Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article originally published in The New England Journal of Medicine. It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer. People with advanced urothelial cancer often receive chemotherapy. If this is the first treatment people with advanced disease are given, it is called first-line treatment. If the cancer stops growing or shrinks with first-line chemotherapy, people can be given different treatment to try to prevent the cancer from growing again. This is called maintenance treatment. It may help people live longer. WHAT HAPPENED IN THE JAVELIN BLADDER 100 STUDY?: In the JAVELIN Bladder 100 study, researchers wanted to find out if maintenance treatment with avelumab would help people with advanced urothelial cancer live longer. Avelumab is a type of medicine called immunotherapy. Immunotherapy helps the body's immune system fight cancer. 700 people took part in the study. To take part, they must have already been treated with first-line chemotherapy. Also, their cancer must have shrunk or not grown with this treatment. They were then treated with either avelumab maintenance treatment plus best supportive care or best supportive care alone. Best supportive care means treatments that help improve symptoms and quality of life. These treatments do not affect the cancer directly and can include medicines to relieve pain. WHAT WERE THE RESULTS?: Researchers found that people treated with avelumab maintenance treatment plus best supportive care lived, on average, 7 months longer than people who received best supportive care alone. People treated with avelumab had more side effects than those not treated with avelumab, but most were not severe. Common side effects with avelumab included persistent tiredness, itchy skin, urinary tract infection, and diarrhea. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from the JAVELIN Bladder 100 study support the use of avelumab as maintenance treatment for people with advanced urothelial cancer whose cancer has shrunk or not grown with first-line chemotherapy. ClinicalTrials.gov NCT number: NCT02603432.

Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.

BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint), PFS, and safety were assessed. RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-Q3: 0.63 (0.39-1.00); by number of cycles-four cycles: 0.69 (0.48-1.00), five cycles: 0.98 (0.57-1.71), and six cycles: 0.66 (0.47-0.92); and by interval-4-<6 wk: 0.75 (0.54-1.04), 6-<8 wk: 0.67 (0.43-1.06), and 8-10 wk: 0.69 (0.47-1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. CONCLUSIONS: Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. PATIENT SUMMARY: Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.

Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial.

BACKGROUND: In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries. OBJECTIVE: To analyze clinically relevant subgroups from JAVELIN Bladder 100. DESIGN, SETTING, AND PARTICIPANTS: Patients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). Median follow-up was >19 mo in both arms (data cutoff October 21, 2019). This trial is registered on ClinicalTrials.gov as NCT02603432. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint) and PFS were analyzed in protocol-specified and post hoc subgroups using the Kaplan-Meier method and Cox proportional hazards models. RESULTS AND LIMITATIONS: Hazard ratios (HRs) for OS with avelumab + BSC versus BSC alone were <1.0 across all subgroups examined, including patients treated with 1L cisplatin + gemcitabine (HR 0.69, 95% confidence interval [CI] 0.50-0.93) or carboplatin + gemcitabine (HR 0.64, 95% CI 0.46-0.90), patients with PD-L1+ tumors treated with carboplatin + gemcitabine (HR 0.67, 95% CI 0.39-1.14), and patients whose best response to chemotherapy was a complete response (HR 0.80, 95% CI 0.46-1.37), partial response (HR 0.62, 95% CI 0.46-0.84), or stable disease (HR 0.70, 95% CI 0.46-1.06). Observations were similar for PFS. Limitations include the smaller size and post hoc evaluation without multiplicity adjustment for some subgroups. CONCLUSIONS: Analyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy. PATIENT SUMMARY: In the JAVELIN Bladder 100 study, maintenance treatment with avelumab helped many different groups of people with advanced cancer of the urinary tract to live longer.

Bumps in the journey toward a new care delivery model.

On a journey to the future, an initial strategy of engagement and design is essential but inevitably inadequate. Instead, as bumps in the road emerge, the ability of leadership to regroup and refocus is the key. This is the story of one such journey-a journey pursuing the triple aim of excellence in patient care, patient and staff satisfaction, and economic sustainability. It is one chapter in the transformation of an 1800-employee patient care services organization. It is not the first chapter nor will it be the last.

Laminar distribution of cortical projection neurons to the pulvinar: A comparative study in cats and mice.

The cortical processing of visual information is thought to follow a hierarchical framework. This framework of connections between visual areas is based on the laminar patterns of direct feedforward and feedback cortico-cortical projections. However, this view ignores the cortico-thalamo-cortical projections to the pulvinar nucleus in the thalamus, which provides an alternative transthalamic information transfer between cortical areas. It was proposed that corticothalamic (CT) pathways follow a similar hierarchical pattern as cortico-cortical connections. Two main types of CT projections have been recognized: drivers and modulators. Drivers originate mainly in Layer 5 whereas modulators are from Layer 6. Little is known about the laminar distribution of these projections to the pulvinar across visual cortical areas. Here, we analyzed the distribution of CT neurons projecting to the lateral posterior (LP) thalamus in two species: cats and mice. Injections of the retrograde tracer fragment B of cholera toxin (CTb) were performed in the LP. The morphology and cortical laminar distribution of CTb-labeled neurons was assessed. In cats, neurons were mostly found in Layer 6 except in Area 17, where they were mostly in Layer 5. In contrast, CT neurons in mice were mostly located in Layer 6 across all areas. Thus, our results demonstrate that CT projections in mice do not follow the same organization as cats suggesting that the transthalamic pathways play distinct roles in these species.

A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides.

BACKGROUND: Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells. OBJECTIVE: To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial. METHODS: rhIL-12 was administered biweekly (100 ng/kg for 2 weeks; 300 ng/kg thereafter). A modified severity-weighted assessment tool (SWAT) and the longest diameter of 5 index lesions measured efficacy. RESULTS: Twenty-three MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) had previously received >3 therapies. Ten of 23 patients (43%) achieved partial responses (PR); 7 (30%) achieved minor responses; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve (52%) ultimately progressed with mean time to progressive disease of 57 days (range, 28-805). Ten completed 6 months of therapy; 1 completed 24 months. Of patients not completing 6 months of therapy, 6 progressed and 6 others discontinued because of adverse events or withdrew consent. Seventeen patients had treatment-related adverse events that were generally mild or moderate in severity, including asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, elevated aspartate and alanine aminotransferase levels, anorexia, and sweating. One patient in PR died of hemolytic anemia, possibly exacerbated by rhIL-12 treatment. LIMITATIONS: The original company was purchased during the conduct of the trial and rhIL-12 is currently unavailable. The quality of life data were not available for inclusion. CONCLUSION: Twice-weekly subcutaneously administered rhIL-12 (100 ng/kg escalated to 300 ng/kg) showed antitumor activity with a response rate of 43% in refractory patients. It was relatively well-tolerated in early-stage MF.

Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors.

PURPOSE: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m(2)/day) following a standard 3 + 3 dose escalation design. RESULTS: The MTD was determined to be 275 mg/m(2). Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m(2) dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. CONCLUSION: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m(2) is recommended for further clinical testing.

CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer.

Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-ß chain (hCG-ß), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-ß-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-ß-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit.

Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder.

Superficial transitional cell carcinoma (STCC) of the bladder is usually managed with intravesical bacille Calmette-Guerin. Recombinant human interleukin-12 (rhIL-12) is a heterodimeric cytokine that induces T-cell and natural killer cell proliferation/activation and production of IFNgamma. It has demonstrated preclinical in vivo bladder antitumor activity and no systemic toxicity. This phase 1 study evaluated intravesical rhIL-12 administration in patients with STCC (Tis, Ta, or T1) who had failed at least one prior intravesical therapy or had at least two recurrences of low-grade tumors. Eligible patients had adequate hematologic, renal, and hepatic function and Karnofsky performance status at least 70%. Cohorts of three patients received 5, 20, 50, 100, and 200 microg rhIL-12 (treated n = 15). Each patient received intravesical rhIL-12 weekly for 6 weeks, with a 2-hour bladder dwell. No patient experienced moderate, severe, or life-threatening systemic toxicity. Treatment-related adverse events included dysuria, urinary frequency, urinary urgency, asthenia, pain, hematuria, bladder spasms, and chills. Specific AE incidences were not dose-related. Among 12 patients without visible pretreatment lesions, 7 remained disease-free and 5 experienced recurrence of STCC within the 4-week follow-up period. Three patients with pretreatment Tis or Ta/T1 lesions had persistent disease at posttreatment follow-up. No patients with persistent tumor manifested antitumor response to rhIL-12. Two-hour dwell urine samples and 24- to 30-hour postdose serum samples showed negligible induction of IFNgamma. In summary, intravesical rhIL-12 was well tolerated by patients with recurrent STCC but showed no clinically relevant evidence of antitumor or immunologic effects.