Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer: The FORT-2 Phase 1b Nonrandomized Clinical Trial.

Importance: The oral pan-fibroblast growth factor receptor inhibitor rogaratinib previously demonstrated encouraging safety and efficacy in a phase 1 study of patients with urothelial cancer (UC) overexpressing FGFR messenger RNA (mRNA). Objective: To evaluate the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab in cisplatin-ineligible patients with FGFR mRNA-positive, locally advanced/metastatic UC. Design, Setting, and Participants: The FORT-2 nonrandomized clinical trial was an open-label, single-arm, multicenter study conducted between May 15, 2018, and July 16, 2021, in 30 centers across Asia, Europe, and North America. Eligible patients had locally advanced/metastatic UC with FGFR1/3 mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022. Interventions: Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days. Main Outcomes and Measures: Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab. Results: Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75.0 [47.0-85.0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg. At the RP2D, the overall response rate was 53.8% in the rogaratinib 600 mg group, including 4 patients (15%) with complete responses; 12 responders (86%) did not have an FGFR3 gene alteration, and 11 (79%) had low PD-L1 expression. Conclusions and Relevance: In this phase 1b nonrandomized clinical trial, rogaratinib plus atezolizumab demonstrated a manageable safety profile, with no unexpected safety signals. Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression. Trial Registration: ClinicalTrials.gov Identifier: NCT03473756.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Ad26.M.Env ZIKV vaccine protects pregnant rhesus macaques and fetuses against Zika virus infection.

At the start of the Zika virus (ZIKV) epidemic in 2015, ZIKV spread across South and Central America, and reached parts of the southern United States placing pregnant women at risk for fetal microcephaly, fetal loss, and other adverse pregnancy outcomes associated with congenital ZIKA syndrome (CZS). For this reason, testing of a safe and efficacious ZIKV vaccine remains a global health priority. Here we report that a single immunization with Ad26.M.Env ZIKV vaccine, when administered prior to conception, fully protects pregnant rhesus macaques from ZIKV viral RNA in blood and tissues with no adverse effects in dams and fetuses. Furthermore, vaccination prevents ZIKV distribution to fetal tissues including the brain. ZIKV associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, although pathology was limited in fetuses from non-immunized, challenged dams. Vaccine efficacy is associated with induction of ZIKV neutralizing antibodies in pregnant rhesus macaques. These data suggest the feasibility of vaccine prevention of CZS in humans.

Urinary neutrophil gelatinase-associated lipocalin as early biomarker for renal disease in dogs with leishmaniosis.

Canine leishmaniosis (CanL), caused by Leishmania sp., presents a wide array of symptoms; renal dysfunction is frequently observed in these dogs and is associated with a poor prognosis and increased mortality. The traditional biomarkers namely urea and creatinine can detect renal damage but only in advanced stages of the disease. However, it has been shown that the symmetric dimethylarginine assay (SDMA) or the protein/creatinine ratio (UPC) and are early biomarkers of renal dysfunction. Their elevation occurs earlier than that of creatinine, but other novel biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) are currently under investigation. Our objective was to determine whether the urine NGAL-creatinine ratio (uNGAL/c) can provide very early diagnosis of kidney disease in CanL. In total, 68 dogs were included in the study: 15 healthy dogs and 53 dogs with CanL who were classified according to International Renal Interest Society (IRIS) classification: IRIS 1 (N= 34), IRIS 2 (N= 9) and IRIS 3/4 (N= 10). IRIS 1 was subdivided according to proteinuria in IRIS 1NP (13 dogs with UPC < 0.2), IRIS 1BL (8 dogs with UPC = 0.2-0.5) and IRIS 1 P (13 dogs with UPC > 0.5). Blood samples were collected for complete hematological and biochemistry analysis including plasma NGAL. Urinalysis included specific gravity, UPC, CysC and NGAL expressed as a ratio with creatinine. The mean concentrations of pCysC and SDMA in CanL, show a statistically significant increase from IRIS 1NP, not being statistically significant for pCysC in the IRIS 1BL group. The UPC show a statistically significant increase from IRIS 1NP. In all groups with CanL for uCysC/c and uNGAL/c was observed a statistically significant increase. The uNGAL/c in the group proteinuric animals, presents a positive correlation with all renal biomarkers studied. In the group of non-proteinuric animals, the uNGAL/c presents a positive correlation with SDMA and UPC. The uNGAL/c can be considered a reliable indicator of renal disease in dogs diagnosed with CanL who are non-azotemic and non-proteinuric.

Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution.

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from in vitro and in vivo models of metastatic prostate cancer (mPC) reveal a high contribution of tumor material to EV-loaded DNA/RNA, validating the findings in two cohorts of longitudinal plasma samples collected from patients during androgen receptor signaling inhibitor (ARSI) or taxane-based therapy. EV-DNA genomic features recapitulate matched-patient biopsies and circulating tumor DNA (ctDNA) and associate with clinical progression. We develop a novel approach to enable transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptome of circulating EVs is enriched for tumor-associated transcripts, captures certain patient and tumor features, and reflects on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.

Efficacy and immunogenicity following dengue virus-1 human challenge after a tetravalent prime-boost dengue vaccine regimen: an open-label, phase 1 trial.

BACKGROUND: Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy. METHODS: We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18-50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27-65 months following booster dosing. These participants were followed-up from days 4-16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457. FINDINGS: In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five [83%] of six in the vaccinee group and all four [100%] in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1-4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI -0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine [90%] of ten), leukopenia (eight [89%] of nine), and elevated aminotransferases (seven [78%] of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three [50%] of six, headache in one [17%], and transient grade 4 aspartate aminotransferase elevation in one [17%]). No deaths were reported. INTERPRETATION: Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development. FUNDING: Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.

Zika purified inactivated virus (ZPIV) vaccine reduced vertical transmission in pregnant immunocompetent mice.

Zika virus (ZIKV) is a significant threat to pregnant women and their fetuses as it can cause severe birth defects and congenital neurodevelopmental disorders, referred to as congenital Zika syndrome (CZS). Thus, a safe and effective ZIKV vaccine for pregnant women to prevent in utero ZIKV infection is of utmost importance. Murine models of ZIKV infection are limited by the fact that immunocompetent mice are resistant to ZIKV infection. As such, interferon-deficient mice have been used in some preclinical studies to test the efficacy of ZIKV vaccine candidates against lethal virus challenge. However, interferon-deficient mouse models have limitations in assessing the immunogenicity of vaccines, necessitating the use of immunocompetent mouse pregnancy models. Using the human stat2 knock-in (hSTAT2KI) mouse pregnancy model, we show that vaccination with a purified formalin-inactivated Zika virus (ZPIV) vaccine prior to pregnancy successfully prevented vertical transmission. In addition, maternal immunity protected offspring against postnatal challenge for up to 28 days. Furthermore, passive transfer of human IgG purified from hyper-immune sera of ZPIV vaccinees prevented maternal and fetal ZIKV infection, providing strong evidence that the neutralizing antibody response may serve as a meaningful correlate of protection.

Protective efficacy of a Zika purified inactivated virus vaccine candidate during pregnancy in marmosets.

Zika virus (ZIKV) infection during pregnancy poses significant threats to maternal and fetal health, leading to intrauterine fetal demise and severe developmental malformations that constitute congenital Zika syndrome (CZS). As such, the development of a safe and effective ZIKV vaccine is a critical public health priority. However, the safety and efficacy of such a vaccine during pregnancy remain uncertain. Historically, the conduct of clinical trials in pregnant women has been challenging. Therefore, clinically relevant animal pregnancy models are in high demand for testing vaccine efficacy. We previously reported that a marmoset pregnancy model of ZIKV infection consistently demonstrated vertical transmission from mother to fetus during pregnancy. Using this marmoset model, we also showed that vertical transmission could be prevented by pre-pregnancy vaccination with Zika purified inactivated virus (ZPIV) vaccine. Here, we further examined the efficacy of ZPIV vaccination during pregnancy. Vaccination during pregnancy elicited virus neutralizing antibody responses that were comparable to those elicited by pre-pregnancy vaccination. Vaccination also reduced placental pathology, viral burden and vertical transmission of ZIKV during pregnancy, without causing adverse effects. These results provide key insights into the safety and efficacy of ZPIV vaccination during pregnancy and demonstrate positive effects of vaccination on the reduction of ZIKV infection, an important advance in preparedness for future ZIKV outbreaks.

Evidence of Zika Virus Reinfection by Genome Diversity and Antibody Response Analysis, Brazil.

We generated 238 Zika virus (ZIKV) genomes from 135 persons in Brazil who had samples collected over 1 year to evaluate virus persistence. Phylogenetic inference clustered the genomes together with previously reported ZIKV strains from northern Brazil, showing that ZIKV has been remained relatively stable over time. Temporal phylogenetic analysis revealed limited within-host diversity among most ZIKV-persistent infected associated samples. However, we detected unusual virus temporal diversity from >5 persons, uncovering the existence of divergent genomes within the same patient. All those patients showed an increase in neutralizing antibody levels, followed by a decline at the convalescent phase of ZIKV infection. Of interest, in 3 of those patients, titers of neutralizing antibodies increased again after 6 months of ZIKV infection, concomitantly with real-time reverse transcription PCR re-positivity, supporting ZIKV reinfection events. Altogether, our findings provide evidence for the existence of ZIKV reinfection events.

Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.

Prospective Assessment of Bone Metabolism Biomarkers and Survival in Metastatic Castration-resistant Prostate Cancer Patients Treated with Radium-223: The PRORADIUM Study.

BACKGROUND: Radium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use. OBJECTIVE: To assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223-treated mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated. RESULTS AND LIMITATIONS: A total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0-1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10-14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3-2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89-2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28-2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003). CONCLUSIONS: Biomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials. PATIENT SUMMARY: In this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool.

Priming with Japanese encephalitis virus or yellow fever virus vaccination led to the recognition of multiple flaviviruses without boosting antibody responses induced by an inactivated Zika virus vaccine.

BACKGROUND: Complex patterns of cross-reactivity exist between flaviviruses, yet there is no precise understanding of how sequential exposures due to flavivirus infections or vaccinations impact subsequent antibody responses. METHODS: We investigated whether B cell priming from Japanese encephalitis virus (JEV) or yellow fever virus (YFV) vaccination impacted binding and functional antibody responses to flaviviruses following vaccination with a Zika virus (ZIKV) purified inactivated virus (ZPIV) vaccine. Binding antibody responses and Fc gamma receptor engagement against 23 flavivirus antigens were characterized along with neutralization titres and Fc effector responses in 75 participants at six time points. FINDINGS: We found no evidence that priming with JEV or YFV vaccines improved the magnitude of ZPIV induced antibody responses to ZIKV. Binding antibodies and Fc gamma receptor engagement to ZIKV antigens did not differ significantly across groups, while antibody-dependent cellular phagocytosis (ADCP) and neutralizing responses were higher in the naïve group than in the JEV and YFV primed groups following the second ZPIV immunization (p ≤ 0.02). After a third dose of ZPIV, ADCP responses remained higher in the naïve group than in the primed groups. However, priming affected the quality of the response following ZPIV vaccination, as primed individuals recognized a broader array of flavivirus antigens than individuals in the naïve group. INTERPRETATION: While a priming vaccination to either JEV or YFV did not boost ZIKV-specific responses upon ZIKV vaccination, the qualitatively different responses elicited in the primed groups highlight the complexity in the cross-reactive antibody responses to flaviviruses. FUNDING: This work was supported by a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of the Army [W81XWH-18-2-0040]. The work was also funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) R01AI155983 to SJK and KM.

Atezolizumab plus Magrolimab, Niraparib, or Tocilizumab versus Atezolizumab Monotherapy in Platinum-Refractory Metastatic Urothelial Carcinoma: A Phase Ib/II Open-Label, Multicenter, Randomized Umbrella Study (MORPHEUS Urothelial Carcinoma).

PURPOSE: The MORPHEUS platform was designed to identify early efficacy signals and evaluate the safety of novel immunotherapy combinations across cancer types. The phase Ib/II MORPHEUS-UC trial (NCT03869190) is evaluating atezolizumab plus magrolimab, niraparib, or tocilizumab in platinum-refractory locally advanced or metastatic urothelial carcinoma (mUC). Additional treatment combinations were evaluated and will be reported separately. PATIENTS AND METHODS: Patients had locally advanced or mUC that progressed during or following treatment with a platinum-containing regimen. The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoints included investigator-assessed progression-free survival (PFS) and overall survival (OS). Safety and exploratory biomarker analyses were also conducted. RESULTS: Seventy-six patients were randomized to receive either atezolizumab plus magrolimab (n = 16), atezolizumab plus niraparib (n = 15), atezolizumab plus tocilizumab (n = 15), or atezolizumab monotherapy (control; n = 30). No additive benefit in ORR, PFS, or OS was seen in the treatment arms versus the control. The best confirmed ORR was 26.7% with atezolizumab plus magrolimab, 6.7% with atezolizumab plus niraparib, 20.0% with atezolizumab plus tocilizumab, and 27.6% with atezolizumab monotherapy. Overall, the treatment combinations were tolerable, and adverse events were consistent with each agent's known safety profile. Trends were observed for shrinkage of programmed death-ligand 1-positive tumors (atezolizumab, atezolizumab plus magrolimab, atezolizumab plus tocilizumab), inflamed tumors, or tumors with high mutational burden (atezolizumab), and immune excluded tumors (atezolizumab plus magrolimab). CONCLUSIONS: The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC.

Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes.

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.

Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment.

PURPOSE: We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. METHODS: We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. RESULTS: A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1-2 irAEs had significantly longer OS compared to those without grade 1-2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39-0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). CONCLUSIONS: Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1-2 irAEs had longer OS. Prospective studies are necessary to confirm our findings.

Urinary cystatin C and N-acetyl-beta-D-glucosaminidase (NAG) as early biomarkers for renal disease in dogs with leishmaniosis.

Canine leishmaniasis (CanL) is a disease caused by Leishmania infantum that can vary from a subclinical infection to a severe disease. Dogs affected with CanL present varying degrees of renal dysfunction. Unfortunately, traditional biomarkers such as urea and creatinine detect renal damage in advanced stages of the disease, so more accurate biomarkers are needed. Hence, we aimed to study how urinary cystatin C (CysC) and N-acetyl-beta-D-glucosaminidase (NAG), behave in dogs with CanL at different stages of the disease. Eighty-six CanL infected dogs were classified according to LeishVet stages: LI (16 dogs), LIIa (12 dogs), LIIb (12 dogs), LIII (16 dogs) and LIV (30 dogs); as a control, 17 healthy dogs were studied. Blood samples were collected for complete haematological and biochemistry analysis including plasma cystatin C. Urine analysis included urine specific gravity (USG), urine protein to creatinine ratio (UPC), CysC and NAG expressed as a ratio with creatinine uCysCc (µg/g) and uNAGc (IU/g). The haematological, biochemical and urinary analysis coincided with the LeishVet guidelines. The statistical study of the uCysCc ratio and the uNAGc, showed significant increase when compared against control starting from group LI (p < 0.05). Interestingly, when the cut-off values were calculated using the ROC curve, uCysCc (258.85 µg/g) and uNAGc (2.25 IU/g) 75 % of the dogs included in LI groups surpassed the threshold. Hence our study indicates that uCysCc and uNAGc, could help to detect early renal damage in CanL affected dogs.