bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.