bluuebunny/crossref_metadata_2025 huggingface dataset:
A pilot curriculum to transition from 2D to 3D image-guided brachytherapy: A preliminary needs assessment.
Authors: Ogunmuyiwa Joy , Aliyu Usman Malami , Joseph Adedayo , Adegboyega Bolanle Comfort , Balogun Onyinye
Published: June 2023

11039

Background: Gynecologic cancers are one of the leading causes of death globally with a disproportionate burden of disease found in low to middle income countries (LMIC). Brachytherapy is often a necessary component in treatment management as it can deliver a high dose of radiation to the tumor while employing a steep dose fall off that spares the adjacent organs at risk. With 3D image guided brachytherapy (3D-IGBT), treatment planning utilizes volumetric images with the target volume and organs at risk contoured, reducing toxicity and improving outcomes when compared to 2D planar imaging. Despite this advantage, only a limited number of LMIC centers perform 3D-IGBT. Transitioning to 3D-IGBT requires considerable planning, resources, and training. The development of a multidisciplinary, computer-based training program to facilitate the transition to 3D-IGBT was identified as a priority of multiple Radiation Oncology departments in Nigeria. The aim of this preliminary needs assessment was to identify the necessary resources and anticipated barriers to development of a pilot training curriculum for the transition to 3D-IGBT. Methods: An anonymous, 16-question online survey was distributed to clinicians, physicists, radiation therapists, and staff within a Radiation Oncology department of a teaching hospital in Lagos, Nigeria. Results: In January 2023, 53 respondents completed the survey. Of the respondents, 36.5% were female and 63.5% were male. The average age was 37.5 (SD = 7.8). Clinical experience ranged from < 5 years (52.6%), 6-10 years (9.4%), to > 10 years (30.2%). Respondents included radiation therapists (28.8%), clinicians (27%), nurses (23.1%), and physicists (15.4%). Multiple barriers to implementation of 3D-IGBT were identified including lack of training (79.2%) or experience (58.5%), lack of financial investment (50.9%), and anticipated repair/replacement of equipment (41.5%). A majority of respondents identified staff training/education (66%) as critical to delivering 3D-IGBT. When asked about the curriculum components needed, most respondents believed that it should include plan review (96.2%), contour review (94.3%), and peer review of clinical cases (92.5%). Conclusions: Various areas of potential need were identified through this preliminary needs assessment, most notably, staff training. These findings suggest that there is an unmet need to further develop and implement a structured didactic and skills-based curriculum to transition from 2D to 3D-IGBT at these institutions. Identified focus areas including contour, peer, and plan review will help guide the refinement of this curriculum. These findings are an important first step in delivery of safe and efficacious 3D-IGBT in an LMIC.
Prognostic value of HER2-low status in breast cancer: A systematic review and meta-analysis.
Authors: Molinelli Chiara , Jacobs Flavia , Agostinetto Elisa , Marta Guilherme Nader , Ceppi Marcello , Bruzzone Marco , Blondeaux Eva , Schettini Francesco , Prat Aleix , Viale Giuseppe , Del Mastro Lucia , Lambertini Matteo , de Azambuja Evandro
Published: June 2023

1104

Background: HER2-Low breast cancer (BC) has been recently identified as a new therapeutic target. However, it is unclear if HER2-Low status has an independent impact on prognosis, both in metastatic and early settings. Methods: A systematic literature research of PubMed, Cochrane and conference proceedings (ASCO meetings, SABCS and ESMO congress) up to December 8, 2022 was performed to identify studies comparing survival outcomes of patients affected by HER2-Low BC vs. HER2-zero BC. HER2-Low status was defined as immunohistochemistry score 1 + or 2+ without in situ hybridization amplification. Pooled hazard ratios (HRs) for survival endpoints in the metastatic [progression-free survival (PFS), overall survival (OS)] and in the early [disease free-survival (DFS) and OS] settings as well as their 95% confidence intervals (95%CI) were calculated using the random-effect model of Der Simonian and Laird. The above-mentioned endpoints were also assessed according to estrogen receptor (ER) status. Results: Among 1,916 identified records, 42 studies including 1,797,377 patients were eligible for this analysis. We show the pooled HRs in the overall population and specific subgroups. In the early setting, HER2-Low status was associated with significant improved DFS (HR 0.86, 95%CI 0.79-0.92, p<0.001) and OS (HR 0.84, 95%CI 0.77-0.92, p<0.001) when compared to HER2-zero status. Improved OS was observed in subgroup analysis for both ER-positive and ER-negative HER2-Low populations, while DFS improvement was observed only in the ER-positive subgroup. Similarly, in the metastatic setting, patients affected by HER2-Low BC showed better OS when compared to those with HER2-zero BC (HR 0.94, 95%CI 0.89-0.98, p=0.008). HER2-Low metastatic BC was associated with significant improvement in OS compared to HER2-zero BC also in ER-positive and ER-negative subgroups. No significant differences were found in terms of PFS. Conclusions: Compared with HER2-zero status, HER2-Low status appears to be associated with an increased OS both in the advanced and early settings, regardless of hormone-receptor expression. [Table: see text]
Safety and clinical activity of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma: Results from the low-dose expansion cohort.
Authors: Movva Sujana , Druta Mihaela , Davis Lara E. , Monga Varun , Milhem Mohammed M. , Bailey Howard Harry , Chugh Rashmi , Bruns Ingmar , Allgood Victoria E , Chawla Sant P.
Published: June 2023

11508

Background: TTI-621 is a recombinant fusion protein combining the Fc region of human IgG1 with a fragment of human SIRPα, designed as a decoy receptor for CD47 on tumor cells to interrupt CD47-SIRPα signaling and promote macrophage-mediated phagocytosis of tumor cells as well as activation of NK cells. Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma (LMS). A phase 1/2 dose escalation study with high- and low-dose expansion cohorts evaluating TTI-621 + doxorubicin in patients (pts) with advanced LMS is ongoing (NCT04996004); results from the low-dose expansion cohort are presented. Methods: This open-label study enrolled anthracycline-naïve pts aged ≥18 y with evaluable unresectable or metastatic high-grade LMS and ≤1 prior line of therapy for advanced disease. Pts in the low-dose expansion cohort received TTI-621 0.2 mg/kg on Days 1 and 8 in combination with doxorubicin 75 mg/m2 on Day 1 of 21-day cycles for a maximum 6 cycles, followed by TTI-621 monotherapy on Days 1 and 15 of 28-day cycles until objective disease progression. Primary objectives for the expansion phase were evaluation of safety and investigation of clinical activity via assessment of overall response and clinical benefit rates as defined by RECIST v1.1 criteria. Results: At data cut-off (Oct 3, 2022), 23 pts were evaluable for safety and 20 for clinical response. In the safety population, 39% had received prior treatment for advanced disease. Two pts (9%) experienced Grade ≥3 AE assessed as related to TTI-621 treatment: pancreatitis (n = 1, 4%) and platelet count decreased (n = 1, 4%). Seven pts (30%) experienced Grade ≥3 AE related to the combination of TTI-621 and doxorubicin, including two pts (9%) each with platelet count decreased and white blood cell count decreased and three pts (13%) with neutrophil count decreased. Grade ≥3 doxorubicin-related AEs were more common (n = 17, 74%); most frequent were neutrophil count decreased (n = 8; 35%), white blood cell count decreased (n = 7; 30%), and neutropenia (n = 6; 26%). One pt experienced an infusion-related reaction (Grade 1 chills) assessed as related to TTI-621. No pts attained complete response, but one pt had a complete resolution of all target lesions. Five pts (25%) attained partial response for an overall response rate of 25%; 11 pts (55%) attained stable disease for a disease control rate of 80%. Conclusions: Addition of TTI-621 to doxorubicin showed promising clinical activity and a favorable safety profile among pts with advanced LMS, including those with prolonged exposure to TTI-621 ( > 360 d). Clinical trial information: NCT04996004 .
A pilot study of lenvatinib plus pembrolizumab in patients with advanced sarcoma.
Authors: Movva Sujana , Avutu Viswatej , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Kelly Ciara Marie , Keohan Mary Louise , Meyers Paul A. , Cohen Seth M. , Hensley Martee Leigh , Konner Jason A. , Schram Alison M. , Lefkowitz Robert A , Erinjeri Joseph Patrick , Qin Li-Xuan , Salcito Tiffany , Seier Kenneth , Tap William D. , D'Angelo Sandra P.
Published: June 2023

11517

Background: New treatment options are needed for sarcomas. Lenvatinib (L) is an oral, multi-tyrosine kinase inhibitor with significant inhibitory activity against VEGF receptor (VEFGR) 1-3, FGF receptor (FGFR) 1-3, KIT, platelet-derived growth factor receptor (PDGFR) alpha/beta, and RET. Experimental models suggest that L can favorably alter the tumor immune environment, and the combination of L and pembrolizumab (P) has proven to be synergistic and effective across multiple solid tumor types, providing rationale for this study. Methods: This is a pilot study evaluating the efficacy of L and P in select sarcomas. Patients who had at least 1 prior regimen but ≤ 3 were enrolled into one of five cohorts (n = 10 each) A: leiomyosarcoma (LMS); B: undifferentiated pleomorphic sarcoma (UPS); C: angiosarcoma and epithelioid hemangioendothelioma (EHE); D: synovial sarcoma (SS) and malignant peripheral nerve sheath tumor (MPNST); and E: osteosarcoma (OS) and chondrosarcoma (CS). Patients were treated with an initial 2-week run-in of L 20 mg orally daily. Subsequently, P was administered at 200 mg IV every 21 days. The primary endpoint for each cohort was the best objective response rate (ORR) documented by RECIST v1.1 by 27 weeks. The combination was considered worthy of further study if 2 or more responses were observed in a cohort. Secondary endpoints included progression-free survival (PFS), overall survival, duration of response, and safety of the combination. Archival tissue and on-treatment biopsies were collected. Results: As of January 31st, 2023, cohorts A, D and E have completed accrual. The best response in the LMS cohort was stable disease (SD). In cohort D there were 3 partial responses (PR): 2 SS; 1 radiation associated high grade MPNST. In cohort E one of 6 patients with OS had a PR. To date, of the 6 patients with angiosarcoma, there was 1 PR in a patient with adrenal primary that occurred after the prespecified 27-week timepoint. One of 5 evaluable patients in Cohort B had a PR. Among the 44 patients evaluable for safety, most common AEs were hypertension (56.8%), diarrhea (45.5%), proteinuria (45.5%), fatigue (40.9%), headache (36.4%) and nausea (36.4%). Most common ≥ grade 3 AEs were hypertension (13.6%), dyspnea (6.8%), non-cardiac chest pain (6.8%), syncope (6.8%). Conclusions: A signal of activity was noted in this pilot study for patients with OS, MPNST, angiosarcoma and SS. In the LMS cohort, there were no responses, and PFS was poor. Enrollment to cohorts B and C is ongoing. Clinical trial information: NCT04784247 . [Table: see text]
Two schedules of vincristine, irinotecan and temozolomide (VIT) for patients with relapsed or refractory Ewing sarcoma: A randomized controlled phase 2 trial.
Authors: Xu Jie
Published: June 2023

11525

Background: Vincristine, irinotecan and temozolomide (VIT) has provided an effective regimen in relapsed or refractory Ewing sarcoma patients. Optimal dose schedule of VIT is still undefined. Methods: We did this phase 2 randomized controlled trial and included patients with relapsed or refractory Ewing sarcoma. They were randomly assigned (1:1) by random number table method to either shorter dx5 schedule (Irinotecan 50mg/m2/d D1-5, Vincristine 1.4mg/m2 D1) or protracted dx5x2 schedule (Irinotecan 20mg/m2/d D1-5,8-12, Vincristine 1.4mg/m2 D1,8) together with a fixed dose of temozolomide (100mg/m2/d D1-5) in both groups. Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to eight cycles. The primary endpoint was objective response rate at 12 weeks (ORR12w). The secondary endpoint was progression-free survival (PFS), overall survival (OS) and safety. The study was powered to detect a 30% improvement in the response rate from 20% of dx5 schedule to 50% of dx5x2 schedule (α = 0.1, 1-β = 0.9, one-sided test favoring dx5x2 schedule since the only difference of clinical importance was an improved response with the inconvenient schedule of dx5x2). A sample size of 30 patients per group (60 randomly assigned patients) was required to detect a significant improvement in ORR12w. Results: Between May 21, 2020, and August 8, 2022, 24 patients were randomly assigned to dx5 schedule while 22 to dx5x2 schedule, respectively. Median follow-up was 10.7 months (IQR 9.7-13.9) in the dx5 group and 8.3 months (IQR 4.4-15.3) in the dx5x2 group. ORR12w was lower in dx5 group than in dx5x2 group (5 [20.8%] of 24 patients vs 12 [54.5%] of 22; p = 0.019). There was no significant difference in PFS between the two groups (median PFS 2.3 months [95% CI 0.0-4.7] in dx5 group vs 4.3 months [2.7-6.0] in dx5x2 group; hazard ratio [HR] 0.956 [95% CI 0.84-1.09]; p = 0.434). Also, there was no significant difference in OS (median OS 14.8 months [95% CI 12.0-17.6] vs 12.8 months [95% CI 6.9-18.7]; HR 0.957 [95% CI 0.81-1.12]; p = 0.594). Patients in dx5 schedule reported more grade 3 and 4 adverse events (AEs) than dx5x2 schedule, including diarrhea/abdominal pain (23[23.7%] of 97 courses vs 8[8.4%] of 95 courses, p = 0.005), vomiting/nausea (6[6.2%] vs 1[1.15%], p = 0.035). Other common grade 3 and 4 AE ( > 5%) were similar between two schedules (p > 0.05), including fatigue (24[24.7%] vs 14[14.7%]), leukopenia (6[6.2%] vs 8[8.4%]), neutropenia (5[5.2%] vs8 [8.4%]), and anemia (5[5.2%] vs 7[7.4%]). Unfortunately, the isolation policy of COVID-19 significantly restricted the speed of recruiting and the sponsor stopped following support to our study. Conclusions: Protracted dx5x2 VIT schedule showed superior efficacy and favorable tolerability compared with the shorter dx5 VIT schedule in patients with relapsed or refractory Ewing sarcoma. Clinical trial information: NCT03359005 .
ALMB-0168, a novel Cx43 hemichannel agonist monoclonal antibody, for metastatic or unresectable osteosarcoma after standard chemotherapy: A multicenter, open-label, single-arm, phase 1 study.
Authors: Shen Jingnan , Guo Wei , Wang Jin , Xie Xianbiao , Xie Lu , Xu Jie , Jing Chen , Lin Jianhua , Li Xianan , Zhou Yong , Wang Guowen , Zhang Xiaojing , Weitao Yao , Dong Yang , Ye Zhaoming , Wang Li , Zeng Yanyan , Wu Yongyong , Yang Xiugao , Zhang Yanfeng
Published: June 2023

11530

Background: The treatment of metastatic or unresectable osteosarcoma after standard chemotherapy remains a significant clinical challenge. Connexin 43 (Cx43) hemichannel has been suggested to be a key regulator of bone homeostasis and represents a new target for bone and breast cancer. ALMB-0168, a first-in-class therapeutic antibody agonist for Cx43 hemichannel, has been shown to suppress the growth and migration of osteosarcoma and breast cancer bone metastases in preclinical studies. Methods: Patients ≥16 years with histologically confirmed osteosarcoma who progressed after standard chemotherapy were eligible. This study consists of accelerated titration followed by a 3+3 design with 7 planned ALMB-0168 dose levels (1, 3, 6, 12, 18, 24, and 30 mg/kg) administered intravenously once every 3 weeks and then dose expansion at the potential recommended phase 2 dose (RP2D). Primary endpoints are safety and tolerability. Adverse events are rated according to the NCI CTCAE v5.0. Key secondary endpoints are overall response rate (ORR) and disease control rate (DCR) assessed using RECIST v1.1. Results: As of August 21, 2022, 14 patients (10 males, 4 females) with median age 27.5 years (range 16–38 years) were enrolled; ECOG PS was 0 in 7 patients (50.0%), 1 in 6 patients (42.9%) and 2 in 1 patient (7.1%). 5 patients received ≥2 prior lines of therapy. Six dose levels (1-24 mg/kg) have been completed in this ongoing study with no dose-limiting toxicities reported. Treatment related adverse events (TRAEs) of any grade occurred in 10 (71.4%) patients and were Grade 3 in 1 patient (infectious pneumonia); no events were Grade 4 or 5. Common TRAEs ( > 10%) were proteinuria (21.4%), anemia (21.4%), hematuria (14.3%), and increased aspartate aminotransferase (14.3%). No Cx43-related cardiac events or severe hepatic events were observed. A total of 13 patients were evaluable for response. ORR was 15.4% (2/13, 95% CI: 1.9–45.5%), including 2 partial responses (PR), 1 patient each at 6 mg/kg and 18 mg/kg. The patient at 6 mg/kg, who had ≥3 prior lines of therapy and lung metastases, achieved durable disease control with stable disease (SD) for 33 weeks followed by PR for 8+ weeks (at the time of analysis). The DCR was 53.8% (7/13, 95% CI: 25.1–80.8%) with 2 PRs and 5 SDs. Conclusions: ALMB-0168 demonstrated encouraging efficacy and tolerable safety in patients with metastatic or unresectable osteosarcoma after standard chemotherapy in a phase 1 dose-escalation trial. Dose escalation is ongoing and dose expansion will start at the potential RP2D levels. Clinical trial information: NCT04886765 .
Fluorine-18 fluorodeoxyglucose (18FDG)-uptake assessment of PDGFRA mutant gastrointestinal stromal tumors (GIST): A retrospective multicenter Italian study.
Authors: Nigro Maria Concetta , Marchetti Andrea , Fumagalli Elena , De Luca Ida , Bertuzzi Alexia Francesca , Grimaudo Maria Susanna , Grignani Giovanni , D'Ambrosio Lorenzo , Merlini Alessandra , Carreca Ignazio , Incorvaia Lorena , Dimino Alessandra , Gasperoni Silvia , Vincenzi Bruno , Pantaleo Maria A. , Nannini Margherita
Published: June 2023

11539

Background: D842V PDGFRA mutation identifies a molecular subtype of GIST, primarly resistant to imatinib and characterized by higher indolent behavior and a prominent immune profile. Although functional imaging with 18FDG-PET plays a proven role in GIST, especially in early assessment tumor response, less is known about 18FDG-uptake according to the GIST molecular subtypes. Taking into account of clinical and molecular features of D842V mutant GIST, we assumed that this subset of GIST could also have a different 18FDG-uptake. Therefore, the aim of the present study has been to investigate the degree of FDG uptake of PDGFRA mutant GIST, focusing on D842V ones, in order to better define the role of functional imaging in this rare and peculiar subset of GIST. Methods: Patients with PDGFRA mutant GIST underwent 18FDG-PET were retrospectively included from seven GIST Italian reference centers. Data on maximum standardized uptake (SUVmax) value of primary tumor or metastatic disease were collected. Results: 71 patients have been included: 37 (55.1%) with D842V PDGFRA mutant GIST (group A) and 34 (47.9%) with PDGFRA non-D842V mutant GIST (group B). Additionally, 30 patients with exon 11 KIT mutant GIST have been included, as control (group C). SUVmax values were obtained from primary tumor and metastatic lesions in 55 (54,4%) and 46 (45,6%) patients, respectively. Considering the whole population of 101 patients, the global median SUVmax was 3,7 (IQR 0-9.1), while the median SUVmax for group A, B, and C was 0, 3.6, and 10.4, respectively. The median SUVmax of PDGFRA mutant GIST was significantly lower than the median value of exon 11 KIT mutant GIST (p < 0.001). Notably, median 18FDG-uptake was significantly lower in D842V PDGFRA mutant GIST compared to PDGFRA non-D842V mutant ones (p = 0.021). Conclusions: PDGFRA D842V-mutant GIST present an overall lower 18FDG uptake compared to other GIST subgroups. This feature could be related to their specific molecular background and is consistent with their higher tendency to an indolent behavior. Therefore, the role of functional imaging with 18FDG-PET in this subset of GIST is limited. Finally, the prognostic value of the 18FDG-uptake degree within all PDGFRA mutant GIST will be investigated in the future.
Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)–resistant succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST).
Authors: Qiu Haibo , Zhou Zhi-wei , Zhou Ye , Wan Xiangbin , Li Ning , Tao Kaixiong , Li Yong , Wu Xin , Chen Zi , Liu Lihui , Men Lichuang , Wang Hengbang , Liang Eric , Wang Cunlin , Jiang Lixin , Yang Dajun , Xu Rui-Hua , Zhai Yifan
Published: June 2023

11540

Background: Treatment of pts with GIST has been transformed by TKIs. However, treatment resistance is a challenge in managing locally advanced or metastatic disease. Pts with SDH-deficient GIST typically present with multifocal and multinodular disease that is insensitive to most TKIs. Olverembatinib is an investigational novel, potent, orally active third-generation TKI with promising activity against GIST in multiple preclinical models. Methods: The aim of this study was to evaluate the safety and efficacy (per RECIST v1.1) of olverembatinib in pts with TKI-resistant metastatic SDH-deficient GISTs (confirmed by immunohistochemistry). Olverembatinib was administered orally once every other day (QOD) in 28-day cycles. Results: As of January 15, 2023, 20 pts with SDH-deficient GIST had received ≥ 1 dose of olverembatinib (median age, 30 [14-56] years), and 19 had received 1 to TKIs (50% of pts ≥ 3; Table). The dose range of olverembatinib was 20 to 50 mg (50 mg cohort [n = 6]; 40 mg [n = 8]; 30 mg [n = 6]). The median (range) treatment duration was 7.8 (1.81-42.3) months. A total of 5 of 20 pts experienced partial response (PR) as the best response. Of 16 evaluable pts treated with > 4 cycles of olverembatinib, the clinical benefit rate (CBR; complete response + PR + stable disease > 4 cycles) was 93.8% (15/16); the longest treatment duration was 42 months. All pts experienced treatment-emergent adverse events (AEs; most, grade 1 or 2); 2 pts experienced grade 3 AEs; the only hematologic AE with an incidence rate ≥ 20% was anemia (55%). A total of 15 (75%) pts experienced treatment-related AEs (grade 3 neutropenia [n = 1]). No treatment-related serious AEs were reported. Conclusions: Olverembatinib was well tolerated up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant, SDH-deficient GIST. A total of 5 PRs were reported among 20 evaluable pts and 15 SDs among 16 pts treated for ≥ 4 cycles (98.3% CBR). These promising findings warrant further investigation. Internal study identifier: HQP1351SJ003. Clinical trial registration: NCT03594422 . [Table: see text]
Longitudinal follow-up and outcomes of pediatric and adult patients with SDH-deficient GIST.
Authors: Dagalakis Urania , Ghabra Shadin , Kaschak Erika , Ilanchezhian Maran , Del Rivero Jaydira , Miettinen Markku , Sutterwhite Audra A , Thomas B. J. , Bernstein Donna , Raygada Margarita , Flowers Crystal , Killian Keith , Meltzer Paul S. , Reilly Karlyne , Wedekind Mary Frances , Widemann Brigitte C. , Sankaran Hari , Blakely Andrew M. , Glod John
Published: June 2023

11542

Background: Gastrointestinal stromal tumor (GIST) are gastrointestinal non-epithelial neoplasms most commonly driven by somatic mutations in KIT or PDGFRA. Approximately ten percent of GIST are due to germline mutations in SDHx or epigenetic loss of expression of SDHC. While KIT and PDGFRa driven GIST respond to treatment with tyrosine kinase inhibitors, effective systemic therapies for SDH-deficient GIST have not yet been identified. SDH-deficient GIST are indolent tumors that typically progress slowly over time. A better understanding of the natural history of patients with these neoplasms is critical to identify effective treatments and improve patient care. A cohort of patients with SDH-deficient GIST is followed at the NIH Clinical Center and through the NIH Pediatric and Wild-type GIST Clinic. The aim of this study is to characterize the long-term outcome of this cohort of patients. Methods: Data from patients with SDH-deficient GIST enrolled in a study Natural History and Biospecimen Acquisition for Children and Adults with Rare Solid Tumors (NCT03739827) from January 2019 through January 2023 at the NIH were evaluated. In addition to review of medical records and imaging, when available, tumors were characterized by sequencing of SDH genes. Germline analysis of SDH genes was offered to consenting patients and families. Results: Clinical information and specimens were collected from 77 GIST patients (median age at diagnosis 21.5, [range 7-57] years; 72.7% (56) female, 21.3% (21) male) were classified by molecular subtypes: 33.8% SDHC epimutation, 28.6% SDHA, 22.1% SDHB, 14.3% SDHC and 1.3% SDHD. Median age at presentation of SDHC epimutation was younger (14.5 years, range: 8-56) when compared to SDHA (27.5 years, range: 7-55), SDHB (22 years, range: 8-54), SDHC (18 years, range: 10-57) and SDHD (39 years, N = 1). Most commonly, patients had at least one surgery (55.8%) while a lower proportion had four or more (7.8%). Primary tumors occurred in the stomach with 26% having metastases at presentation the most common location being the liver (10.4%). Overall, 64.9% of patients were treated with imatinib, 39% were treated with sunitinib and 15.6% received other additional systemic therapies. Within the cohort there were 13% of patients with paragangliomas and 6.5% with chondromas while only 9.1% had a family history of GIST. Conclusions: Longitudinal follow-up of an SDH-deficient GIST patient cohort will allow for better understanding of the natural history including treatment history and survival of patients with this rare disease and will help to optimize strategies for treatment and follow-up of these patients.
Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors (GIST) as ≥4th line therapy: Long-term update from a single-arm, phase 2 trial.
Authors: Li Jian , Zhang Xinhua , Zhou Yongjian , Zhang Jun , Zhou Ye , Wang Ming , Wu Xin , Deng Yanhong , Huang Zhao , Dong Juan , Shen Lin
Published: June 2023

11543

Background: In INVICTUS study (NCT03353753), ripretinib as ≥4th line (4L) GIST therapy significantly improved median progression-free survival (mPFS) versus placebo (hazard ratio 0.15, 95% confidence interval [CI] 0.09–0.25; mPFS 6.3 vs 1.0 months) with a satisfactory safety profile. In the primary analysis (data cut-off: 26 Feb 2021) of the bridging study (NCT04282980) of INVICTUS, ripretinib as ≥4L therapy showed consistent efficacy and safety profiles in Chinese GIST patients to those in INVICTUS, with mPFS of 7.2 months and objective response rate (ORR) of 18.4% (7/38 patients). The overall survival (OS) data was immature at the primary analysis. Here we report the long-term updates of this bridging study. Methods: Patients received ripretinib 150 mg once daily continuously in 28-day cycles until progressive disease or other protocol-specified events for treatment discontinuation. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 GIST-Specific Standard. Secondary endpoints included ORR by IRR, time to best response (TBR), duration of response (DOR), OS and safety. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Results: Overall, 39 patients were enrolled. Thirty-eight patients received continuous ripretinib treatment and were included in the efficacy analysis set. All 39 patients received at least one dose of ripretinib and were included in the safety set. The updated data cut-off was 23 Aug 2022. The overall median follow-up (90% CI) was 23.00 (11.99, 24.87) months. In the efficacy analysis set, mPFS (90% CI) by IRR was 6.44 (2.89, 8.31) months and ORR was 21.1% (8/38 patients). Median TBR and median DOR for the 8 patients with confirmed partial response were 2.25 and 8.57 months, respectively. The median OS (95% CI) in the efficacy analysis set was 25.56 (11.73, not evaluable) months. In the safety set, 20.5% of patients experienced ≥1 grade 3/4 treatment-related treatment-emergent adverse events (TRAEs). Compared to the primary analysis, the increase in TRAEs and new TRAEs leading to dose modification were minimal after 18 months of additional follow-up. Conclusions: After long-term follow-up, the more mature results continued to support the clinically meaningful benefit in PFS and also demonstrated clinically meaningful benefit in OS in Chinese ≥4L GIST patients, while the safety profile remained satisfactory. Clinical trial information: NCT04282980 .
Phase 1 trial of avelumab with hypofractionated thoracic radiation therapy (HT-RT) in patients with metastatic soft-tissue sarcomas (mSTS).
Authors: Zaidi Shane H , Fotiadis Nicos , Augustin Yolanda , Napolitano Andrea , Goggin Caitriona , Asare Bernice , Barquin Elizabeth , Edmunds Steven , Thway Khin , Benson Charlotte , Jones Robin L , Miah Aisha B
Published: June 2023

11552

Background: Combining HT-RT with anti PD-L1 therapy may enhance local and distant tumour control in mSTS. This was a Phase 1 trial to evaluate the safety, tolerability, and efficacy of avelumab in patients with mSTS. Methods: This was a single centre phase 1 trial of avelumab with HT- RT in patients with mSTS (NCT03602833). Patients > 18 years with at least 2 pulmonary metastases, ECOG performance status 0-1 were eligible between Oct 2018-Apr 22. Patients received HT-RT (36 Gy in 12 fractions), with concurrent intravenous avelumab (10 mg/kg q14d) until disease progression. The primary end point was safety of avelumab with HT-RT. Secondary endpoints included local control rate at 3 months. Dose limiting Toxicity (DLT) assessed from start of HR-CT and avelumab up to Cycle 7 avelumab and defined as: ≥ G2 pneumonitis, ≥ G2 myelitis, ≥ G3 non-haem toxicity, ≥ any other G4 and/or HT-RT interruption > 5 days. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). Results: 12 patients were treated in this trial. Histological subtypes: leiomyosarcoma (n = 2), undifferentiated pleomorphic sarcoma (n = 2), and spindle cell sarcoma (n = 2). The median age was 57.5 (37-68) years, 7 were female (58%). All patients had lung metastases. 1 previously received SBRT to the lung, and 5 (42%) patients had received prior systemic treatment. 12 patients received at least one cycle of avelumab, median 9 (range: 1-37), and treatment was discontinued in 11 (92%) patients; 10 (83%) stopping for progressive disease, 1 (8%) patient for G4 immune-mediated hepatitis after DLT period and 1 patient completed and continues on compassionate-use avelumab. Eleven (92%) completed radiotherapy (36 Gy, 12 fractions). No DLTs or treatment-related deaths were observed. HT-RT toxicity: 3 G2 acute (1 oesophagitis, 2 skin) noted up to 11 weeks. 13 G1 late toxicities (5 pneumonitis, 5 skin, 1 cardiac, 1 myelitis, 1 oesophagitis) reported. Avelumab toxicities: 2 G3 (1 ALT rise, 1 viral infection) and 3 G4 (1 AST rise, 1 hepatitis, 1 sepsis) reported after DLT observation period. The median follow-up was 21.8 (range 3.2-31.9) months with a 3-month local control rate of 50% (95% CI, 21%-74%). RECIST responses at 3 months were 0 CR, 1 (8%) PR, 5 (42%) SD and 5 (42%) PD. Conclusions: Avelumab in combination with thoracic radiotherapy was safe with encouraging anti-tumour activity in patients with metastatic soft-tissue sarcomas. Additional molecular biomarker analyses are in progress. Clinical trial information: NCT03602833 .
Results of SOC-2082 phase 2 study using metronomic gemcitabine, doxorubicin and docetaxel plus nivolumab as second/third-line therapy for advanced sarcoma.
Authors: Omelchenko Nadezhda , Chawla Neal Shiv , Makrievski Stefan , Leao De Melo Guilherme , Valencia Chrysler , Ahari Amir , Moradkhani Ania , Chua Victoria , Quon Doris , Brigham Don Arlen , Chawla Sant P. , Gordon Erlinda Maria
Published: June 2023

11555

Background: Metronomic dosing of gemcitabine, doxorubicin and docetaxel causes less severe side effects than standard chemotherapy for advanced sarcoma. The addition of nivolumab to this regimen has potential to have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival (PFS); Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, ≥ 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles are continued every three weeks if the toxicity grade is ≤1. Results: This report on the modified intent-to-treat population (n=59). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. Best Overall Response = 8 PR, 44 SD, 7 PD. The disease control rate ( CR+PR+SD) was 88.1%. Median PFS was 5.1 (95% CI: 2.837-7.363) months; 6 month PFS rate 52.5%. Median OS, 15.3 (95% CI: 5.48-25.12) months, with 6-month OS 88%. Safety analysis: Grade 3/4 TRAEs include fatigue (n=18), nausea (n=13), neutropenia (n=10), thrombocytopenia (n=9), anemia (n=9), diarrhea (n=1). There were no unexpected adverse events. Conclusions: Taken together, the data suggests that nivolumab in combination with metronomic doses of gemcitabine, doxorubicin and docetaxel (1) may have synergistic activity, and (2) by indirect comparison, may be as effective as standard first line therapy for advanced sarcoma with manageable toxicity. Clinical trial information: NCT04535713 .
Metronomic dosing of selinexor in select soft tissue sarcomas (STS).
Authors: Alshibany Aisha , Salawu Abdulazeez , Gupta Abha A. , Al-Ezzi Esmail Mutahar , Genta Sofia , Malone Eoghan Ruadh , Watson Geoffrey Alan , Vornicova Olga , Wang Lisa , Arones Limore , Phillips Madeline J. , Lee Jasmine , Abdul Razak Albiruni Ryan
Published: June 2023

11557

Background: Selinexor (S) is a first-in-class, oral, selective inhibitor of nuclear export (SINE). S has a demonstrated anti-tumor activity in STS. However, the use of S can be associated with toxicities, such as nausea, anorexia and fatigue. A modified dosing schedule may improve the tolerability of S without compromising its efficacy. Methods: We evaluated S when given metronomically in patients (pts) with advanced metastatic leiomyosarcoma, endometrial stromal sarcoma, and malignant peripheral nerve sheath tumors. S was administered daily for 4-days in a row followed by 3-days break, repeated weekly in a 28-days cycle. Dose levels (DL) were escalated using a 3+3 design to determine maximum tolerated dose. DL included 2.5mg (DL1), 5mg (DL2), 7.5mg (DL3), 10 mg (DL4), 12.5 mg (DL5), 15 mg (DL6) and 17.5 mg (DL7). S was administered until unacceptable toxicities or disease progression. Imaging was performed every 8 weeks. Primary objectives were safety and tolerability as well as the determination of the recommended phase II dose. Secondary objectives were anti-tumor activity, toxicity profile, and pharmacokinetics (PK) profile. Results: Twenty-five pts (22 females/3 males, median age 59 years [range 35-84]) were enrolled at different DL (3, 3, 4, 6, 6, 3 pts at DL1 to DL6 respectively). The most common adverse events (AE) of any grade were constipation (n = 11, 50%), nausea (n = 11, 50%), and dysgeusia (n = 10, 45%). Eight (36%) pts experienced G3/4 AE while on trial; most were hematological toxicities seen in 3 (14%) pts (anemia, neutropenia, and leukopenia, n = 1 each). Non-hematological G3/4 AE were seen in 5 (23%) pts (Including: colonic obstruction, atrial fibrillation, and spinal cord compression, n = 1 each). Two Dose limiting toxicities were experienced, at DL4 (thrombocytopenia) and DL5 (transaminitis). Twenty-two pts were evaluable for response; 10 (45%) pts had stable disease (SD) as best response. Eight pts with SD had disease stability of > 4 months. Twelve pts (55%) had progressive disease. Median progression-free survival was 2.4 months (95% CI 1.7-5.3 months). PK data is awaiting final analysis. Conclusions: Metronomic S demonstrated tolerability in selected sarcoma pts. Signs of potential clinical benefit was seen in the form of SD. Further data comparison with historical controls and PK analysis are needed to put this finding into perspective. Clinical trial information: NCT04811196 .
A phase II study of talimogene laherparepvec (T-VEC) and pembrolizumab in patients with advanced sarcoma: Results of expansion cohorts.
Authors: Kelly Ciara Marie , Avutu Viswatej , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Rosenbaum Evan , Cordover Emma , Ariyan Charlotte Eielson , Bartlett Edmund , Crago Aimee Marie , Singer Samuel , Antonescu Cristina R. , Hwang Sinchun , Erinjeri Joseph Patrick , Seier Kenneth , Qin Li-Xuan , Tap William D. , D'Angelo Sandra P.
Published: June 2023

11570

Background: The open-label, single-center phase II study of T-VEC and pembrolizumab in patients with advanced sarcoma met its primary endpoint and demonstrated a best objective response rate of 30% at 24 weeks per RECIST v1.1 (Kelly CM, et al, Jama Oncology, 2020). Responses were seen in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, (MFS), epithelioid sarcoma (ES), cutaneous angiosarcoma (AS), and undifferentiated sarcoma not otherwise specified. Here, we report the efficacy observed in three histology specific expansion cohorts: 1) UPS/MFS, 2) cutaneous AS and 3) ES. Methods: Patients refractory to ≥ 1 prior line of systemic therapy or declined standard of care systemic therapy received pembrolizumab intravenously and intratumoral T-VEC injections on day 1 of a 21-day cycle. The primary endpoint was best objective response (ORR, complete and partial responses per RECIST v 1.1) by 24 weeks estimated for each subtype-specific cohort. Secondary objectives included: adverse events (AEs, TRAEs), median PFS and correlatives. Results: Twenty-one patients enrolled in the expansion cohorts: median age 72 years (range: 39-85), male 57%, ≤ 1 prior line of therapy (43%). Treatment was well tolerated in twenty patients; one patient discontinued study therapy due to grade 3 immune mediated hepatitis. Nineteen patients were evaluable for efficacy (one patient withdrew from the study and another discontinued treatment before week 24). Subtype specific best ORR by 24 weeks per RECIST v 1.1: UPS/MFS – 11% (n = 1/9)[95% CI: 0.0-0.48]; AS – 43% (n = 3/7)[95% CI: 0.1-0.82]; ES – 0% (n = 0/3). The best ORR overall for the AS cohort was 71% (n = 5/7)[95% CI: 0.03-0.95]. Median PFS (weeks) was 14.9 [CI:7-111] for UPS/MFS and 54 [95% CI: 3- not reached] for AS (Table). Conclusions: TVEC and pembrolizumab demonstrated acceptable safety and promising anti-tumor activity in cutaneous AS [head & neck (n = 4) and Stewart-Treves syndrome involving the upper extremity (n = 1)]. Five AS patients experienced a partial response with durable disease control, remaining on study for 1-2 years or more. Two delayed responses were observed in the AS cohort after the pre-specified 24-week criteria. One AS responder progressed on immune checkpoint inhibition prior to study entry. Correlative analyses are ongoing. Clinical trial information: NCT03069378 . [Table: see text]
Trabectedin failure-free survival (TFFS) after resuming trabectedin (T) in advanced myxoid liposarcoma (MLPS) patients.
Authors: Fabbroni Chiara , Franza Andrea , Fucà Giovanni , Fumagalli Elena , Gronchi Alessandro , Morosi Carlo , Sangalli Claudia , Collini Paola , Casali Paolo Giovanni , Sanfilippo Roberta
Published: June 2023

11573

Background: To explore the time to trabectedin failure-free survival after resumption of T in advanced MLPS patients who were stable or responding to T at the time of discontinuation. Methods: We retrospectively collected the cases of all patients with advanced MLPS treated with T at our institution from September 2002, highlighting those who were free from progression (according to RECIST) after 6 cycles of T. Trabectedin failure-free survival (TFFS) was defined as time from the first cycle of T to progression (PD) or death, whichever occurred first. Survival analyses were performed using the Kaplan-Meier method. Results: Since September 2002, 75 patients with recurrent myxoid liposarcoma received T at our institution. A total of 56 patients were free from progression (according to RECIST) after 6 cycles of T and were included in this analysis. Among them, 25/56 (45%) interrupted their treatment in absence of progression, while 31/56 (55%) patients received T until progression of disease. In the former group, 11/25 had surgery of their residual disease, 3/25 received radiotherapy, 5/25 interrupted T for toxicity and 6/25 patients shared the decision to stop with the clinician. Among patients who received surgery, 2/11 had monofocal disease (longest diameter < or = 5cm), 4/11 had monofocal disease (longest diameter between 10-18 cm) and 5/11 had plurifocal disease. The interruption of T in these 25 patients occurred after a median of 12 cycles (interquartile range = 9-14). Median TFFS was 43.4 months (95%CI 38.7-NA). In the concurrent group of patients who received T continuously, the median TFFS was 14.2 months (95% CI: 10.8-21.9). Conclusions: While the longer TFFS of patients undergoing discontinuation cannot be compared with the shorter of those who did not interrupt, the former group being biased favorably (feasibility and exploitation of surgery, other likely determinants of physician’s decision to stop), we speculate that there may be a subgroup of selected patients with advanced myxoid liposarcoma primarily responding to T, who could benefit from a “stop and go” policy, thus prolonging the overall time interval within which T remains active. Prospective studies in selected subgroups of MLPS patients on optimization of treatment strategy with T are worthwhile.
Risk stratification tools to help decide on adjuvant chemotherapy usage in resected soft tissue sarcomas: A 10 year review of an Irish sarcoma centre experience.
Authors: Weadick Catherine , Keogh Rachel J , Goggin Caitriona , Murphy Jake , Feeley Linda , Bennett Michael William , O'Reilly Seamus , Redmond Henry Paul , Kelly Jason , O'Mahony Deirdre , Noonan Sinead , Clover Jim , Bambury Richard Martin
Published: June 2023

11575

Background: Soft tissue sarcoma (STS) is comprised of 80 pathologic subtypes based on a combination of distinctive morphological, immunohistochemical and molecular features. Adult-type soft tissue and visceral sarcomas are rare, with an estimated incidence of 4-5/100,000/year in Europe. The National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of neo-adjuvant or adjuvant systemic treatment in resectable stage III (high grade tumours which are >5cm) and also in those who need to undergo an amputation or radical resection with adverse functional outcomes. The Sarculator risk prediction tool has identified a threshold of risk above which the administration of chemotherapy may provide an overall survival benefit. This can be applied to the most common histologic subtypes. Patients affected by these subtypes and with a 10-year predicted OS likelihood <60% are considered as high risk and therefore, should be considered for adjuvant chemotherapy. Alternatively, tumours considered at high risk of recurrence based on size >5cm and high grade histology, may benefit from adjuvant chemotherapy. Therefore, the aim of this project is to review the outcomes of resected extremity/trunk soft tissue sarcoma and assess the prognostic accuracy of these risk prediction methods. Methods: All new patients with resected STS discussed in the STS MDT in Cork University Hospital between Jan 2012 – Dec 2021 were identified. The histology and imaging of the identified patients were reviewed. Data regarding demographics, histology, treatment and outcomes was collected. Risk assessment using AJCC and Sarculator score was done on all patients with an extremity or trunk sarcoma. Overall survival was recorded and assessed including Kaplan Meier method for time to event analysis. Results: 200 patients were identified as having an STS resected - 134 of these were located on the trunk or extremities representing 24 different histological subtypes. Sarculator score was calculated for 60 of these (well differentiated liposarcomas, desmoid tumours, and dermatofibrosarcoma protuberans were excluded). 3 patients received adjuvant chemotherapy and 4 patient neoadjuvant chemotherapy. Overall survival data is presented below. Conclusions: Our cohort is representative of the broad histological subtypes expected in sarcoma. Sarculator score results correlate with international outcomes, with higher scores associated with increased mortality. In our cohort, sarculator score was more predictive of outcome than tumour grade/size alone. [Table: see text]
DCK expression by RNAseq as a potential biomarker of gemcitabine response in sarcoma.
Authors: Liebner David A. , Fetzer Erin A , Husain Marium , Chen James Lin , Tinoco Gabriel
Published: June 2023

11578

Background: Deoxycytidine kinase (DCK) is responsible for activation of gemcitabine by phosphorylation of gemcitabine to its monophosphate form. Studies have suggested that DCK expression may be correlated to response to gemcitabine in various solid tumors, and that downregulation of DCK may be at least partly responsible for gemcitabine-resistance in vitro. However, the significance of DCK expression in sarcomas as a biomarker of response to gemcitabine remains poorly characterized. Methods: Participants enrolled in the prospective Electronic Health Record (EHR)-Based Comprehensive Bone and Soft Tumor Registry ( NCT02677961 ) at The Ohio State James Cancer Center who had received gemcitabine-based chemotherapy for the treatment of bone and soft tissue sarcoma were eligible for this study. A total of 179 patients were identified who had received at least one cycle of gemcitabine-based chemotherapy, between January 1st, 2014, to December 31st, 2022. Whole exome RNASeq expression data was available for 36 of these patients who had received gemcitabine-based chemotherapy in the setting of active disease. Results: Of the 36 patients included in this study, 22 were female and 14 were male. Nine different main disease types were identified in the patient subset. These include angiosarcoma (8), chondrosarcoma (1), leiomyosarcoma (16), liposarcoma (3), malignant peripheral nerve sheath tumor (1), myxofibrosarcoma (2), osteosarcoma (2), undifferentiated pleomorphic sarcoma (3), and undifferentiated spindle cell sarcoma (1). The median time to treatment discontinuation (TTD) among all patients was 178 days. Among DCK low-expressors (n = 16), the median TTD was 86 days; among high-expressors (n = 16), the median TTD was not reached. Differences between groups did not reach statistical significance (HR = 0.55, p = 0.14). Conclusions: DCK expression by clinical RNASeq is a potential biomarker of gemcitabine-response in sarcoma, but larger studies are necessary to evaluate the potential clinical significance and possible role of DCK expression in identifying patients most likely to benefit from gemcitabine-based chemotherapy.