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1.
Lancet Oncol ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31753727

RESUMO

BACKGROUND: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. FINDINGS: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. INTERPRETATION: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. FUNDING: Eli Lilly and Company.

2.
J Clin Oncol ; : JCO1901882, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721643

RESUMO

PURPOSE: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation. PATIENTS AND METHODS: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory. RESULTS: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy. CONCLUSION: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.

3.
J Clin Oncol ; : JCO1900646, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31689155

RESUMO

PURPOSE: Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS: Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS: Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION: DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.

4.
J Clin Oncol ; : JCO1901638, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31774688

RESUMO

PURPOSE: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

5.
J Immunother Cancer ; 7(1): 275, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651359

RESUMO

BACKGROUND: Antibodies targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have shown clinical activity in the treatment of metastatic renal cell carcinoma (mRCC). This phase Ib cohort of the JAVELIN Solid Tumor trial assessed the efficacy and safety of avelumab (anti-PD-L1) monotherapy in patients with mRCC as either first-line (1 L) or second-line (2 L) treatment. METHODS: Patients with mRCC with a clear-cell component who were treatment naive (1 L subgroup) or had disease progression after one prior line of therapy (2 L subgroup) received avelumab 10 mg/kg intravenous infusion every 2 weeks. Endpoints included confirmed best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), PD-L1 expression, and safety. RESULTS: A total of 62 patients were enrolled in the 1 L subgroup, and 20 patients were enrolled in the 2 L subgroup. In the 1 L and 2 L subgroups, confirmed objective response rates were 16.1 and 10.0%, median DOR was 9.9 months (95% confidence interval [CI], 2.8-not evaluable) and not evaluable (95% CI, 6.9-not evaluable), median PFS was 8.3 months (95% CI, 5.5-9.5) and 5.6 months (95% CI, 2.3-9.6), and median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3-not evaluable), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 51 patients in the 1 L subgroup (82.3%) and 14 patients in the 2 L subgroup (70.0%). Grade ≥ 3 TRAEs occurred in eight patients in the 1 L subgroup (12.9%) and one patient in the 2 L subgroup (5.0%). No treatment-related deaths occurred. CONCLUSION: Avelumab showed clinical activity and a manageable safety profile in both the 1 L and 2 L treatment setting in patients with mRCC. These data support the use of avelumab in combination with other agents in mRCC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01772004 ; registered 21 January, 2013.

6.
Eur Urol Oncol ; 2(6): 643-648, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31411994

RESUMO

BACKGROUND: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patients with papillary histology. OBJECTIVE: To determine the benefit of CN in synchronous metastatic papillary RCC. DESIGN, SETTING, AND PARTICIPANTS: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database, a retrospective analysis was performed for patients with papillary mRCC treated with or without CN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median overall survival (OS) and progression-free survival (PFS) were determined for both patient groups. Cox regression analysis was performed to control for imbalances in individual IMDC risk factors. RESULTS AND LIMITATIONS: In total, 647 patients with papillary mRCC were identified, of whom 353 had synchronous metastatic disease. Of these, 109 patients were treated with CN and 244 were not. The median follow-up was 57.1mo (95% confidence interval [CI] 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2mo (95% CI 12.0-16.1). Median OS for patients with CN was 16.3mo, compared to 8.6mo (p<0.0001) in the no-CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45-0.85; p=0.0031). Limitations include the retrospective nature of the analysis. CONCLUSIONS: The use of CN in patients with mRCC and papillary histology appears to be associated with better survival compared to no CN after adjustment for risk criteria. Selection of appropriate candidates for CN is crucial. A clinical trial in this rare population may not be possible. PATIENT SUMMARY: In a population of patients with advanced papillary kidney cancer, we found that surgical removal of the primary kidney tumor was associated with better overall survival.

7.
Eur Urol Oncol ; 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31411990

RESUMO

BACKGROUND: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence. OBJECTIVE: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC. DESIGN, SETTING, AND PARTICIPANTS: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses. RESULTS AND LIMITATIONS: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1-108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN+ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design. CONCLUSIONS: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials. PATIENT SUMMARY: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

8.
Eur Urol Oncol ; 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412004

RESUMO

Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.

9.
J Oncol Pract ; 15(8): 431-432, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31404515
10.
Eur Urol ; 76(6): 861-867, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31445844

RESUMO

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited. OBJECTIVE: To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies. DESIGN, SETTING, AND PARTICIPANTS: Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo. INTERVENTION: All patients received first-line IO combination therapies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors. RESULTS AND LIMITATIONS: In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] -8% to 22%, p =  0.4), TTF was 14.3 versus 10.2 mo (p =  0.2), TNT was 19.7 versus 17.9 mo (p =  0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46-1.12, p =  0.14), 0.65 (95% CI 0.38-1.11, p =  0.11), and 1.74 (95% CI 0.82-3.68, p =  0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3-57%, p =  0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p =  0.4; n = 55). Limitations include the study's retrospective design and sample size. CONCLUSIONS: There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially. PATIENT SUMMARY: There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

11.
Eur Urol Oncol ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31307962

RESUMO

BACKGROUND: The effect of local treatment on survival in advanced-stage patients has gained interest in several malignancies; however, limited data exist regarding urothelial carcinoma (UC). OBJECTIVE: To test the impact of surgery of the primary tumor site on cancer-specific mortality (CSM) and overall mortality (OM) in patients affected by metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: Individual patient-level data from a multicenter collaboration, including metastatic UC patients treated with first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011 from hospitals in the USA, Europe, Israel, and Canada. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox regression analyses were used to assess the effect of surgery on CSM and OM in patients affected by metastatic UC using 3-mo landmark analyses. Subgroup analyses were performed on the basis of the number of metastasis sites involved and including only patients treated with surgery before the start of chemotherapy. RESULTS AND LIMITATIONS: Of the 326 patients included in the study, 47 (14%) were treated with surgery of the primary tumor site. Median (interquartile range) follow-up was 43 (33-45)mo. Of the patients treated with surgery, 28 (60%) were affected by a primary bladder cancer and 19 (40%) by a primary upper urinary tract tumor. On multivariable analyses, surgery was associated with a protective effect on CSM (hazard ratio [HR]: 0.59, confidence interval [CI]: 0.35-0.98, p=0.04) and OM (HR: 0.45, CI: 0.37-0.99, p=0.04) compared with patients treated with chemotherapy only. Similar results were found considering patients only surgically treated before the start of chemotherapy. After stratifying according to the number of metastatic sites, surgery has an effect on survival in patients with only one metastatic site, while no survival benefit was observed in patients with two or more metastatic sites. The study is limited by its retrospective nature. CONCLUSIONS: We found that surgery of the primary tumor site is associated with improved survival in patients with metastatic UC who received standard chemotherapy. This effect disappears in patients affected by two or more metastatic sites. Our results need to be validated in a high-quality prospective trial. PATIENT SUMMARY: In our multicenter, retrospective series, surgery in metastatic urothelial cancer patients improve survival compared with patients treated with chemotherapy only. This effect was evident in patients with limited disease extent, identified as one metastatic site.

12.
Eur Urol ; 76(4): 425-429, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31303258

RESUMO

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3-4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

13.
Br J Clin Pharmacol ; 85(11): 2499-2511, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271459

RESUMO

AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

14.
Cancer Immunol Immunother ; 68(7): 1143-1155, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177328

RESUMO

Enhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. ph(es)E2TM was designed to contain five evolution-selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. These ph(es)E2TM substitutions score 0 to 1 in blocks substitutions matrix (BLOSUM), indicating minimal biochemical alterations. h(es)E2TM recombinant protein is recognized by a panel of anti-HER2 mAbs, demonstrating the preservation of HER2 protein structure. Compared to native human HER2, electrovaccination of HER2 transgenic mice with ph(es)E2TM induced a threefold increase in HER2-binding antibody (Ab) and elevated levels of IFNγ-producing T cells. ph(es)E2TM, but not pE2TM immune serum, recognized HER2 peptide p95 355LPESFDGDPASNTAP369, suggesting a broadening of epitope recognition induced by the minimally modified HER2 vaccine. ph(es)E2TM vaccination reduced tumor growth more effectively than wild-type HER2 or HER2 vaccines with more extensive modifications. The elevation of tumor immunity by ph(es)E2TM vaccination would create a favorable tumor microenvironment for neoantigen priming, further enhancing the protective immunity. The fundamental principle of exploiting evolution-selected amino acid substitutions is novel, effective and applicable to vaccine development in general.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/terapia , Receptor ErbB-2/imunologia , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Animais , Antígenos de Neoplasias/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral/transplante , Células Dendríticas/imunologia , Evolução Molecular , Feminino , Imunogenicidade da Vacina/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor ErbB-2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Tolerância a Antígenos Próprios/genética , Microambiente Tumoral/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico
15.
Oncologist ; 24(9): 1151-e817, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31171735

RESUMO

LESSONS LEARNED: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. BACKGROUND: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. METHODS: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. RESULTS: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached). CONCLUSION: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

16.
Eur Urol Oncol ; 2(3): 248-256, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31200838

RESUMO

BACKGROUND: Several ongoing phase 2 trials are evaluating new neoadjuvant therapy regimens in patients with muscle-invasive bladder cancer (MIBC). The 1-yr recurrence-free survival (RFS) after radical cystectomy (RC), with or without perioperative chemotherapy, can be used to model statistical assumptions and interpret outcomes from these studies. OBJECTIVE: To provide a benchmark for predicting 1-yr RFS in patients with cT2-4N0 MIBC. DESIGN, SETTING, AND PARTICIPANTS: We identified 950 patients with clinical stage T2-4N0 MIBC undergoing RC at 27 centers between 1990 and 2016. We assessed 1-yr RFS rates for patients managed with no perioperative chemotherapy, neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), or NAC followed by AC. Cox regression analyses tested for 1-yr postsurgical RFS predictors. A Cox-based nomogram was developed to estimate 1-yr RFS and its accuracy was assessed in terms of Harrell's c-index, a calibration plot, and decision curve analysis. We report 1-yr RFS rates across the nomogram tertiles. RESULTS AND LIMITATIONS: The 1-yr RFS rates were 67.9% (95% confidence interval [CI] 64-72) after no perioperative chemotherapy, 76.9% (95% CI 72-83%) after NAC, 77.8% (95% CI 71-85%) after AC, and 57% (95% CI 37-87) after NAC+AC. On multivariable analysis, positive surgical margins (p=0.002), pT stage (p<0.0001), and pN stage (p<.0001) were significantly associated with RFS, while NAC was not (p=0.6). The model including all these factors yielded a c-index of 0.76 (95% CI 0.72-0.79), good calibration, and a high net benefit. The 1-yr RFS rates across nomogram tertiles were 90.5% (95% CI 87-94%), 73.4% (95% CI 68-79%), and 51.1% (95% CI 45-58%), respectively. The results lack external validation. CONCLUSIONS: Benchmark 1-yr RFS estimates for phase 2 design of new neoadjuvant trials are proposed and can be used for statistical assumptions, pending external validation. PATIENT SUMMARY: Our prognostic model predicting 1-yr survival free from recurrence of bladder cancer after radical cystectomy, with or without standard chemotherapy, could provide an improvement to the quality of phase 2 clinical trial designs and interpretation of their results.

17.
Oncologist ; 24(9): 1149-e807, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31152080

RESUMO

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

18.
Cancer ; 125(18): 3155-3163, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150110

RESUMO

BACKGROUND: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS: The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS: Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07-fold (P < .001) in comparison with cystectomy alone. CONCLUSIONS: A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.

19.
Eur Urol Focus ; 5(6): 927-929, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31103605

RESUMO

Trials SWOG 8949 and EORTC 30947 had the same eligibility criteria and established the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. The more recently published CARMENA trial calls into question the need for cytoreductive nephrectomy. A systematic comparison of CARMENA and SWOG 8949 suggests that cytoreductive nephrectomy may be beneficial for patients receiving immunotherapy but not targeted therapy. The approval of immune checkpoint inhibitors for previously untreated metastatic renal cell carcinoma underlines the need for another randomized phase 3 trial of cytoreductive nephrectomy for patients receiving powerful modern immunotherapies.

20.
Oncologist ; 24(10): 1348-1355, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30936379

RESUMO

BACKGROUND: The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. MATERIALS AND METHODS: A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. RESULTS: Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1-38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7-93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8-17.6) and 49.3% (95% CI: 28.2-67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. CONCLUSION: Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. IMPLICATIONS FOR PRACTICE: Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

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