A Coproduced Family Reporting Intervention to Improve Safety Surveillance and Reduce Disparities.

OBJECTIVES: Examine family safety-reporting after implementing a parent-nurse-physician-leader coproduced, health literacy-informed, family safety-reporting intervention for hospitalized families of children with medical complexity. METHODS: We implemented an English and Spanish mobile family-safety-reporting tool, staff and family education, and process for sharing comments with unit leaders on a dedicated inpatient complex care service at a pediatric hospital. Families shared safety concerns via predischarge surveys (baseline and intervention) and mobile tool (intervention). Three physicians with patient safety expertise classified events. We compared safety-reporting baseline (via survey) versus intervention (via survey and/or mobile tool) with generalized estimating equations and sub-analyzed data by COVID-19-era and educational attainment. We also compared mobile tool-detected event rates with hospital voluntary incident reporting. RESULTS: 232 baseline and 208 intervention parents participated (78.2% consented); 29.5% of baseline families versus 38.2% of intervention families reported safety concerns (P = .09). Adjusted odds ratio (95% CI) of families reporting safety concerns intervention versus baseline was 1.6 (1.0-2.6) overall, 2.6 (1.3-5.4) for those with < college education, and 3.1 (1.3-7.3) in the COVID-19-era subgroup. Safety concerns reported via mobile tool (34.6% of enrolled parents) included 42 medical errors, 43 nonsafety-related quality issues, 11 hazards, and 4 other. 15% of mobile tool concerns were also detected with voluntary incident reporting. CONCLUSIONS: Family safety-reporting was unchanged overall after implementing a mobile reporting tool, though reporting increased among families with lower educational attainment and during the COVID-19 pandemic. The tool identified many events not otherwise captured by staff-only voluntary incident reporting. Hospitals should proactively engage families in reporting to improve safety, quality, and equity.

Impact of the COVID-19 Pandemic on Childhood Lead Testing and Blood Lead Levels.

OBJECTIVE: To evaluate the effect of the COVID-19 pandemic on childhood lead testing and blood lead levels. METHODS: A retrospective analysis of lead tests and results was performed across 3 urban medical centers during the pre-COVID-19 (March 10, 2019-March 9, 2020) and COVID-19 (March 10, 2020-March 10, 2022) periods. Interrupted time series analysis with quasi-Poisson regression was used to evaluate changes in lead testing between study periods. The relationship between sociodemographic features with detectable (≧2 µg/dL) and elevated (≧3.5 µg/dL) blood lead levels (BLLs) was assessed with multivariable logistic regression. RESULTS: Among a total of 16,364 lead tests across 10,362 patients, weekly testing rates significantly decreased during COVID-19 (relative risk (RR) 0.64, 95% (confidence interval) CI 0.53-0.78). Census tracts with the greatest proportion of pre-1950s housing had a stronger association with detectable BLLs during the COVID-19 period (pre-COVID-19 adjusted odds ratio (aOR) 1.73, 95% CI 1.35-2.20; aOR 2.58, 95% CI 2.13-3.12; interaction P value .014). When limited to 1 year following COVID-19 (March 10, 2020-March 10, 2021), the association between both elevated BLLs (pre-COVID-19: aOR 1.49, 95% CI 0.87-2.53; COVID-19: aOR 3.51, 95% CI 1.98-6.25; interaction P value .032) and detectable BLLs with pre-1950s housing were greater during the COVID-19 period (pre-COVID-19: aOR 1.73, 95% CI 1.35-2.20; COVID-19: aOR 2.56, 95% CI 1.95-3.34; interaction P value .034). CONCLUSIONS: The COVID-19 pandemic led to a significant reduction in lead surveillance and magnified the effect of known risk factors for lead exposure. Concerted clinical, public health, and community advocacy are needed to address care gaps and excess cases of lead poisoning.

A Patient Portal Intervention to Promote Adolescent and Young Adult Self-Management Skills.

OBJECTIVE: Failure to transfer care to adult medicine is associated with gaps in health care access and poor health outcomes among young adults. We examined whether a patient portal educational intervention is acceptable and can improve adolescent and young adult (AYA) self-management skills toward transition readiness to adult care. METHODS: We conducted a single site feasibility study using a mixed research method consisting of 1) a patient portal one-on-one educational intervention with pre- and postsurveys adapted from the Transition Readiness Assessment Questionnaire to assess participant self-management skills and portal user activity; 2) portal user experience was assessed through semistructured interviews until thematic saturation was reached. Study participants were 13 to 25 years old and received care at an academic-affiliated community pediatric clinic. Descriptive statistics were used to describe participant characteristics, paired t tests, or Wilcoxon signed-rank tests to assess outcomes of survey response changes pre- versus postintervention. RESULTS: Sixty percent of enrolled participants (N = 78) completed the surveys. Following the educational intervention, we observed an increase in participants self-reporting knowing how to access their protected health information P < .0001, (95%, confidence interval [CI], 1-2) and in the proportion of participants self-reporting to strongly agree to know their medication P = .025 (95%, CI 0-1). We also observed an increase in portal user access at 3 weeks; the median number of logins was 2 per participant (range 1-36, P < .0001). The Portal user experience was strongly positive. CONCLUSION: Our patient portal educational intervention suggests that AYAs welcome a patient portal to access protected health information and is associated with an increase in the proportion of participants self-reporting to strongly agree with knowing their medication. While these results are encouraging, this is a quasiexperimental study designed on the frame of feasibility. Our study was not adequately powered, limiting our findings' significance. Future interventions would benefit from a larger sample size with a comparison group to ascertain the effect of a patient portal on self-management skills in a diverse AYA population and inform best practices.

Pharmacokinetics, Tolerability, and Safety of Doravirine and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Tablets in Adolescents Living With HIV: Week 24 Results From IMPAACT 2014.

BACKGROUND: We studied the pharmacokinetics (PK) and safety of 100-mg doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination (100/300/300 mg DOR FDC) treatment in adolescents with HIV-1. METHODS: Adolescents ages 12 to younger than 18 years were enrolled in 2 sequential cohorts. Cohort 1 evaluated intensive PK and short-term safety of 100-mg single-dose doravirine in adolescents ≥35 kg. Cohort 2 participants either initiated treatment with DOR FDC (antiretroviral (ARV)-naïve) or switched to DOR FDC from a previous ARV regimen (virologically suppressed). The first 10 Cohort 2 participants had intensive PK evaluations, and safety, sparse PK, and HIV RNA were assessed through week 24. RESULTS: Fifty-five adolescents, median age 15.0 years and baseline weight 51.5 kg, were enrolled. Nine participants completed Cohort 1 PK assessments (8 of the 9 participants weighed ≥45 kg) and 45 initiated study drug in Cohort 2. The doravirine geometric mean (GM) AUC 0-∞ was 34.8 µM∙hour, and the GM C 24 was 514 nM after a single dose, with a predicted steady-state GM C 24,ss,pred of 690 nM. Cohort 2 enrolled adolescents weighing ≥45 kg. Plasma concentrations of doravirine, tenofovir, and lamivudine achieved by Cohort 2 participants were similar to those reported in adults. No drug-related serious or grade 3 or 4 adverse events occurred. Forty-two of 45 participants (93.3%; 95% CI: [81.7, 98.6]) achieved or maintained HIV-1 RNA <40 copies/mL. CONCLUSIONS: Doravirine and DOR FDC achieved target PK in adolescents with HIV-1. DOR FDC was well-tolerated and maintained excellent virologic efficacy through 24 weeks, offering a favorable option for adolescents.

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial.

BACKGROUND: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing. FINDINGS: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir. INTERPRETATION: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.

Bone targeted therapy and skeletal related events in the era of enzalutamide and abiraterone acetate for castration resistant prostate cancer with bone metastases.

BACKGROUND: In an era of multiple life-prolonging therapies for metastatic castration resistant prostate cancer (mCRPC), the optimal timing of initiation and duration of antiresorptive bone targeted therapy (BTT) to prevent skeletal related events (SREs) is unknown. METHODS: To assess practice patterns of BTT use and its associations with clinical outcomes in a high-volume center in the modern era of metastatic CRPC management, a retrospective cohort of patients treated for mCRPC with BM between 2007 and 2017 was identified from a single institutions clinical research database. Study endpoints included time from the diagnosis of CRPC to the onset of SRE or OS. Cox proportional hazards model assessed association of BTT use with time to first SRE and OS. RESULTS: In total, 249 patients were identified; median follow-up was 7.7 (95%CI: 5.7-10.2) years. On multivariable analysis, patients with 4 or more BM at diagnosis of mCRPC who received BTT with abiraterone acetate or enzalutamide as first line therapy had a 42% reduced risk of developing an SRE (HR 0.58; 95%CI: 0.36-0.95) compared to those who never received BTT or received it in second line. No such effect was observed in patients with 1-3 BM. No OS difference was noted in patients who received BTT, whether with first line therapy or without. This study is limited by retrospective nature at a single institution. CONCLUSIONS: Our hospital registry data indicate a potential benefit in terms of SRE prevention for early use of antiresorptive BTT in combination with life prolonging CRPC therapies for patients with CRPC and at least 4 BM.

Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial.

PURPOSE: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

PURPOSE: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. PATIENTS AND METHODS: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. RESULTS: Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean C max ss of 104 ± 45 ng/mL and AUCτ ss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (C max ss, 315 ng/mL and AUCτ ss, 3,817 ng•h/mL). CONCLUSIONS: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

Transcriptome analysis reveals overlap in fusion genes in a phase I clinical cohort of TNBC and HGSOC patients treated with buparlisib and olaparib.

PURPOSE: Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present. METHODS: RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes. RESULTS: A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival. CONCLUSIONS: In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.

Mutations and Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma.

We previously showed that alterations in mTOR pathway genes were correlated with response to rapalog therapy in metastatic renal cell carcinoma (mRCC), when the analysis focused on extremes of response. Herein, we expand on the prior cohort and examine genetic correlations with rapalog response in a dataset not selected for extremes of response. Tumors from 58 patients from the phase III trial of temsirolimus and 51 local patients with mRCC treated with rapalogs were studied. Somatic mutations were investigated using a targeted sequencing platform covering 27 genes. Clinical benefit (CB) was defined as patients with complete remission, partial response, or stable disease lasting at least 22 weeks. Mutational analyses focused on 5 mTOR pathway genes (TSC1, TSC2, MTOR, PTEN, PIK3CA) and 6 genes commonly mutated in RCC (BAP1, KDM5C, PBRM1 SETD2, TP53, and VHL). Among the 109 patients, 93 (85%) patients had clear cell histology, and 31 (28%) showed CB. Nine of 30 (30%) patients harboring mTOR pathway mutations in their tumor achieved CB versus 22 of 79 (28%) in the wild-type group. There was no distinct association between any individual or combination of mTOR pathway gene mutations and CB. Three of 7 patients with TSC1 mutations showed CB. In addition, none of the 6 genes commonly mutated in RCC showed a mutation pattern that correlated with CB. Overall, in this large and diverse population of patients with mRCC, there is no suggestion of a correlation between response to rapalog therapy and mutation status for mTOR pathway genes.

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

Importance: To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease. Objective: To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer. Design, Setting, and Participants: A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy. Interventions: Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks. Main Outcome and Measures: The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy. Results: Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater. Conclusions and Relevance: The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.

Loss of PTEN Expression Detected by Fluorescence Immunohistochemistry Predicts Lethal Prostate Cancer in Men Treated with Prostatectomy.

BACKGROUND: PTEN deletion is associated with relapse after therapy for localized prostate cancer. There are limited data on PTEN loss as detected by immunohistochemistry (IHC) and the risk of lethal disease after surgery. OBJECTIVE: To determine whether PTEN loss as detected by quantitative fluorescence IHC (FIHC) predicts lethal disease outcomes after surgery for prostate cancer. DESIGN, SETTING AND PARTICIPANTS: We used formalin-fixed, paraffin-embedded radical prostatectomy specimens to construct tissue microarrays and perform dual FIHC for PTEN and AMACR for masking tumor epithelium, plus semi-quantitative multispectral imaging analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of PTEN status analyzed continuously and dichotomously (low [expression in the lowest quartile] vs higher [expression >lowest quartile]) with disease outcomes (metastasis and death) was assessed with adjustment for age, Gleason score, and stage in multivariable analyses. The prognostic ability of PTEN was assessed using logistic regression models. RESULTS AND LIMITATIONS: Low PTEN expression was associated with a higher risk of metastatic disease as both a continuous (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.14-1.92; p<0.003) and dichotomous (HR 1.92, 95% CI 1.02-3.63; p=0.04) variable. A significant association between low PTEN expression and poorer overall survival was observed (continuous: HR 1.89, 95% CI 1.37-2.63; p<0.001; dichotomous: HR 2.66, 95% CI 1.34-5.28; p=0.005). Addition of PTEN status to clinicopathologic factors (age, Gleason score, and stage) incrementally improved a prognostic model assessing 10-yr outcomes for metastatic disease (area under the curve [AUC] 0.76 vs 0.80) and death (AUC 0.70 vs 0.75). CONCLUSIONS: Low PTEN expression detected by FIHC in primary prostate cancer is an independent prognostic biomarker for metastatic disease and death after definitive therapy. FIHC for PTEN is a viable clinical diagnostic assay in this context. PATIENT SUMMARY: We looked at loss of the PTEN protein in prostate tumors from men treated with surgery. Men with PTEN loss were at higher risk of metastasis and death. Assessing PTEN status may be useful in better determination of the risk of poorer outcomes.

Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.

PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.

Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer.

BACKGROUND: Improved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer. METHODS: This was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes. RESULTS: Planned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction. CONCLUSIONS: The combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.

Impact of new systemic therapies on overall survival of patients with metastatic castration-resistant prostate cancer in a hospital-based registry.

BACKGROUND: In 2004, docetaxel was shown to prolong the overall survival (OS) of patients with metastatic castration-resistance prostate cancer (mCRPC). Since 2010, five new systemic therapies have been shown to prolong OS in men with mCRPC. We sought to evaluate the aggregate impact of these newer therapies on the OS of patients with mCRPC. METHODS: Two cohorts of patients diagnosed with mCRPC between 2004 and 2007, treated with drugs used in the limited treatment era only (A), and between 2010 and 2013, treated also with newer therapies (B), were identified from the Dana-Farber Cancer Institute database. The analysis endpoint was OS within 5 years after mCRPC diagnosis. Kaplan-Meier method assessed time-to-event distributions with median (95% confidence interval (CI)). A piece-wise regression model assessed the association between endpoint and treatment cohorts with estimate of hazard ratio (HR) with 95% CI within two time segments in univariate and multivariable analyses adjusting for relevant covariates. RESULTS: Compared to cohort A (n = 318), cohort B (n = 272) patients in newer therapy era demonstrated an OS advantage (2.8 vs. 2.2 years) with a 41% decreased risk of death (HR = 0.59; 95% CI, 0.47-0.74; P < 0.0001), and a 3-year OS rate of 46% vs. 33%. This benefit was accentuated (median OS 2.7 vs. 2.1 years; HR = 0.46; 95% CI, 0.32-0.67; P < 0.0001) in patients who initially presented with de-novo metastatic disease (de-novo). On multivariable analysis, longer OS was associated with cohort B vs. A and performance status 0 vs. 1. CONCLUSIONS: Using a single-institution registry, mCRPC patients treated since 2010 had a significant survival improvement vs. those treated before 2010. Although the median survival was only modestly improved and less than predicted when simply adding each newer drug survival advantage, the cumulative benefit from the new therapies was more pronounced in longer-term survivors and de-novo patients.

Independent Validation of EarlyR Gene Signature in BIG 1-98: A Randomized, Double-Blind, Phase III Trial Comparing Letrozole and Tamoxifen as Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone Receptor-Positive, Early Breast Cancer.

BACKGROUND: EarlyR gene signature in estrogen receptor-positive (ER+) breast cancer is computed from the expression values of ESPL1, SPAG5, MKI67, PLK1, and PGR. EarlyR has been validated in multiple cohorts profiled using microarrays. This study sought to verify the prognostic features of EarlyR in a case-cohort sample from BIG 1-98, a randomized clinical trial of ER+ postmenopausal breast cancer patients treated with adjuvant endocrine therapy (letrozole or tamoxifen). METHODS: Expression of EarlyR gene signature was estimated by Illumina cDNA-mediated Annealing, Selection, and Ligation assay of RNA from formalin-fixed, paraffin-embedded primary breast cancer tissues in a case-cohort subset of ER+ women (N = 1174; 216 cases of recurrence within 8 years) from BIG 1-98. EarlyR score and prespecified risk strata (≤25 = low, 26-75 = intermediate, >75 = high) were "blindly" computed. Analysis endpoints included distant recurrence-free interval and breast cancer-free interval at 8 years after randomization. Hazard ratios (HRs) and test statistics were estimated with weighted analysis methods. RESULTS: The distribution of the EarlyR risk groups was 67% low, 19% intermediate, and 14% high risk in this ER+ cohort. EarlyR was prognostic for distant recurrence-free interval; EarlyR high-risk patients had statistically increased risk of distant recurrence within 8 years (HR = 1.73, 95% confidence interval = 1.14 to 2.64) compared with EarlyR low-risk patients. EarlyR was also prognostic of breast cancer-free interval (HR = 1.74, 95% confidence interval = 1.21 to 2.62). CONCLUSIONS: This study confirmed the prognostic significance of EarlyR using RNA from formalin-fixed, paraffin-embedded tissues from a case-cohort sample of BIG 1-98. EarlyR identifies a set of high-risk patients with relatively poor prognosis who may be considered for additional treatment. Further studies will focus on analyzing the predictive value of EarlyR signature.

Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer.

BACKGROUND: TP53, PTEN, and RB1 tumor suppressor genes (TSGs) are recurrently altered in treatment-resistant prostate cancer. Cooperative loss of two or more TSGs may drive more aggressive disease. OBJECTIVE: To determine clinical outcomes of single and compound TSG alterations across the spectrum of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Massively parallel targeted sequencing using castration-sensitive prostate cancer (CSPC; localized [L] and metastatic [M1]) and castration-resistant prostate cancer (CRPC) specimens (n=285). TSG altered (TSG-alt) was any copy number loss or deleterious mutation of one or more TSGs (TP53, PTEN, and RB1). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For L-CSPC, event-free survival (EFS) and time to CRPC were estimated. For M1-CSPC and M1-CRPC, overall survival (OS) was estimated. Cox regression models assessed the association between cumulative TSG hits (zero hits vs one hit vs two to three hits) and outcomes with multivariable analyses adjusted for clinicopathological factors. RESULTS AND LIMITATIONS: TSG variants increased with advanced disease (L-CSPC: 39%; M1-CSPC: 63%, M1-CRPC: 92%). TSG-alt L-CSPC had shorter EFS (median 2.6yr, hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.22-3.13) and time to CRPC (median 9.5mo, HR 3.36, 95% CI 1.01-11.16). Cumulative gene hits led to an incremental risk of relapse (EFS: one gene, HR 1.69, 95% CI 0.99-2.87; two to three genes, HR 2.70, 95% CI 1.43-5.08; both versus zero genes, p=0.004). There was evidence of inferior OS with increasing TSG hits in the metastatic cohorts. Only four (8%) patients in the M1-CRPC cohort were TSG-neg, one of whom died after 5.2yr. Multivariable analyses adjusting for mutational and copy number burden did not demonstrate a significant independent association of increasing gene hits and poorer outcomes. CONCLUSIONS: Deleterious TSG variants are associated with an increased risk of relapse (L) and death (M1) in CSPC. Poorer outcomes are seen with compound gene hits in both early and advanced disease, and this may in part reflect increasing global genomic instability. PATIENT SUMMARY: Men with prostate tumors with compound tumor suppressor gene mutations have poorer outcomes. These findings help identify patients with aggressive features who may benefit from intensified treatment.

Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer: A Randomized Phase II Trial.

PURPOSE: To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer. PATIENTS AND METHODS: Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms. RESULTS: Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected. CONCLUSION: In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer.

BACKGROUND: Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. METHODS: Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). RESULTS: There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. CONCLUSIONS: Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases.

Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed.Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081-8. ©2018 AACR.