Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities.

BACKGROUND: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis. MATERIALS AND METHODS: Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher's Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate. RESULTS: Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. CONCLUSIONS: In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.

A League of Its Own? Established and Emerging Therapies in Undifferentiated Pleomorphic Sarcoma.

OPINION STATEMENT: Over the last decade in soft tissue sarcoma (STS) research, the shifting landscape towards more precise subtype classification and the increasing study of novel therapeutic strategies has prompted a need to highlight current knowledge of effective subtype specific therapies. Undifferentiated pleomorphic sarcoma (UPS), formerly known as malignant fibrous histiocytoma (MFH), is among the most common subtypes of STS arising in the trunk or extremities of adults. Administration of systemic chemotherapy is the primary management in locally advanced and metastatic UPS. While anthracycline-based chemotherapy continues to be standard of care in this setting, outcomes in locally advanced or metastatic UPS remain poor. Recent studies highlight the unique characteristics of UPS that may contribute to its greater sensitivity to immune checkpoint inhibition (ICI) compared to other STS subtypes. With the promise of benefit from novel therapies, including ICI or ICI plus chemotherapy, for a subset of patients with UPS comes the need to identify biomarkers predictive of response to therapy. Ongoing and future clinical trials should place strong emphasis on correlative biomarker studies to learn more about the unique biology of UPS and to identify patients for whom ICI-based therapy will be effective.

Larotrectinib Treatment for Patients With TRK Fusion-Positive Salivary Gland Cancers.

BACKGROUND: Larotrectinib is a first-in-class, highly selective, and central nervous system-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. We report the efficacy and safety of larotrectinib in patients with TRK fusion-positive salivary gland cancers. PATIENTS AND METHODS: Patients with TRK fusion-positive salivary gland cancer treated with larotrectinib were identified from two clinical trials (NCT02122913 and NCT02576431). Patients received larotrectinib 100 mg twice daily (BID) except for one patient who received 150 mg BID in the phase I trial. The primary endpoint was objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: At the data cut-off (July 20, 2020), 24 patients with TRK fusion-positive salivary gland cancer had been treated. The most common histologies were secretory carcinoma (54%), adenocarcinoma (25%), and mucoepidermoid carcinoma (13%). All 24 patients had an ETV6-NTRK3 gene fusion. The ORR was 92% (95% confidence interval, 73-99). Best overall response was complete response in three (13%) patients, partial response in 19 (79%), and progressive disease in two (8%). The rate of progression-free survival at 24 months was 78% (median follow-up 30.9 months). Most treatment-related adverse events (AEs) were grade 1-2, and no patients discontinued treatment due to AEs. CONCLUSION: Larotrectinib demonstrated robust and durable efficacy in patients with TRK fusion-positive salivary gland tumors of various histologies, and a favorable safety profile. These findings support NTRK gene fusion testing in patients with advanced salivary gland cancers. CLINICALTRIALS.GOV NUMBERS: NCT02122913 and NCT02576431.

Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma.

BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

Immune Checkpoint Markers in Superficial Angiosarcomas: PD-L1, PD-1, CD8, LAG-3, and Tumor-Infiltrating Lymphocytes.

ABSTRACT: Cutaneous angiosarcomas may express programmed death ligand-1 (PD-L1) and PD-L1 expression, and the presence of tumor-infiltrating lymphocytes (TILs) correlates with outcome. These observations provide a basis for PD-1/PD-L1 inhibitor therapy. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that interacts with the PD-L1 axis and is considered to be a marker of immune exhaustion. The presence of LAG-3-positive lymphocytes in cutaneous angiosarcoma has not been established. We reviewed 10 cases of treatment naive angiosarcoma of skin and superficial soft tissue and assessed for PD-L1 (ZR3) expression, presence of TILs, and expression of CD8, PD1, and LAG-3 by tumor-associated inflammatory cells by immunohistochemistry. All 10 angiosarcomas were positive for PD-L1: 7 with high expression and 3 with low expression. TILs were present in all tumors: brisk in 7 and nonbrisk in 3. CD8 lymphocytes were present in all tumors with a range of 212-1274 cells per square millimeter (mean 557 CD8 cells/mm2). LAG-3-positive lymphocytes were present in 9 of 10 angiosarcomas with a range of 0-728 cells/mm2 (mean 146 LAG-3 cells cells/mm2). The ratio of LAG-3 lymphocytes to CD8 lymphocytes was 0%-59% (mean 27%). The PD1 cell counts were intermediate between CD8 and LAG3 counts. Cutaneous angiosarcomas frequently express PD-L1, have prominent numbers of CD8 positive, and have smaller numbers of LAG-3-positive and PD-1-positive TILs. Our findings provide further evidence of PD-L1 expression in cutaneous angiosarcoma and the promise for immune checkpoint inhibitor therapy.

Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: a multicentre, multigroup, phase 2 trial.

BACKGROUND: Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. METHODS: We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m2 on cycle one, day 1, then 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. FINDINGS: Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred. INTERPRETATION: In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. FUNDING: Pfizer.

Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of the current study was to determine quality of life and tumor control from a prospective phase 2 clinical trial evaluating deintensified chemoradiotherapy for favorable risk, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. METHODS: Patients with T0-T3, N0-N2c, M0, p16-positive disease and a minimal smoking history were treated with 60 grays of intensity-modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m2 ). The primary study endpoint was the pathologic complete response rate based on biopsy of the primary site and dissection of pretreatment positive lymph node regions. The pathologic complete response rate as previously reported was 86%. Herein, the authors report secondary endpoint measures of local control, regional control, cause-specific survival, distant metastasis-free survival, and overall survival, and patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [EORTC QLQ-C30] and the Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events [PRO-CTCAE]). RESULTS: A total of 44 patients enrolled with a median follow-up of 36 months (88% with ≥2 years). The 3-year local control, regional control, cause-specific survival, distant metastasis-free survival, and overall survival rates were 100%, 100%, 100%, 100%, and 95%, respectively. The mean before and 3-year after EORTC QOL scores were: global: 80 of 78; swallowing: 11 of 11; dry mouth: 16 of 41; and sticky saliva: 6 of 29. The mean before and 3-year after PRO-CTCAE scores were: swallowing: 0.4 of 0.7; and dry mouth: 0.4 of 1.4. Approximately 39% of patients required a feeding tube (median duration, 15 weeks; none were permanent). There were no ≥grade 3 late adverse events reported. CONCLUSIONS: For patients with favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma, a substantially decreased intensity of therapy with 60 grays of intensity-modulated radiotherapy and weekly low-dose cisplatin produced better preservation of quality of life compared with standard therapies while maintaining excellent 3-year tumor control and survival. Cancer 2018;124:2347-54. © 2018 American Cancer Society.

Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this study was to demonstrate the feasibility and efficacy of induction chemotherapy, surgery, and pathology-guided adjuvant therapy to treat transorally resectable squamous head and neck cancer. METHODS: Patients had squamous head and neck cancer that was resectable by the transoral route and advanced-stage disease (American Joint Committee on Cancer stage III-IV, T3-T4 tumors, and/or positive lymph nodes). They received treatment with weekly carboplatin at an area under the curve of 2, plus paclitaxel 135 mg/m2 , and daily lapatinib 1000mg for 6 weeks followed by surgical resection. Pathology that revealed margins <5 mm, extracapsular extension, N2a of N2b lymph node status, perineural invasion, or lymphovascular space invasion resulted in adjuvant radiotherapy concurrent with weekly cisplatin. Pathology with N2c/N3 lymph node status or positive margins resulted in radiation with bolus cisplatin. The primary endpoint was the clinical response rate to induction chemotherapy, and a key secondary endpoint was feasibility. RESULTS: Toxicity was modest, and 37 of 40 patients completed study procedures as planned. The clinical response rate was 93%, the pathologic complete response rate was 36%, and the clinical response did not predict for a pathologic complete response. No patient on study follow-up has recurred or died. Twenty-nine of 39 patients who underwent surgery avoided radiation. Speech and swallowing function were well preserved. CONCLUSIONS: The study met both its primary efficacy endpoint and the secondary feasibility endpoint. Neoadjuvant, systemic therapy and surgical resection followed by risk-adapted adjuvant therapy resulted in high response rates and excellent long-term outcomes and should be further studied. Cancer 2018;124:2986-92. © 2018 American Cancer Society.

Enhancing Next-Generation Sequencing-Guided Cancer Care Through Cognitive Computing.

BACKGROUND: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. MATERIALS AND METHODS: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. RESULTS: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. CONCLUSION: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. IMPLICATIONS FOR PRACTICE: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data.

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.

BACKGROUND: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab. METHODS: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol. RESULTS: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects. CONCLUSIONS: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society.

A randomized phase II study of carboplatin with weekly or every-3-week nanoparticle albumin-bound paclitaxel (abraxane) in patients with extensive-stage small cell lung cancer.

BACKGROUND: Platinum plus etoposide is the standard therapy for extensive-stage small cell lung cancer (ES-SCLC) and is associated with significant myelosuppression. We hypothesized that the combination of carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) would be better tolerated. We investigated carboplatin with nab-paclitaxel on every-3-week and weekly schedules. METHODS: This noncomparative randomized phase II trial used a two-stage design. The primary objective was objective response rate, and secondary objectives were progression-free survival, overall survival, and toxicity. Patients with ES-SCLC and an Eastern Cooperative Oncology Group performance status ≤2 and no prior chemotherapy were randomized in a 1:1 ratio to arm A (carboplatin area under the curve [AUC] of 6 on day 1 and nab-paclitaxel of 300 mg/m(2) on day 1 every 3 weeks) or arm B (carboplatin AUC of 6 on day 1 and nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15 every 21 days). Response was assessed after every two cycles. RESULTS: Patients required frequent dose reductions, treatment delays, and omission of the weekly therapy. The trial was closed because of slow accrual. CONCLUSION: Carboplatin and nab-paclitaxel demonstrated activity in ES-SCLC but required frequent dose adjustments.

Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without Mannitol.

BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without mannitol. METHODS: This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m2 dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m2 cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol.

Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.

Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed. Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US. Design, Setting, and Participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023. Main Outcomes and Measures: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation. Results: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001). Conclusions and Relevance: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

Sinonasal Squamous Cell Carcinoma Survival Outcomes Following Induction Chemotherapy vs Standard of Care Therapy.

OBJECTIVE: To compare oncologic outcomes in sinonasal squamous cell carcinoma (SNSCC) treated with standard of care (SOC) definitive therapy, consisting of surgery or chemoradiotherapy, vs induction therapy followed by definitive therapy. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care hospital. METHODS: The medical records of patients with biopsy-proven SNSCC treated between 2000 and 2020 were reviewed for demographics, tumor characteristics, staging, treatment details, and oncologic outcomes. Patients were matched 1-to-1 by age, sex, and cancer stage according to treatment received. Time-to-event analyses were conducted. RESULTS: The analysis included 26 patients with locally advanced SNSCC who received either induction therapy (n = 13) or SOC (n = 13). Baseline demographics, Charlson Comorbidity Index, and median follow-up time were well balanced. Weekly cetuximab, carboplatin, and paclitaxel were the most common induction regimen utilized. Tolerance and safety to induction were excellent. Objective responses were observed in 11 of 13 patients receiving induction. No difference in disease-free survival was found between the induction and SOC groups at 1 or 3 years. However, when compared with SOC, induction therapy resulted in significant improvement in overall survival at 2 years (100% vs 65.3%, P = .043) and 3 years (100% vs 48.4%, P = .016) following completion of definitive therapy. Two patients in the SOC group developed metastatic disease, as compared with none in the induction group. CONCLUSIONS: Induction therapy was safe and effective. When compared with SOC, induction therapy improved 3-year overall survival.

A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck.

PURPOSE: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. PATIENTS AND METHODS: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. RESULTS: 52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79). CONCLUSIONS: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Health Insurance Payer Type and Ethnicity Are Associated with Cancer Clinical Trial Enrollment Among Adolescents and Young Adults.

Purpose: Adolescents and young adults (AYAs) have experienced inferior improvements in cancer survival outcomes. One potential explanation is the low rate of enrollment in cancer clinical trials. While the reasons behind this are multifactual, sociodemographic factors are probably contributory. We examined the impact of factors such as insurance type and race/ethnicity on clinical trial enrollment among AYAs treated for cancer at an academic medical center. Methods: We identified AYAs (ages 15-39 years) treated for cancer at the University of North Carolina between April 2014 and April 2019. Cancer registry data were linked to electronic health record data to associate treatment and sociodemographic factors with clinical trial enrollment. A multivariable log-binomial model was used to estimate adjusted risk ratios. Results: In a 5-year period, 1574 AYA patients were identified, 59% female, 21% non-Hispanic Black and 9% Hispanic. Overall, 37% of AYAs participated in any clinical trial and 14% enrolled on a therapeutic trial. When compared to publicly insured AYAs, those with private insurance [adjusted RR: 1.52, 95% CI: 1.05-2.22] or with no insurance [adjusted RR: 2.12, 95% CI: 1.34-3.33] were more likely to enroll in a therapeutic clinical trial. Hispanic AYAs were less likely to enroll [adjusted RR: 0.50, 95% CI: 0.27-0.93] when compared to non-Hispanic White patients. Conclusions: Rates of clinical trial enrollment among AYAs vary based on health insurance type and race/ethnicity, suggesting possible disparities in access. Attention to resource, cultural, and language barriers may improve trial enrollment and cancer outcomes among vulnerable AYA subpopulations.

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors.

BACKGROUND: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. METHODS: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified. CONCLUSIONS: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.