Identifying participants' preferences for modifiable chemotherapy-induced peripheral neuropathy prevention clinical trial factors: an adaptive choice-based conjoint analysis.

PURPOSE: There are no recommended treatments for chemotherapy-induced peripheral neuropathy (CIPN) prevention. Recruitment to CIPN prevention clinical trials is challenging because it is difficult to enroll patients between the time of cancer diagnosis and the initiation of neurotoxic chemotherapy. The purpose of this exploratory-sequential mixed-methods study was to determine patients' preferences that could affect the choice to participate in CIPN prevention clinical trials. METHODS: First, twenty cognitive interviews were conducted with adults who completed less than three neurotoxic chemotherapy infusions to clarify clinical trial attributes and levels thought to be important to patients when deciding whether to enroll in CIPN prevention trials (i.e., type of treatment, clinical tests, reimbursement, survey delivery; length of visits, timing of follow-up, when to begin treatment). Second, another eighty-eight patients completed an adaptive choice-based conjoint analysis survey that incorporated the finalized attributes and levels. Each level was assigned a part-worth utility score using Hierarchical Bayes Estimation. The relative importance of each attribute was calculated. RESULTS: The attributes with the highest relative importance values were type of treatment (27.1%) and length of study visits (20.2%). The preferred levels included non-medicine treatment (53.49%), beginning treatment after experiencing CIPN (60.47%), email surveys (63.95%), assessments that include surveys and clinical exams (39.53%), under 30-min visits (44.19%), $50/week reimbursement (39.53%), and 1-month post-chemotherapy follow-up visits (32.56%). CONCLUSIONS: Patients' preferences for participation may be included in the design of future CIPN prevention clinical trials to potentially bolster study enrollment.

Systemic treatments in MDM2 positive intimal sarcoma: A multicentre experience with anthracycline, gemcitabine, and pazopanib within the World Sarcoma Network.

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Characteristics of mismatch repair deficiency in sarcomas.

Due to the efficacy of immune checkpoint inhibitor therapy in tumors with deficient mismatch repair, there has been a surge in demand for mismatch repair deficiency testing in various tumor types. Mismatch repair deficiency is not known to play a significant role in the pathogenesis of sarcomas, and the utility of testing these tumor types is not established. This study aimed to determine the frequency, pattern, and clinicopathologic correlates of mismatch repair deficiency in sarcomas. Three hundred and four sarcomas were profiled using a genomic platform that employs massively parallel sequencing to interrogate 447 cancer-associated genes. Mismatch repair status was evaluated by determining the number of small insertion/deletion events occurring in homopolymer regions per megabase of exonic sequence data across all genes.  Molecular characteristics of mismatch repair-deficient sarcomas were compared to mismatch repair-deficient carcinomas (n = 70) also identified using the sequencing panel. Seven sarcomas (2.3%) were classified as mismatch repair-deficient: four unclassified sarcomas, and one each of pleomorphic rhabdomyosarcoma, epithelioid leiomyosarcoma and malignant PEComa. One patient had an established diagnosis of Lynch syndrome. In the remaining patients, the mismatch repair gene mutation was confirmed or suspected to be somatic. Mismatch repair immunohistochemistry confirmed the mismatch repair-deficiency status of all cases with alterations in the tested proteins. As expected, mismatch repair-deficient sarcomas showed a significantly elevated tumor mutation burden relative to mismatch repair-proficient sarcomas (median 16 versus 4.6, p < 0.001). However, in comparison to mismatch repair-deficient carcinomas, mismatch repair-deficient sarcomas showed a lower tumor mutation burden (median 28 versus 16, p = 0.006) and a significantly greater degree of chromosomal instability. Among mismatch repair-deficient sarcomas, PD-L1 was variably expressed on tumor-associated macrophages but not on tumor cells. Three patients received pembrolizumab: two progressed and one has stable disease with five months follow-up. Mismatch repair deficiency in histologically classifiable sarcomas is rare (1%) and is more common in unclassified sarcomas (10%). Additional study is required to determine the predictive role of mismatch repair-deficiency in sarcomas for immunotherapy.

Imatinib-induced drug reaction with eosinophilia and systemic symptoms in solid tumors: a patient with dermatofibrosarcoma protuberans and successful desensitization management.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, potentially life-threatening drug-induced hypersensitivity reaction, characterized by cutaneous eruptions, fever, diffuse lymphadenopathy, along with hypereosinophilia, and elevated liver function tests, which in severe cases may lead to fulminant hepatic failure and death. Although DRESS syndrome has been associated with over 50 different drugs including imatinib, it has never been reported in association with imatinib treatment in solid tumors. We recently treated a patient with metastatic dermatofibrosarcoma protuberans, a rare cutaneous mesenchymal tumor characterized by constitutive activation of the PDGFß receptor and high sensitivity to imatinib therapy, who had a DRESS reaction to imatinib. Given an initial dramatic clinical and radiological response to treatment and lack of effective alternative targeted therapies, following imatinib discontinuation and resolution of DRESS, we cautiously reintroduced imatinib therapy using a desensitization protocol under the care of the allergy and immunologic clinic. Imatinib was carefully titrated from an initial dose of 50 mg to a target dose of 400 mg daily, while tapering down the prednisone dose. The patient was able to tolerate the treatment without recurrent episodes of DRESS or interruptions, and gained additional 6 months of clinical benefit from imatinib treatment. Although suspected causative drugs should not be reintroduced in DRESS whenever possible, in this case of metastatic disease and lack of effective alternative treatments, a carefully designed drug rechallenge helped minimize the risk of overt clinical reaction and resulted in an overall clinical benefit.

Surveillance Imaging Patterns and Outcomes Following Radiation Therapy and Radical Resection for Localized Extremity and Trunk Soft Tissue Sarcoma.

BACKGROUND: Optimal surveillance imaging (SI) regimens following radiation therapy (RT) and radical resection for localized soft tissue sarcoma (STS) are unknown and practice patterns vary. METHODS: Between 2006 and 2014, 94 patients with localized STS of the extremity/trunk treated with preoperative RT and radical resection were identified. Timing of local recurrence (LR), distant recurrence (DR), and SI were evaluated. The Kaplan-Meier method was used to determine recurrence-free and overall survival (OS), and the method of recurrence detection (SI or due to signs/symptoms) was determined. RESULTS: Median tumor size was 7.5 cm, and 92% were intermediate/high grade. After a median follow-up of 60 months for surviving patients, 30 patients (32%) recurred, including 5 LRs and 26 DRs. The median time to LR and DR was 36.2 months (range 14.4-65.7) and 10.4 months (range 5.2-76.9), respectively, and the 5-year local recurrence-free survival (RFS), distant RFS, and OS was 95, 71, and 76%, respectively. Local SI was performed for 90% of patients, mostly by magnetic resonance imaging (MRI; 91%). Of the five LRs, two were detected by SI and three had signs/symptoms preceding imaging. All patients underwent distant SI. Of the 26 DRs, 23 (88%) were in the lung. SI detected 22 (85%) DRs, and only 4 of 26 had signs/symptoms prompting imaging. CONCLUSION: Given excellent local control with RT and radical resection for intermediate/high-grade STS of the extremity/trunk, SI of the primary site should be reserved for select patients at high risk of LR. Conversely, due to frequent occurrence of asymptomatic DR in the lungs, periodic lung SI is appropriate. Routine abdominopelvic SI may not be indicated for most histologies.

Cost-Effectiveness of Surveillance for Distant Recurrence in Extremity Soft Tissue Sarcoma.

BACKGROUND: Optimal distant recurrence (DR) surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of different imaging modalities performed at guideline-specified intervals. METHODS: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for American Joint Committee on Cancer stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest X-ray (CXR), chest computed tomography (CCT), and positron emission tomography-computed tomography (PET/CT). Probabilities, utilities, and costs were extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER). RESULTS: CCT was the most effective and most costly strategy with CXR the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER was $12,113/QALY for CXR versus $104,366/QALY for CCT while PET/CT was never cost-effective. Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 33% or as the WTP increases beyond $120,000/QALY. CONCLUSIONS: Optimal DR surveillance imaging for stage II-III extremity STS should be individualized based on patients' risks for DR. These results suggest CXR, or CCT performed at more protracted intervals, may be preferred for lower-risk patients (i.e., DR risk <33%), whereas CCT may be preferred for higher-risk patients (i.e., DR risk >33%). Further study of optimal strategies is needed. In the interim, these findings may help to refine guidelines to reduce resource overutilization during routine surveillance of lower-risk sarcoma patients.

NCCN Guidelines Insights: Bone Cancer, Version 2.2017.

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

Long-term outcomes in treatment of retroperitoneal sarcomas: A 15 year single-institution evaluation of prognostic features.

BACKGROUND: Retroperitoneal sarcomas are connective tissue tumors arising in the retroperitoneum. Surgical resection is the mainstay of treatment. Debate has arisen over extent of resection, changes in histological classification/grading, and interest in incorporating radiotherapy. Therefore, we reviewed our institution's experience to evaluate prognostic factors. METHODS: Retrospective chart review of all primary RPS patients at Johns Hopkins Hospital from 1994 to 2010. Histologic diagnosis and grading were re-evaluated with current criteria. Prognostic factors for survival, and recurrence were assessed. RESULTS: One hundred thirty-one primary RPS patients met inclusion criteria. Median survival for patients who undergo en-bloc resection to negative margins (R0/R1) is 81.7 months. Surgical margins and grade were the most important factors for survival along with age, gender, presence of metastases and resection of ≥5 organs. Five-year survival for R0/R1 resection was 60%, similar to compartmental resection. Radiotherapy significantly decreased local recurrence (P = 0.026) on multivariate analysis. Grade in leiomyosarcomas and dedifferentiation in liposarcomas dictated patterns of local versus distal recurrence. CONCLUSIONS: En bloc surgical resection to R0/R1 margins remains the cornerstone of therapy and provides comparable outcomes to compartmental resections. Grade remains important for prognosis, and histology dictates recurrence patterns. Radiotherapy appears promising for local control and warrants further investigation. J. Surg. Oncol. 2016;114:56-64. © 2016 Wiley Periodicals, Inc.

Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia.

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.

Exploring Influencing Factors of Anxiety Improvement Following Mindfulness-Based Music Therapy in Young Adults with Cancer.

The purpose of this secondary analysis was to explore physiological, psychological, and situational influencing factors that may affect the impact of a mindfulness-music therapy intervention on anxiety severity in young adults receiving cancer treatment. Young adults receiving cancer treatment for ≥ eight weeks were recruited from adult and pediatric oncology outpatient centers at Dana-Farber Cancer Institute. Participants were asked to attend up to four, in-person (offered virtually via Zoom video conference after the onset of the COVID-19 pandemic) 45-min mindfulness-based music therapy sessions over twelve weeks with a board-certified music therapist. Participants completed questionnaires about anxiety, stress, and other cancer treatment-related outcomes before and after participating in the intervention. Changes in anxiety (i.e., PROMIS Anxiety 4a) over time were compared among baseline physiological (e.g., age or sex), psychological (e.g., stress), and situational influencing (i.e., intervention delivery format) factors using Wilcoxon-rank sum tests. Thirty-one of the 37 enrolled participants completed the baseline and post-intervention measures and were eligible for inclusion in the secondary analysis. Results revealed that higher baseline physical functioning (median change = -6.65), anxiety (median change=-5.65), fatigue (median change = -5.6), sleep disturbance (median change = -5.6),female sex (median change = -5.15), or virtual intervention delivery(median change = -4.65) were potential physiological, psychological, or situational influencing factors associated with anxiety improvement following mindfulness-based music therapy. Additional investigation into physiological, psychological, or situational influencing factors associated with anxiety response will help to tailor the design of future mindfulness-music therapy interventions to decrease psychological distress and address the unique psychosocial concerns among young adults receiving cancer treatment. Trial Registration ClinicalTrials.gov Identifier: NCT03709225.

Immune-related Adverse Events after Immune Checkpoint Blockade-based Therapy Are Associated with Improved Survival in Advanced Sarcomas.

The association between immune-related AEs (irAE) and outcome in patients with sarcoma is not known. We retrospectively reviewed a cohort of patients with advanced sarcoma treated with immune checkpoint blockade (ICB)-based therapy. Association of irAEs with survival was assessed using a Cox regression model that incorporated irAE occurrence as a time-dependent covariate. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one grade ≥ 3 irAE. The most common irAEs were hypothyroidism (8.3%), arthralgias (5.3%), pneumonitis (4.6%), allergic reaction (3.8%), and elevated transaminases (3.8%). Median progression-free survival (PFS) and overall survival (OS) from the time of study entry were 11.4 [95% confidence interval (CI), 10.7-15.0) and 74.6 weeks (CI, 44.9-89.7), respectively. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the HR for an irAE (HR, 0.662; CI, 0.421-1.041) approached, but did not reach statistical significance for PFS (P = 0.074). Patients had a significantly lower HR for OS (HR, 0.443; CI, 0.246-0.798; P = 0.007) compared with those without or before an irAE. Gene expression profiling on baseline tumor samples found that patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways. SIGNIFICANCE: irAE after ICB therapy was associated with an improved OS; it also approached statistical significance for improved PFS. Patients who had an irAE were more likely to have an inflamed tumor microenvironment at baseline.

Population-based rare variant detection via pooled exome or custom hybridization capture with or without individual indexing.

BACKGROUND: Rare genetic variation in the human population is a major source of pathophysiological variability and has been implicated in a host of complex phenotypes and diseases. Finding disease-related genes harboring disparate functional rare variants requires sequencing of many individuals across many genomic regions and comparing against unaffected cohorts. However, despite persistent declines in sequencing costs, population-based rare variant detection across large genomic target regions remains cost prohibitive for most investigators. In addition, DNA samples are often precious and hybridization methods typically require large amounts of input DNA. Pooled sample DNA sequencing is a cost and time-efficient strategy for surveying populations of individuals for rare variants. We set out to 1) create a scalable, multiplexing method for custom capture with or without individual DNA indexing that was amenable to low amounts of input DNA and 2) expand the functionality of the SPLINTER algorithm for calling substitutions, insertions and deletions across either candidate genes or the entire exome by integrating the variant calling algorithm with the dynamic programming aligner, Novoalign. RESULTS: We report methodology for pooled hybridization capture with pre-enrichment, indexed multiplexing of up to 48 individuals or non-indexed pooled sequencing of up to 92 individuals with as little as 70 ng of DNA per person. Modified solid phase reversible immobilization bead purification strategies enable no sample transfers from sonication in 96-well plates through adapter ligation, resulting in 50% less library preparation reagent consumption. Custom Y-shaped adapters containing novel 7 base pair index sequences with a Hamming distance of ≥2 were directly ligated onto fragmented source DNA eliminating the need for PCR to incorporate indexes, and was followed by a custom blocking strategy using a single oligonucleotide regardless of index sequence. These results were obtained aligning raw reads against the entire genome using Novoalign followed by variant calling of non-indexed pools using SPLINTER or SAMtools for indexed samples. With these pipelines, we find sensitivity and specificity of 99.4% and 99.7% for pooled exome sequencing. Sensitivity, and to a lesser degree specificity, proved to be a function of coverage. For rare variants (≤2% minor allele frequency), we achieved sensitivity and specificity of ≥94.9% and ≥99.99% for custom capture of 2.5 Mb in multiplexed libraries of 22-48 individuals with only ≥5-fold coverage/chromosome, but these parameters improved to ≥98.7 and 100% with 20-fold coverage/chromosome. CONCLUSIONS: This highly scalable methodology enables accurate rare variant detection, with or without individual DNA sample indexing, while reducing the amount of required source DNA and total costs through less hybridization reagent consumption, multi-sample sonication in a standard PCR plate, multiplexed pre-enrichment pooling with a single hybridization and lesser sequencing coverage required to obtain high sensitivity.

Exploring the Feasibility of a Mindfulness-Music Therapy Intervention to Improve Anxiety and Stress in Adolescents and Young Adults with Cancer.

CONTEXT: Adolescent and young adults (AYAs) with cancer experience significant psychological distress due to cancer treatment that can persist long after treatment. However, little is known regarding optimal interventions to support the psychosocial needs of AYAs with cancer. OBJECTIVE: The overall objective of this single arm, longitudinal, pilot study was to determine the feasibility of implementing a mindfulness-based music therapy intervention to improve anxiety and stress in AYAs receiving cancer treatment. METHODS: AYAs (15 - 39 years old) who were to receive cancer treatment for ≥ eight weeks were recruited from the pediatric, melanoma, sarcoma, breast, lymphoma, and leukemia oncology outpatient centers at Dana-Farber Cancer Institute. The music therapy intervention included four sessions of individual mindfulness-based music therapy in-person or using Zoom over twelve weeks. Prior to-and after the intervention period, participants completed the Patient-Reported Outcomes Measurement Information Anxiety 4a and Perceived Stress Scale. Changes in patient-reported outcomes are compared using Wilcoxon signed-rank tests. RESULTS: Over ∼14 months, 37 of 93 eligible AYAs were enrolled to the study (39.8% consent rate). Overall, 27 of 37 (73%) participants (Median age=32; 56.8% Female) completed at least two music therapy sessions and the baseline measures and end of study measures. Participation in the mindfulness-based music therapy sessions resulted in significant pre-to-posttest improvements in perceived stress (median change: -4.0, P = 0.013) and non-significant changes in anxiety (median change: -1.9, P = 0.20). Satisfaction and acceptability were highly rated. CONCLUSIONS: The delivery of a four-session mindfulness-based music therapy intervention to AYAs receiving chemotherapy was feasible and significantly improved perceived stress. These preliminary findings should be confirmed in a randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03709225.

Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial.

Importance: Angiosarcoma is a rare sarcoma subtype with a poor outcome. Carotuximab plus pazopanib produced a median progression-free survival (PFS) of 7.8 months in pazopanib-naive patients with chemotherapy-refractory angiosarcoma in a phase 1/2 trial. Objective: To determine whether carotuximab plus pazopanib improves PFS compared with pazopanib alone in patients with advanced angiosarcoma. Design, Setting, and Participants: The TAPPAS Trial: An Adaptive Enrichment Phase 3 Trial of TRC105 and Pazopanib vs Pazopanib Alone in Patients With Advanced Angiosarcoma was a multinational, multicenter, open-label, parallel-group, phase 3 randomized clinical trial of 123 patients 18 years or older with advanced angiosarcoma that was conducted between February 16, 2017, and April 12, 2019, at 31 sites in the US and the European Union. Patients were randomized 1:1 to receive pazopanib alone or carotuximab plus pazopanib. The trial incorporated an adaptive enrichment design. Inclusion criteria were no more than 2 prior lines of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. The efficacy analysis used the intent-to-treat population; the safety analysis included all patients who received a dose of either study drug. Exposures: Oral pazopanib, 800 mg/d, or intravenous carotuximab, 10 mg/kg, administered weekly, plus oral pazopanib, 800 mg/d, with dose modification allowed per patient tolerance or until disease progression. Main Outcomes and Measures: The primary end point was PFS, assessed by blinded independent radiographic and cutaneous photographic review per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Secondary end points included the objective response rate and overall survival. An interim analysis to determine the final sample size was conducted after enrollment of 123 patients. PFS in the group receiving pazopanib alone was compared with PFS in the group receiving carotuximab plus pazopanib using the log rank test. Results: Of 114 patients with evaluable data (53 in the pazopanib arm and 61 in the carotuximab plus pazopanib arm), 69 (61%) were female and the median age was 68 years (range, 24-82 years); 57 (50%) had cutaneous disease and 32 (28%) had had no prior treatment. The primary end point (PFS) was not reached (hazard ratio [HR], 0.98; 95% CI, 0.52-1.84; P = .95), with a median of 4.3 months (95% CI, 2.9 months to not reached) for pazopanib and 4.2 months (95% CI, 2.8-8.3 months) for the combination arm. The most common all-grade adverse events in the single-agent pazopanib arm vs the combination arm were fatigue (29 patients [55%] vs 37 [61%]), headache (12 patients [23%] vs 39 [64%]), diarrhea (27 patients [51%] vs 35 [57%]), nausea (26 patients [49%] vs 29 [48%]), vomiting (12 patients [23%] vs 23 [38%]), anemia (5 patients [9%] vs 27 [44%]), epistaxis (2 patients [4%] vs 34 [56%]), and hypertension (29 patients [55%] vs 22 [36%]). Conclusions and Relevance: In this phase 3 randomized clinical trial, carotuximab plus pazopanib did not improve PFS compared with pazopanib alone in patients with advanced angiosarcoma. Trial Registration: ClinicalTrials.gov Identifier: NCT02979899.

Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma.

PURPOSE: Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors. EXPERIMENTAL DESIGN: We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD. RESULTS: We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline. CONCLUSIONS: In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.

Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center.

BACKGROUND: Angiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN). METHODS: Patients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks. RESULTS: For the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy. CONCLUSIONS: ICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.

Identified Enrollment Challenges of Adolescent and Young Adult Patients on the Nonchemotherapy Arm of Children's Oncology Group Study ARST1321.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma.

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.