Abstract
Background
In this study, we investigated whether outcomes with atezo (anti–PD-L1) monotherapy in mUC varied between women and men across Phase (Ph) 1-3 trials in different treatment ...settings.
Methods
In this post hoc analysis, we assessed baseline characteristics, objective response rate (ORR; RECIST 1.1) and overall survival (OS) outcomes by sex in pts with previously treated mUC (Ph 1, PCD4898g; Ph 2, IMvigor210 Cohort 2; Ph 3, IMvigor211; Ph 3b, SAUL) and cisplatin-ineligible, untreated mUC (Ph 2, IMvigor210 Cohort 1).
Results
Across cohorts, 2459 pts were evaluated (including 464 in the IMvigor211 chemo arm); 22% were female (Table). Age was generally similar by sex, except in IMvigor210 Cohort 1 (median age: female, 77 y; male, 72 y). Median body mass index (BMI) was also similar by sex, except in PCD4898g (female, 23 kg/m2; male, 28 kg/m2). ECOG PS varied by sex across studies, but no consistent trend was seen. Median treatment duration was similar in females vs males, except in PCD4989g (44 d vs 108 d) and IMvigor210 Cohort 1 (123 d vs 106 d). ORR tended to be numerically higher in males (except in IMvigor210 Cohort 1; Table), although no statistically significant differences in ORR were seen except in IMvigor210 Cohort 2. Follow-up (Table) and treatment discontinuation varied by trial but were similar by sex. Median OS was similar by sex across studies; in the only randomised study, IMvigor211, no significant difference in OS benefit with atezo (vs chemo) by sex was seen (HR 95% CI: female, 0.87 0.64, 1.18; male, 0.83 0.69, 0.98; P = 0.7462). Data evaluating disease and treatment characteristics by sex and outcomes accounting for potential confounders will be presented.
Table:927PPCD4989gIMvigor210IMvigor211IMvigor211SAULIMvigor210Cohort 2Atezo ArmChemo ArmCohort 1Female/male, n23/7269/241110/357103/361225/77923/96Median follow-up, mo37.832.917.317.412.629.3Investigator-assessed ORR (95% CI), %aFemale13 (3, 34)6 (2, 14)11 (6,19)8 (3, 15)12 (8, 17)26 (10, 48)Male31 (20, 43)20 (15, 26)14 (11, 18)15 (12, 19)14 (12, 17)26 (18, 36)mOS (95% CI), moFemale13.1 (4.0, 24.5)7.9 (5.0, 11.9)8.0 (5.8, 11.3)8.0 (6.3, 9.5)8.3 (6.5, 10.0)16.2 (4.4, not estimable)Male9.6 (7.3, 17.5)7.9 (6.5, 9.6)8.9 (8.0, 9.8)8.0 (7.1, 9.0)9.0 (7.6, 10.5)16.7 (10.1, 24.9)Data cutoff date31 Dec 201612 Jul 201713 Mar 201713 Mar 201716 Sep 201812 Jul 2017aFor IMvigor211, ORR-evaluable n = 108/354 (atezo) and 103/358 (chemo); for SAUL, ORR-evaluable included pts with measurable and nonmeasurable disease
Conclusions
No significant OS differences by sex were seen across all Ph 1-3 atezo mUC studies. ORR was numerically higher in male pts with previously treated mUC, with less-pronounced differences in larger studies (e.g., IMvigor211, SAUL).
Clinical trial identification
NCT01375842, NCT02951767, NCT02108652, NCT02302807, NCT02928406.
Editorial acknowledgement
Paige Davies, PhD, of Health Interactions, funded by F. Hoffmann-La Roche, Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche, Ltd.
Funding
F. Hoffmann-La Roche, Ltd.
Disclosure
J. Hoffman-Censits: Full / Part-time employment: Johns Hopkins Medicine; Research grant / Funding (institution): Sibley Hospital Foundation; Honoraria (self): AstraZeneca; Honoraria (self): Foundation Medicine; Non-remunerated activity/ies, Medical Writing Services: Genentech. J.E. Rosenberg: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merck; Shareholder / Stockholder / Stock options: Illumina; Honoraria (self): UpToDate; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Honoraria (self): Medscape; Honoraria (self): Vindico; Honoraria (self): Peerview; Honoraria (self): Chugai Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy: Agensys; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Licensing / Royalties: Predictor of platinum sensitivity; Advisory / Consultancy: Inovio, Bioclin, QED Therapeutics, Western Oncolytics, GSK; Advisory / Consultancy: Adicet Bio, Sensei Biotherapeutics, Fortress Biotech, Pharmacyclics; Research grant / Funding (institution): Agensys, Mirati Therapeutics, Novartis, Viralytics, Incyte. M. van Der Heijden: Honoraria (institution), Research grant / Funding (institution): Astellas; Honoraria (institution), Research grant / Funding (institution): BMS; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Travel / Accommodation / Expenses: MSD; Honoraria (institution): Janssen. R. Dreicer: Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): BMS; Honoraria (self): Eisai; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Astellas; Honoraria (self): Janssen. J.L. Perez Gracia: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Janssen. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): Ada Cap; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Shareholder / Stockholder / Stock options: Bellicum; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol Myer Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Genentech; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Innocrin; Advisory / Consultancy: Janssen; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Pharmacyclics- consultant; Progenics- grant (inst); Roche labs- grant (inst), consultant; Sanofi Aventis- Grant (inst); Seattle Genetics- Consultant, Grant (inst); Tyme (Stock/Investment); Urogen- Consultant: Pfizer. M.M. Retz: Full / Part-time employment: Technical University- Munich, Germany. R. Sabbatini: Full / Part-time employment: AOU Policlinico di Modena, Italy; Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. E. Naglieri: Research grant / Funding (institution): Roche. C. Caserta: Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Astellas. R. Iacovelli: Advisory / Consultancy, Speaker Bureau / Expert testimony: IPSEN; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi. L. Galli: Full / Part-time employment: AOUP; Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer. R. McDermott: Advisory / Consultancy, Personal fees: Clovis; Research grant / Funding (self), Grants and personal fees: Pfizer; Research grant / Funding (self), Grants: Amgen; Research grant / Funding (institution), Research funding and personal fees: Bristol Meyers Squibb; Research grant / Funding (self): Merck; Research grant / Funding (self): Bayer; Research grant / Funding (self): Janssen; Research grant / Funding (self): Celgene. R. Morales Barrera: Full / Part-time employment: Vall d’ Hebron Hospital; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Astellas, Aveo; Research grant / Funding (institution): Blueprint, BN Immunotherapeutics, BI, BMS; Research grant / Funding (institution): Cougar Biotech, Deciphera, Exelixis; Research grant / Funding (institution): GSK, Incyte, Janssen, Karyopharm Therapeutics INC., Laboratoires Leurquin Mediolanum SAS, S.A., Medimmune, Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix, Novartis, Pfizer, Puma Biotech, SFJ, Teva; Honoraria (self), Advisory / Consultancy, Speaker Bureau
Abstract
Background
CUP are heterogeneous tumors that share the unique characteristic of metastases with no identifiable origin. The outcome of patients (pts) with CUP is poor despite empiric ...chemotherapy that has activity against a wide variety of neoplasms such as the cisplatin-gemcitabine combination (Culine S, JCO 2002). Molecular tests may identify primary sites in up to 80% of pts, and results suggest that at least 1/3 of identified primaries may not be sensitive to empiric chemotherapy used in CUPs (Gross-Goupil G 2012). In the GEFCAPI 04 phase III trial, we hypothesized that tailored treatment will improve outcomes.
Methods
Eligible pts had pathologically-confirmed metastatic CUPs and were treatment naïve. Pts belonging to pre-defined favorable subsets were excluded. After relevant workup had identified no primary site, pts were randomized 1:1 to either Arm A (Cisplatin 100 mg/m² d1+ Gemcitabine 1250 mg/m², day 1 and 8, q3w) or Arm B (gene expression test followed by à la carte treatment according to the suspected primary). The test consisted of the Tissue Of Origin (Pathwork, n = 21) or CancerTYPE ID (Biotheranostics, n = 222). The primary endpoint was PFS (HR = 0.625, power=80%, 5% bilateral test). Stratification was on site, PS and LDH level. Secondary endpoints were PFS in pts with pre-defined cancers likely insensitive to cisplatin-gemcitabine and OS.
Results
From 03/12 to 02/18, 243 pts from 4 EU countries were randomized (Arm A: 120, Arm B: 123). Primary cancers most often reported by tests were pancreatico-biliary cancer (19%), squamous cell carcinoma (11%, kidney cancer (8%), and lung cancer (8%). Treatment was tailored by molecular test results in 91/123 arm B pts (74%). PFS by central review was similar: HR = 0.95 (0.72-1.25); p = 0.7; medians: 5.3 m arm A vs 4.6 m arm B. PFS by local review also showed no significant difference: HR = 0.80 (0.60-1.06); p = 0.12; medians 5.8 vs 6.4 m. OS was also similar in the overall population (HR: 0.92 (0.69-1.23), medians: 10 vs 10.7 m) and in 60 pts with suspected cancers likely insensitive to GC.
Conclusions
In GEFCAPI 04, using a molecular test followed by tailored systemic treatment did not improve outcomes of pts with CUP.
Clinical trial identification
2011-A01202-39.
Legal entity responsible for the study
Institut Gustave Roussy.
Funding
Programme Hospitalier de Recherche Clinique (PHRC) from the French Ministry of Health.
Disclosure
K. Fizazi: Advisory / Consultancy: Astellas; Advisory / Consultancy: AAA; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Curevac; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Jonhson; Honoraria (self), Advisory / Consultancy: Roche. C.A. Schnabel: Full / Part-time employment: bioTheranostics. All other authors have declared no conflicts of interest.
We present a Risk Atlas of Mexico City based on a Geographical Information System (RA-GIS). We identified the prevalent social risk to the more relevant hazards in Mexico City (CDMX): earthquakes, ...volcanic eruptions, floods, landslides, forest fires, and land subsidence. A total of 274 shape-file maps were generated in this project. Seismic hazard was estimated for return periods (RP) of 20, 125, 250, and 475 years. Three areas in central and northwestern CDMX were identified along the Younger Chichinautzin Monogenetic Volcanic Field with a high probability of forming a new volcano. Subsidence is concentrated to the east and southeast of CDMX, where subsidence rates are among the highest worldwide. Flooding events were estimated for RP of 2, 5, 10, 50, and 100 years, and most of them are concentrated in the central and northern sectors of the city. During the dry season (December–April), southern CDMX has very high probability of forest fire occurrence. There is high susceptibility of landslides on the west and southwest of the city. The goals of this RA-GIS are to provide a tool to the local and federal authorities and all organizations responsible for disaster prevention and mitigation to: (1) improve the knowledge of the potential physical and social impact of local hazards; (2) provide elements for disaster prevention, mitigation, preparedness, and response; (3) benefit decision-makers with robust risk data; (4) provide information for land-use planning; and (5) support further research to reduce the impact of disasters caused by natural phenomena.
The comprehensive management of organic urban solid waste is a concern due to its direct and indirect impact on the environment. Anaerobic Digestion (AD) has been recognized as an alternative and ...environmentally friendly technology for waste disposal, converting them into organic fertilizers and renewable energy. This research presents an experiment involving four reactors fed with household organic waste, three inoculated with canine, goat, and rabbit manure, and one without inoculum. The experiment was observed for 30 consecutive days to analyze the pH and temperature parameters involved in the AD process in domestic reactors. Statistical methodology, including one-way analysis of variance for assessing the effect of the type of inoculum, Tukey's simultaneous confidence intervals for mean differences, and 90 % confidence intervals for μ in temperature and manure, was utilized. Additionally, main effects analysis of the factors of average temperature and pH were conducted. The results of the one-factor experiment show that the type of inoculum does not significantly influence the variation in pH, while temperature remains relatively stable throughout the AD process. However, the analysis of main effects indicates that goat manure tends to stabilize the temperature with minimal variation, whereas variation is more heterogeneous in the other experiments.
Objectives
To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint ...inhibitors (ICIs).
Patients and Methods
We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression‐free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni‐ and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line).
Results
Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio aOR 0.73, 95% confidence interval CI 0.43–1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio aHR 0.93, 95% CI 0.73–1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81–1.27). Patients with mixed‐histology UTUC had a significantly lower ORR and shorter PFS vs mixed‐histology LTUC (aOR 0.20, 95% CI 0.05–0.91 and aHR 1.66, 95% CI 1.06–2.59), respectively).
Conclusion
Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed‐histology UTUC had a lower ORR and shorter PFS compared to mixed‐histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.
Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor ...outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM-based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view.
Generation 4 of polyamidoamine dendrimer (G4-PAMAM) has several biological effects due to its tridimensional globular structure, repetitive branched amides, tertiary amines, and amino-terminal ...subunit groups liked to a common core. G4-PAMAM is cytotoxic due to its positive charges. However, its cytotoxicity could increase in cancer cells due to the excessive intracellular negative charges in these cells. Furthermore, this work reports G4-PAMAM chemical structural characterization using UHPLC-QTOF-MS/MS (LC-MS) by electrospray ionization to measure its population according to its positive charges. Additionally, the antiproliferative effects and intracellular localization were explored in the HMC-1 and K-562 cell lines by confocal microscopy. The LC-MS results show that G4-PAMAM generated multivalent mass spectrum values, and its protonated terminal amino groups produced numerous positive charges, which allowed us to determine its exact mass despite having a high molecular weight. Additionally, G4-PAMAM showed antiproliferative activity in the HMC-1 tumor cell line after 24 h (IC
= 16.97 µM), 48 h (IC
= 7.02 µM) and 72 h (IC
= 5.98 µM) and in the K-562 cell line after 24 h (IC
= 15.14 µM), 48 h (IC
= 14.18 µM) and 72 h (IC
= 9.91 µM). Finally, our results showed that the G4-PAMAM dendrimers were located in the cytoplasm and nucleus in both tumor cell lines studied.
Optical tweezers have enabled the exploration of picoNewton forces and dynamics in single-molecule systems such as DNA and molecular motors. In this work, we used optical tweezers to study the ...folding/unfolding dynamics of the APTSTX1-aptamer, a single-stranded DNA molecule with high affinity for saxitoxin (STX), a lethal neurotoxin. By measuring the transition force during (un)folding processes, we were able to characterize and distinguish the conformational changes of this aptamer in the presence of magnesium ions and toxin. This work was supported by molecular dynamics (MD) simulations to propose an unfolding mechanism of the aptamer-Mg+2 complex. Our results are a step towards the development of new aptamer-based STX sensors that are potentially cheaper and more sensitive than current alternatives.
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