Current cannabis use and pain management among US cancer patients.

BACKGROUND: National studies reporting the prevalence of cannabis use have focused on individuals with a history of cancer without distinction by their treatment status, which can impact symptom burden. While pain is a primary motivation to use cannabis in cancer, the magnitude of its association with cannabis use remains understudied. METHODS: We examined cannabis use and pain management among 5523 respondents of the Behavioral Risk Factor Surveillance System with a cancer history. Survey-weighted prevalence proportions of respondents' cannabis use are reported, stratified on cancer treatment status. Regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer-related pain and cannabis use. RESULTS: Cannabis use was slightly more prevalent in those undergoing active treatment relative to those who were not undergoing active treatment (9.3% vs. 6.2%; P=0.05). Those under active treatment were more likely to use cannabis medicinally (71.6% vs. 50.0%; P=0.03). Relative to those without cancer-related pain, persons with pain under medical control (OR 2.1, 95% CI, 1.4-3.2) or uncontrolled pain were twice as likely to use cannabis (OR 2.0, 95% CI, 1.1-3.5). CONCLUSIONS: Use of cannabis among cancer patients may be related to their treatment and is positively associated with cancer-related pain. Future research should investigate the associations of cannabis use, symptom burden, and treatment regimens across the treatment spectrum to facilitate interventions.

ARTISTRY-7: phase III trial of nemvaleukin alfa plus pembrolizumab vs chemotherapy for platinum-resistant ovarian cancer.

Standard single-agent nonplatinum chemotherapy provides only modest benefit in a small proportion of patients with platinum-resistant/-refractory ovarian cancer, with objective response rates of 6-20% and progression-free survival of ≈3-4 months. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel cytokine designed to capture and expand the therapeutic potential of high-dose interleukin-2 (IL-2) while mitigating its associated toxicity issues. Nemvaleukin preferentially activates cytotoxic CD8+ T cells and natural killer cells with minimal, non-dose-dependent effects on CD4+ regulatory T cells. The global, randomized, open-label, phase III ARTISTRY-7 trial will compare efficacy and safety of nemvaleukin plus pembrolizumab with chemotherapy in patients with platinum-resistant ovarian cancer. The primary end point is investigator-assessed progression-free survival. Clinical Trial Registration: GOG-3063; ENGOT-OV68; NCT05092360 (ClinicalTrials.gov).

In many patients with ovarian cancer who are treated with platinum-based chemotherapy, the tumor comes back after a few months and fails to respond to repeated treatment. This type of disease is called platinum-resistant ovarian cancer (PROC). Researchers are searching for new medicines to help more patients with PROC. One treatment approach that has shown promise in different cancers is called immunotherapy. These medicines work by helping the body's immune system attack cancer cells. One of the immunotherapies being studied is called nemvaleukin. It is designed to trigger specific immune responses that may result in the immune system attacking cancer cells while potentially avoiding other immune responses that can block the attack or cause certain unwanted side effects. Nemvaleukin is being studied in a variety of cancer types. In a worldwide clinical trial called ARTISTRY-7, researchers are investigating how nemvaleukin works in patients with PROC when given with another immunotherapy called pembrolizumab. Patients who participate in this trial will be randomly assigned to one of four treatment groups: the combination of nemvaleukin and pembrolizumab, nemvaleukin by itself, pembrolizumab by itself, or a type of chemotherapy selected by the treating physician. The main purpose of ARTISTRY-7 is to understand whether the combination of nemvaleukin and pembrolizumab helps patients with PROC live longer without their cancer getting worse. At the time of this writing, ARTISTRY-7 is open for new patients to join.

RaPiDS (GOG-3028): randomized Phase II study of balstilimab alone or in combination with zalifrelimab in cervical cancer.

Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors that have emerged as promising investigational agents for the treatment of cervical cancer, particularly in the setting of previously-treated, recurrent/metastatic disease. Here we describe the rationale and design of RaPiDS (NCT03894215), a two-arm Phase II study evaluating the safety, tolerability and efficacy of balstilimab administered alone or in combination with zalifrelimab in patients with advanced cervical cancer who progressed after first-line, platinum-based chemotherapy. Patients will be randomized in a 1:1 ratio. The primary end point is objective response rate, and key secondary objectives include safety, duration of response, progression-free survival, overall survival and quality of life outcomes.

Lay abstract Current treatment options for women with recurrent/metastatic cervical cancer are limited. Immunotherapy is altering the therapeutic landscape in this setting yet opportunities remain to improve on current outcomes. Dual blockade of different immune checkpoints is an approach shown to be highly effective in other cancers. Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors showing promise in patients with advanced cervical cancer. The RaPiDS trial is designed to characterize the safety and activity of balstilimab, alone and in combination with zalifrelimab, in patients with recurrent/metastatic cervical cancer who progressed after prior platinum-based chemotherapy. Clinical trial registration: NCT03894215 (ClinicalTrials.gov).

Practice patterns in post-treatment surveillance in patients with primary epithelial ovarian cancer.

BACKGROUND: The Society of Gynecologic Oncology created guidelines to standardize cost-effective clinical surveillance for detection of recurrence of gynecologic cancers. OBJECTIVE: To determine practice patterns for surveillance of primary ovarian cancer after complete response to therapy and to identify the percentage of clinicians who follow the surveillance guidelines endorsed by the Society of Gynecologic Oncology. METHODS: A single-institution retrospective cohort study was conducted including patients with epithelial ovarian cancer with a complete response to primary therapy between January 2012 and December 2016. Patients were excluded if they were participating in clinical trials that required routine imaging. Data on surveillance and recurrence were collected. Descriptive statistics as well as Fisher's exact test and chi-square test were performed due to the exploratory nature of the study. RESULTS: A total of 184 patients met the inclusion criteria. Median follow-up for the cohort was 37 months (range 6-80). Surveillance was completed in compliance with Society of Gynecologic Oncology guidelines in 78% of patients. Of 39 visits that were non-compliant, 44% (17) were patient initiated (scheduling conflict, missed appointment), 15% (6) were due to the provider intentionally scheduling alternative follow-up, while 41% (16) were off schedule due to problem visits (patient complaint of symptoms). Patients with early-stage cancers were more likely than advanced-stage patients to be non-compliant (33% vs 15%, p=0.006). Patients with non-serous histologies had a higher frequency of non-compliance (31% vs 16%, p=0.035). When stratified by early versus advanced stage, there was no difference in progression-free survival or overall survival based on compliance. CONCLUSIONS: Overall, there was a relatively high rate of compliance with Society of Gynecologic Oncology surveillance guidelines for patients with epithelial ovarian cancer. Patients with non-serous histologies and patients with early-stage disease had a higher rate of non-compliance, and these patients may represent special groups that would benefit from additional survivorship education.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma.

BACKGROUND: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). MATERIALS AND METHODS: DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. RESULTS: In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. CONCLUSION: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. IMPLICATIONS FOR PRACTICE: Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma.

BACKGROUND: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS. PATIENTS AND METHODS: The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines. RESULTS: Genomic MDM2 amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity. CONCLUSION: MDM2 amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of MDM2 as a predictive biomarker in DDLPS is warranted. IMPLICATIONS FOR PRACTICE: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. This study found that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that MDM2 amplification may be a useful biomarker in DDLPS.

Outpatient desensitization in selected patients with platinum hypersensitivity reactions.

Platinum-based chemotherapies are a standard treatment for both initial and recurrent gynecologic cancers. Given this widespread use, it is important to be aware of the features of platinum hypersensitivity reactions and the subsequent treatment of these reactions. There is also increasing interest in the development of desensitization protocols to allow patients with a history of platinum hypersensitivity to receive further platinum based therapy. In this review, we describe the management of platinum hypersensitivity reactions and the desensitization protocols utilized at our institution. We also describe the clinical categorizations utilized to triage patients to appropriate desensitization protocols.

Use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk in the Women's Health Initiative.

BACKGROUND: Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis, and its inhibition through non-steroidal anti-inflammatory drugs (NSAIDs) may reduce pancreatic cancer incidence. METHODS: We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trials cohorts. Among 117,452 women, ages 55-79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs and pancreatic cancer risk. RESULTS: Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI: 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI: 0.52-0.86). Use of total or individual non-aspirin NSAIDs were not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI: 0.10-0.75) relative to those without (HR 0.75, 95% CI: 0.61-0.92; P-interaction=0.03). CONCLUSIONS: Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes. IMPACT: This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.

Associations of Cancer Patients' Demographic and Clinical Characteristics With Cannabis-Related Interest and Behaviors.

Background: Cannabis interest and use is increasing in the United States, yet research on its use among cancer patients is limited. Methods: Individuals with cancer completed an anonymous cross-sectional questionnaire. Multivariable logistic regressions estimated odds ratios (OR) between patients' demographic and clinical characteristics with cannabis-related interest, current use, and provider recommendation. Results: Participants (n = 943) were, on average, 61.7 years old. Older patients were less likely to use cannabis products (OR = 0.42, confidence interval [95% CI]: 0.26-0.69) and less likely to be interested in cannabis (OR = 0.60, 95% CI: 0.44-0.84) than younger patients. Those with higher education were less likely to be using cannabis (OR = 0.41, 95% CI: 0.25-0.67) and less likely to have received a provider recommendation of cannabis use than the least educated (OR = 0.38, 95% CI: 0.19-0.76). Cancer spread and type were significant correlates of provider recommendation of cannabis use. Conclusions: Additional research is warranted to better understand cancer patients' motivations for cannabis use and interest.

Testing the feasibility of mobile ecological momentary assessment for symptom burden and management among metastatic cancer patients.

Background: Individuals who have metastatic cancer experience substantial physical and psychological distress (e.g., pain, depression, anxiety) from their disease and its treatment compared to patients with less advanced disease. As the burden of symptoms varies over time, ecological momentary assessment (EMA) may be used to better understand patients' symptom trajectories, complimenting traditional longitudinal data collection methods. However, few have used EMA in patients with metastatic disease. The current study adds to the existing literature by exploring interrelated, common cancer-related symptoms of pain, anxiety, and depression and use of cannabis-based products, opioid medications, other (nonopioid) pain medications, and medications for anxiety or depression. Methods: An eight-day prospective observational feasibility study was conducted among 50 patients with metastatic cancer recruited from seven solid cancer clinics at The Ohio State University Comprehensive Cancer Center. Participants completed a week of interval-contingent mobile EMA, administered daily at 9 a.m., 3 p.m., and 8 p.m., and a comprehensive interviewer-administered questionnaire on Day 8. Participants were queried on their symptom burden and management strategies (i.e., use of medications and cannabis). We considered EMA to be feasible if a priori retention (80%) and adherence goals (75%) were met. Results: Seventy-nine percent of eligible patients contacted enrolled in the study (n = 50 of 63). Among those enrolled, 92% were retained through Day 8 and 80% completed >90% of EMAs, exceeding a priori objectives. Participants' average pain, anxiety, and depressive symptoms across the week of EMA ranged from 1.7 to 1.8 (1 to 5 scale). Symptoms varied little by day or time of administration. On Day 8, significant proportions of participants reported past-week use of medications and cannabis for symptom management. Conclusions: Participants exceeded a priori adherence and retention objectives, indicating that mobile EMA is feasible among metastatic cancer patients, addressing a gap in the existing literature and informing future research. Restricting eligibility to participants with a minimum cutoff of symptom burden may be warranted to increase observations of symptom variability and provide opportunities for future health interventions. Future research is needed to test the acceptability and quality of data over a longer study period in this patient population.

Feasibility and safety of sequential research-related tumor core biopsies in clinical trials.

BACKGROUND: There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed. METHODS: This institutional review board-approved, retrospective study included chart and interventional radiology case review from 6 phase 1/2 studies at the National Cancer Institute. RESULTS: One hundred forty-two of 150 protocol patients who were approached gave consent for research biopsies. Patients' median age was 56 years (range, 27-78 years), their median body mass index was 25.8 kg/m(2) (range, 14.4-46.2 kg/m(2) ), they had an Eastern Cooperative Oncology Group performance status of 0 or 1, and they had normal end-organ function. Baseline biopsies were collected from 138 of 142 patients (97%), and paired specimens were collected from 96 (70%). Most patients had metastatic gynecologic cancers (85%), and 78% had target disease below the diaphragm with a median size of 2.7 cm (range, 1-14.5 cm). Protocol therapies included kinase inhibitors (35%), angiogenesis inhibitors (54%), and olaparib/carboplatin (11%); therapy was not interrupted for biopsies. All adverse events were uncomplicated and were observed in 4 patients (liver subcapsular hematoma in 1 patient, vasovagal syncope in 2 patients, and pneumothorax in 1 patient). The complication rate in obese patients was similar to that in nonobese patients (3 of 108 patients vs 1 of 34 patients, respectively). Sixty-seven patients (48%) were receiving bevacizumab at the time of subsequent biopsies. The complication rate was not different between patients who were and were not receiving bevacizumab (3 of 67 patients vs 1 of 71 patients, respectively). Ninety-five percent of biopsies yielded useable material. CONCLUSIONS: Serial percutaneous core-needle biopsies can be obtained safely and yield material applicable for multiple translational applications. Obesity and/or concomitant antiangiogenic therapy and depth of disease did not increase the risk or preclude the successful acquisition of useful tissue.

Marijuana and Cannabidiol Use Prevalence and Symptom Management Among Patients with Cancer.

Symptoms such as pain, nausea, and anxiety are common in individuals with cancer. Treatment of these issues is often challenging. Cannabis products may be helpful in reducing the severity of these symptoms. While some studies include data on the prevalence of cannabis use among patients with cancer, detailed data remain limited, and none have reported the prevalence of cannabidiol (CBD) use in this population. Adult patients with cancer attending eight clinics at a large, NCI-designated Comprehensive Cancer Center completed a detailed, cannabis-focused questionnaire between 2021 and 2022. Eligible participants were diagnosed with invasive cancer and treated in the past 12 months. Summary statistics were calculated to describe the sample regarding cannabis use. Approximately 15% (n = 142) of consented patients (n = 934) reported current cannabis use (defined as use within the past 12 months). Among which, 75% reported cannabis use in the past week. Among current cannabis users, 39% (n = 56; 6% overall) used CBD products. Current users reported using cannabis a median of 4.5 (interquartile range: 0.6­7.0) days/week, 2.0 (1.0­3.0) times per use/day, and for 3 years (0.8­30.0). Use patterns varied by route of administration. Patients reported moderate to high relief of symptoms with cannabis use. This study is the most detailed to date in terms of cannabis measurement and provides information about the current state of cannabis use in active cancer. Future studies should include complete assessments of cannabis product use, multiple recruitment sites, and diverse patient populations. SIGNIFICANCE: Clinicians should be aware that patients are using cannabis products and perceive symptom relief with its use.

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.

PURPOSE: Soft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma. MATERIALS AND METHODS: This review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data. RESULTS: Despite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A. CONCLUSION: CDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma.

Drivers of genomic loss of heterozygosity in leiomyosarcoma are distinct from carcinomas.

Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

PURPOSE: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. EXPERIMENTAL DESIGN: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. CONCLUSIONS: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target.

Sarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors.

PURPOSE: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma. METHODS: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy. RESULTS: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug. CONCLUSIONS: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.

Association of Liver-Directed Local Therapy With Overall Survival in Adults With Metastatic Intrahepatic Cholangiocarcinoma.

Importance: Intrahepatic cholangiocarcinoma is an aggressive hepatobiliary malignant neoplasm characterized by local progression and frequent metastasis. Definitive local therapy to the liver in the setting of metastatic intrahepatic cholangiocarcinoma may improve overall survival. Objective: To compare the overall survival of patients with metastatic intrahepatic cholangiocarcinoma treated with chemotherapy alone vs chemotherapy with definitive liver-directed local therapy. Design, Setting, and Participants: This cohort study used the National Cancer Database to identify 2201 patients with metastatic intrahepatic cholangiocarcinoma diagnosed between January 2004 and December 2014 who received chemotherapy with or without hepatic surgery or external beam radiation to a dose 45 Gy or higher. Multiple imputation, Cox proportional hazards, propensity score matching, and landmark analysis were used to adjust for confounding variables. Analyses were performed between September 2018 and February 2019. Exposures: Chemotherapy alone and chemotherapy with liver-directed surgery or radiation. Main Outcomes and Measures: Overall survival. Results: A total of 2201 patients (1131 [51.4%] male; median [interquartile range] age, 63 [55-71] years) who received chemotherapy alone (2097 [95.3%]) or chemotherapy with liver-directed local therapy (total, 104 [4.7%]; surgery, 76 [73.1%]; radiation, 28 [26.9%]) were identified. Patients treated with chemotherapy alone had larger median (interquartile range) primary tumor size (7.0 [4.4-10.0] cm vs 5.6 [4.0-8.3] cm; P = .048) and higher frequency of lung metastases (383 [25.9%] vs 7 [6.7%]; P = .004). Patients treated with liver-directed local therapy had higher frequency of distant lymph node metastases (34 [32.7%] vs 528 [25.2%]; P = .045). Liver-directed local therapy was associated with higher overall survival compared with chemotherapy alone on multivariable analysis (hazard ratio [HR], 0.60; 95% CI, 0.48-0.74; P < .001). A total of 208 patients treated with chemotherapy alone were propensity score matched with 104 patients treated with chemotherapy plus liver-directed local therapy. Liver-directed local therapy continued to be associated with higher overall survival (HR, 0.57; 95% CI, 0.44-0.74; P < .001), which persisted on landmark analysis at 3 months (HR, 0.61; 95% CI, 0.47-0.79; log-rank P < .001), 6 months (HR, 0.68; 95% CI, 0.50-0.92; log-rank P = .01), and 12 months (HR, 0.68; 95% CI, 0.47-0.98; log-rank P = .04). Conclusions and Relevance: In this study, the addition of hepatic surgery or irradiation to chemotherapy was associated with higher overall survival when compared with chemotherapy alone in patients with metastatic intrahepatic cholangiocarcinoma. These findings may be valuable given the paucity of available data for this disease and should be validated in an independent cohort or prospective study.