Avelumab in Combination with Eribulin Mesylate in Metastatic Urothelial Carcinoma: BTCRC GU-051, a Phase 1b Study.

BACKGROUND: Patients with metastatic urothelial carcinoma (mUC) have poor prognosis, so further development of novel combinations for these patients is needed. OBJECTIVE: To assess the safety and efficacy of eribulin mesylate (eribulin) with avelumab in mUC. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, phase 1b study in which patients with mUC who were cisplatin-ineligible and treatment-naïve or platinum-resistant were treated with eribulin and avelumab. A 3 + 3 design was used. The study was prematurely terminated because the free study drug became unavailable, but we performed extended follow-up for patients enrolled in the study. INTERVENTION: Patients received eribulin 1.1 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort 0, or eribulin 1.4 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort +1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objectives were to determine the maximum tolerated dose (MTD) of eribulin with avelumab and assess the objective response rate. A key secondary endpoint was to assess efficacy by evaluating the disease control rate. Exploratory endpoints included PD-1 expression on T cells in peripheral blood and in tumor cells, and tumor DNA sequencing. RESULTS AND LIMITATIONS: A total of six patients were enrolled in the MTD group (n = 3 in cohort 0 and n = 3 in cohort +1). No dose-limiting toxicity (DLT) was observed in cohort 0, whereas two DLT events were observed in cohort +1. Two patients in cohort 0 had a partial response that was durable, with one patient having a durable response for 7.8 mo. Disease control was observed in 4/6 patients (66.7%). Owing to the early termination, MTD could not be determined. CONCLUSIONS: While early termination of this trial precludes any definitive conclusions, the combination of eribulin and avelumab shows promise in mUC. We observed that treatment was better tolerated and efficacious at lower doses of eribulin. Further research is warranted for this combination in mUC. PATIENT SUMMARY: We evaluated different doses of eribulin (a chemotherapy drug) in combination with a fixed dose of avelumab (an antibody used to treat several different cancers) in a small group of patients with metastatic cancer of the urinary tract. The lower dose of eribulin was easier to tolerate and the combination had an anti-cancer effect. This trial is registered at ClinicalTrials.gov as NCT03502681.

Group-led creative writing and behavioural health in cancer: a randomised clinical trial.

BACKGROUND: Cancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively. METHODS: We conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. PRIMARY OBJECTIVE: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients' mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms. RESULTS: Of 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI -4.31 to -2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI -2.6 to -0.1), anxiety (p=0.0366, 95% CI -4.1 to -0.2), depression (p=0.0441, 95% CI -3.9 to -0.1) and anger (p=0.0494, 95% CI -3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores. CONCLUSION: CWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.

Medical Service Use and Charges for Cancer Care in 2018 for Privately Insured Patients Younger Than 65 Years in the US.

Importance: Currently, there are limited published data regarding resource use and spending on cancer care in the US. Objective: To characterize the most frequent medical services provided and the associated spending for privately insured patients with cancer in the US. Design, Setting, and Participants: This cohort study used data from the MarketScan database for the calendar year 2018 from a sample of 27.1 million privately insured individuals, including patients with a diagnosis of the 15 most prevalent cancers, predominantly from large insurers and self-insured employers. Overall societal health care spending was estimated for each cancer type by multiplying the mean total spending per patient (estimated from MarketScan) by the number of privately insured patients living with that cancer in 2018, as reported by the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Analyses were performed from February 1, 2018, to July 8, 2021. Exposures: Evaluation and management as prescribed by treating care team. Main Outcomes and Measures: Current Procedural Terminology and Healthcare Common Procedure Coding System codes based on cancer diagnosis code. Results: The estimated cost of cancer care in 2018 for 402 115 patients with the 15 most prevalent cancer types was approximately $156.2 billion for privately insured adults younger than 65 years in the US. There were a total of 38.4 million documented procedure codes for 15 cancers in the MarketScan database, totaling $10.8 billion. Patients with breast cancer contributed the greatest total number of services (10.9 million [28.4%]), followed by those with colorectal cancer (3.9 million [10.2%]) and prostate cancer (3.6 million [9.4%]). Pathology and laboratory tests contributed the highest number of services performed (11.7 million [30.5%]), followed by medical services (6.3 million [16.4%]) and medical supplies and nonphysician services (6.1 million [15.9%]). The costliest cancers were those of the breast ($3.4 billion [31.5%]), followed by lung ($1.1 billion [10.2%]) and colorectum ($1.1 billion [10.2%]). Medical supplies and nonphysician services contributed the highest total spent ($4.0 billion [37.0%]), followed by radiology ($2.1 billion [19.4%]) and surgery ($1.8 billion [16.7%]). Conclusions and Relevance: This analysis suggests that patients with breast, colorectal, and prostate cancers had the greatest number of services performed, particularly for pathology and laboratory tests, whereas patients with breast, lung, lymphoma, and colorectal cancer incurred the greatest costs, particularly for medical supplies and nonphysician services. The cost of cancer care in 2018 for the 15 most prevalent cancer types was estimated to be approximately $156.2 billion for privately insured adults younger than 65 years in the US.

Radiotherapy and Receptor Tyrosine Kinase Inhibition for Solid Cancers (ROCKIT): A Meta-Analysis of 13 Studies.

Background: We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods: Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results: A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions: The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

Postoperative chemotherapy and radiation improve survival following cardiac sarcoma resection.

OBJECTIVE: Cardiac sarcoma represents a rare and aggressive form of cancer with a paucity of data to produce outcome-driven evidence-based guidelines. Current surgical management consists of resection with postoperative therapy (chemotherapy, radiation, or both) offered on a selective, individualized basis. This study was designed to determine whether postoperative therapy was associated with improved overall survival after resection. METHODS: The National Cancer Database was used to identify patients with cardiac sarcoma between 2004 and 2015. Patient characteristics were stratified by treatment (surgical, nonsurgical, and none), and treatment was analyzed by stage. Overall survival, assessed with Kaplan-Meier methodology, was compared between patients who received postoperative therapy and those who did not following resection. Multivariable survival modeling using a Weibull model identified risk factors associated with survival while controlling for confounders. RESULTS: The study included 617 patients diagnosed with cardiac sarcoma. Only 24% (149/617) of patients were diagnosed with early-stage disease. Angiosarcoma represented 48% (298/617) of cases and was the most commonly identified histologic subtype. 60% (372/617) underwent surgical resection and 58% (216/372) of those patients were treated with postoperative therapy. Following surgery, median survival was more than doubled for patients treated with postoperative therapy (19 months vs 8 months, P = .026). However, 5-year overall survival was similar between the groups. Multivariable analysis confirmed an improvement in survival with postoperative therapy (hazard ratio, 0.68; 95% confidence interval, 0.51-0.91, P = .009). CONCLUSIONS: Postoperative therapy is associated with better median survival following resection of cardiac sarcoma. However, at 5 years, the difference in overall survival is not statistically significant.

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Increased ß-adrenergic receptor (ß-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly ß2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective ß-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

The exercise in all chemotherapy trial.

BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.

Alterations of DNA damage response genes correlate with response and overall survival in anti-PD-1/PD-L1-treated advanced urothelial cancer.

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti-PD-1/PD-L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti-PD-1/PD-L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum-based chemotherapy. DDR alterations (including ATM) were associated with a non-significantly higher ORR to PD-1/PD-L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non-significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20-1.38, p = 0.19). ATM alterations were associated with a non-significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65-19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD-1/PD-L1 blockade versus 24% ORR in patients with <3 DDR alterations. In summary, DDR alterations were associated with non-significantly higher ORR and longer OS for patients with advanced UC receiving anti-PD-1/PD-L1 agents. ATM alterations were associated with shorter OS.

Toxicity in combination immune checkpoint inhibitor and radiation therapy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitor with radiation therapy (ICI + RT) is under investigation for improved patient outcome, so we performed a systematic review/meta-analysis of toxicities for ICI + RT compared to immune checkpoint inhibitor (ICI) therapy alone. MATERIALS AND METHODS: A PRISMA-compliant systematic review of studies in MEDLINE (PubMed) and in the National Comprehensive Cancer Network guidelines was conducted, with primary outcome grade 3 + toxicity. Criteria for ICI alone were: phase III/IV trials that compared immunotherapy to placebo, chemotherapy, or alternative immunotherapy; and for ICI + RT: prospective/retrospective studies with an arm treated with ICI + RT. Meta-analysis was performed by random effects models using the DerSimonian and Laird method. The I2 statistic and Cochran's Q test were used to assess heterogeneity, while funnel plots and Egger's test assessed publication bias. RESULTS: This meta-analysis included 51 studies (n = 15,398), with 35 ICI alone (n = 13,956) and 16 ICI + RT studies (n = 1,442). Our models showed comparable grade 3-4 toxicities in ICI + RT (16.3%; 95% CI, 11.1-22.3%) and ICI alone (22.3%; 95% CI, 18.1-26.9%). Stratification by timing of radiation and irradiated site showed no significant differences, but anti-CTLA-4 therapy and melanoma showed increased toxicity. The grade 5 toxicities were 1.1% and 1.9% for ICI alone and ICI + RT respectively. There was significant heterogeneity, but not publication bias. CONCLUSIONS: The random effects model showed comparable grade 3-4 toxicity in using ICI + RT compared to ICI alone in CNS melanoma metastases, NSCLC, and prostate cancer. ICI + RT is safe for future clinical trials in these cancers.

Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

BACKGROUND: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. MATERIALS AND METHODS: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. RESULTS: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003). CONCLUSIONS: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. IMPLICATIONS FOR PRACTICE: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Effect of creative writing on mood in patients with cancer.

OBJECTIVE: To determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood. METHOD: We piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient's mental health before and after intervention. Patients with metastatic or unresectable cancer were included. PRIMARY ENDPOINT: (1) Feasibility and (2) mood scores before and after CWW using ETS. RESULTS: A total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group. CONCLUSIONS: It is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.

Attendance at National Cancer Institute and Children's Oncology Group Facilities for Children, Adolescents, and Young Adults with Cancer in Pennsylvania: A Population-Based Study.

Purpose: Adolescents and young adults (AYAs) with cancer are a vulnerable population with decreased attendance at National Cancer Institute (NCI) comprehensive cancer centers and Children's Oncology Group (COG) facilities. Decreased attendance at NCI/COG facilities has been associated with poor cancer outcomes. The objective of this study was to evaluate cancer care patterns of AYAs compared with children, within Pennsylvania, and factors associated with attending an NCI/COG facility. Methods: Data from the Pennsylvania Cancer Registry between 2010 and 2015 for patients aged 0-39 years at cancer diagnosis were used. Primary analyses focused on age at diagnosis, insurance status, race, ethnicity, gender, cancer type, stage, diagnosis year, and distance to the NCI/COG facility. The primary outcome was receipt of care at an NCI/COG facility. Odds ratios (ORs) were calculated using multivariable logistic regression models. Sensitivity analyses were conducted to test and estimate robustness. Results: A sample of 15,002 patients, ages 0-39, was obtained, including 8857 patients (59%) who attended an NCI/COG facility. Patients were significantly less likely to attend an NCI/COG facility if they were aged 31-39 years (OR 0.054, 95% confidence interval [CI] 0.04-0.07), non-White (OR 0.890, 95% CI 0.80-0.99), Hispanic (OR 0.701, 95% CI 0.59-0.83), female (OR 0.915, 95% CI 0.84-1.00), had Medicaid insurance (OR 0.836, 95% CI 0.75-0.93), and lived further from an NCI/COG facility. Sensitivity analyses largely corroborated the performed estimates. Conclusions: AYAs with cancer in Pennsylvania have disproportionate attendance at specialized NCI/COG facilities across a variety of demographic domains. Enhancing the attendance of AYAs with cancer at these specialized centers is crucial to improve cancer outcomes.

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049-0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33-3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34-0.80). When adjusting for CA19-9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09-2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.

Exceptional Responders in Oncology: A Systematic Review and Meta-Analysis of Patient Level Data.

PURPOSE: We aim to systematically review and analyze the available literature on "exceptional responders" in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. MATERIALS AND METHODS: A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. RESULTS: The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). CONCLUSIONS: There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity.

Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%. To improve the overall and durable response rates for advanced-stage melanoma, combined targeted and immune-based therapies are under investigation. Here, we investigated how the natural products called schweinfurthins, which have selective anti-proliferative activity against many cancer types, impact anti-(α)PD-1-mediated immunotherapy of murine melanomas. Two different compounds efficiently reduced the growth of human and murine melanoma cells in vitro and induced plasma membrane surface localization of the ER-resident protein calreticulin in B16.F10 melanoma cells, an indicator of immunogenic cell death. In addition, both compounds improved αPD-1-mediated immunotherapy of established tumors in immunocompetent C57BL/6 mice either by delaying tumor progression or resulting in complete tumor regression. Improved immunotherapy was accomplished following only a 5-day course of schweinfurthin, which was associated with initial tumor regression even in the absence of αPD-1. Schweinfurthin-induced tumor regression required an intact immune system as tumors were unaffected in NOD scid gamma (NSG) mice. These results indicate that schweinfurthins improve αPD-1 therapy, leading to enhanced and durable anti-tumor immunity and support the translation of this novel approach to further improve response rates for metastatic melanoma.

Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics. SIGNIFICANCE: These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.