). PATIENTS AND METHODS: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. RESULTS: Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS ≥ 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar. CONCLUSIONS: Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. ≥ 2) to more accurately predict outcomes.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/secondary , Female , Follow-Up Studies , Humans , Indazoles , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Patient Safety , Prognosis , Prospective Studies , Risk Factors , Survival Rate , Young AdultABSTRACT
PURPOSE: CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts. METHODS: Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response. RESULTS: Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms. CONCLUSION: With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Ipilimumab/administration & dosage , Nivolumab/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Urothelium/pathology , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/analysis , Carcinoma , Disease Progression , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Metastasis , Treatment OutcomeABSTRACT
BACKGROUND: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). SUBJECTS, MATERIALS, AND METHODS: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. RESULTS: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. CONCLUSION: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. IMPLICATIONS FOR PRACTICE: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors' knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/secondary , Female , Follow-Up Studies , Humans , Indazoles , Kidney Neoplasms/pathology , Male , Middle Aged , Prognosis , Prospective Studies , Quality of Life , Survival Rate , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3. CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.