tbuckley/cabot-search huggingface dataset:
Efficacy and safety of IBI110 (anti-LAG-3 antibody) plus sintilimab (anti-PD-1 antibody) in patients with advanced alveolar soft part sarcoma: Results from a phase II study.
Authors: Jiayong Liu, Zhichao Tan, Zhengfu Fan, Chujie Bai, Ruifeng Xue, Shu Li, Tian Gao, Lu Zhang, Xinyu Wang
Journal: Journal of Clinical Oncology (2024)

11559 Background: Lymphocyte-activation gene 3 (LAG-3) has emerged as a novel target for immunotherapy (IO). Co-inhibition of LAG-3 and PD-1 may enhance immune checkpoint inhibition with synergistic effects. Herein, we report a phase II study evaluating the safety and efficacy of an anti-LAG-3 antibody (IBI110) plus sintilimab in patients (pts) with advanced alveolar soft part sarcoma (ASPS). Methods: Eligible pts with metastatic or unresectable ASPS were enrolled in two cohorts: cohort A (IO-naïve, defined as no history of previous immune checkpoint inhibitors, including but not limited to anti-PD-1/PD-L1/CTLA-4 antibodies) and cohort B (IO-failed, defined as imaging-confirmed disease progression after treatment with anti-PD-1/PD-L1 antibodies). All pts received IBI110 200 mg plus sintilimab 200 mg intravenously once every three weeks (Q3W). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS), assessed by the investigator per RECIST v1.1, and safety. Secondary endpoints included overall survival (OS) and 6-month PFS rate. Results: As of January 20, 2024, the study enrolled 28 pts (males: 57.1%, median age: 30.5 years, ECOG PS 0: 100%; TNM stage IV: 100%; lung metastasis: 100%), including 20 pts in cohort A and 8 pts in cohort B. The median treatment duration was 11 cycles. There were 15 pts in cohort A and 4 pts in cohort B remaining on treatment as of the cutoff date. Response was evaluable in 27 pts. The best responses were 3 complete responses (CR), 8 partial responses (PR), and 9 stable diseases (SD) in cohort A; 2 PR and 5 SD in cohort B. ORR was 55.0% in cohort A and 28.6% in cohort B. The 6-month PFS rate was 94.7% in cohorts A and 66.7% in cohort B. At a median follow-up of 8.0 months, median PFS was not reached in cohort A and was 14.7 months in cohort B. Median OS was not reached in both cohorts. Treatment-related adverse events (TRAEs) occurred in 27 (96.4%) pts, including grade ≥3 TRAEs in 9 (32.1%) pts. The most frequent TRAEs were hyperuricemia (57.1%), increased blood lactate dehydrogenase (42.9%), and hypertriglyceridemia (42.9%), all of which were grade 1-2. Immune-related adverse events (irAEs) occurred in 27 (96.4%) pts, including grade ≥3 irAEs in 9 (32.1%) pts. Serious TRAE occurred in 2 (7.1%) pts with type 1 diabetes mellitus. TRAE leading to treatment interruption occurred in 1 (3.6%) pt due to type 1 diabetes mellitus. No TRAE led to treatment discontinuation or death. Conclusions: Co-inhibition of LAG-3 and PD-1 showed encouraging efficacy in pts with advanced ASPS. Compared to anti-PD-1 monotherapy, the combination treatment improved ORR in IO-naïve pts and restored IO effectiveness in previously IO-failed pts. The safety profiles were acceptable and manageable in all pts. Clinical trial information: MR-11-22-004975.
Combination targeted therapy of avapritinib and sunitinib for patients with refractory advanced gastrointestinal stromal tumors after failure of standard treatments: Early results from a multi-institutional pilot study.
Authors: Xinhua Zhang, Yanzhe Xia, Ming Wang, Tao Chen, Wei Li, Jian Li, Ye Zhou, Haoran Qian, Shirong Cai, Ke-Jing Tang, Yulong He
Journal: Journal of Clinical Oncology (2024)

11535 Background: The objective of this study was to explore the efficacy and safety of the combination of avapritinib and sunitinib in refractory GISTs. Methods: This was a multi-institutional prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. From Jan 2022 to Sep 2023, participants were administered avapritinib at 100–200mg QD combined with sunitinib at 25–37.5mg QD continuously in 28-day cycles until PD or discontinuation. Clinical outcomes including ORR, survival and safety were assessed. Results: Twenty pts, generally heavily pretreated (65% with ≥4 prior TKIs, and 70% had progressed on ripretinib) were enrolled across seven participating centers. Median sum of target lesions was 27.0cm (range, 6.6–80.8). Among them, nine pts had primary KIT 11 mutation, 10 harbored KIT 9and one harbored KIT 17. Nine pts had KIT activation-loop (AL) mutations without KITATP-binding pocket (ABP) mutations ( KITAL pos ABP neg ), 2 had KIT ABP mutations without KIT AL mutations ( KITAL neg ABP pos ). ORR was 20% (4 PR), 15 pts (75%) had SD, one (5%) had PD with a CBR (PR+SD≥16w) of 75%, assessed via mRECIST v1.1. Tumor shrinkage was observed in 18 pts (90%), with a median best percent change in target lesions of -20.2% (range, -54.5% to 16.1%). With a median follow-up duration of 11.3 months (range, 2.3–20.9), 12 pts progressed, 3 were withdrawal, 7 were dead and 5 continued to receive combination therapy. Median PFS (mPFS) was 6.6 months (95% CI 5.8-7.4). Median OS was not reached. mPFS in pts with primary KIT 11 was similar compared to those with KIT 9. Regarding secondary KIT mutations, mPFS was numerically longer in KIT AL pos ABP neg pts compare to without (6.9 months VS 2.3 months, p=0.251). mPFS was significantly shorter in pts with KITAL neg ABP pos than without (1.1 months VS 6.9 months, p&lt;0.001). Three pts carrying KIT 16 L783V exhibited significantly longer mPFS than others (18.2 months VS 6.4 months, p=0.041). The dose of avapritinib (100–150 mg/d) and sunitinib (25–37.5 mg/d) could be tolerated. Common adverse events (AEs) were anemia, leukopenia, diarrhea, fatigue, periorbital and face oedema, and memory impairment. Common grade ≥3 AEs included leukopenia (30.0%), neutropenia (25.0%), anemia (20.0%), diarrhea (20.0%), and gastrointestinal hemorrhage (15.0%). Conclusions: The combination of avapritinib and sunitinib provided meaningful clinical benefit with an acceptable safety profile in pts with refractory GISTs, except for those harbored KITAL neg ABP pos mutations. Clinical trial information: NCT05461664 .
SARC037: Phase II results of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in patients (pts) with relapsed/refractory Ewing sarcoma (ES).
Authors: Patrick Joseph Grohar, Karla V. Ballman, Rachel Heise, Leo Mascarenhas, John Glod, Mary Frances Frances Wedekind, Jenna Marie Gedminas, Steven G. DuBois, Robert G. Maki, Brian D. Crompton, William Douglas Figg, Rochelle Bagatell, Theodore Willis Laetsch, Mark Diamond, Fariba Navid, Ryan David Roberts, Brigitte C. Widemann, Denise K. Reinke, Rashmi Chugh
Journal: Journal of Clinical Oncology (2024)

11508 Background: Trabectedin(T) is a marine-derived minor groove DNA binding compound that alters transcription factor activity. Preclinical data suggests that T suppresses the oncogenic driver of ES, EWS::FLI1. This suppression requires a threshold concentration of T and is potentiated by low doses of Irinotecan(I). Preliminary clinical activity and reversal of the EWS::FLI1 transcriptome was seen in patients (pts) in the phase I portion of SARC037. Here we report the phase II results of T with I at the recommended dose in pts with relapsed/refractory ES. Methods: In this open-label multicenter study, T was given at 1 mg/m 2 as a 1-h infusion on day(D)1 with I at 25 mg/m 2 intravenously on D2 and D4 of a 21D cycle. Key eligibility criteria were EWS::FLI1 fusion transcript, age ≥6 years, ECOG ≤2, adequate organ function, and willing to have a research biopsy if safely accessible. The primary objective was to determine the objective response rate (ORR) assessed by RECIST v1.1. Secondary objectives were progression-free survival (PFS), duration of response (DOR), and safety. This study used a Simon two-stage design that required 4 or more responses (CR or PR) at the final analysis to establish treatment activity. Results: 18 pts enrolled from 12/2022-12/2023 across 6 sites, 8F/10M, median age 21y (9-43). Pts had a median of 3 (1-7) prior therapy lines, including I in 67% of pts. Of 16 pts evaluable for response at the cutoff date, 5 pts had a PR, and 2 pts had SD. Two pts have evaluations pending and two pts were removed for toxicity before the first evaluation. Median time to response was 2.6 months(m), 6-month PFS was 37.7% (95% CI 18.3%, 77.7%), and all responses were sustained at the time of data cutoff at 10.4+, 7.5+, 5.5+, 5.0+ and 4.6+ m. There were no G5 AEs. Most pts had molecular profiling, translocation testing, as well as ctDNA collection, quantitation, and analysis. A subset of pts had pre- and post-treatment biopsies for RNA sequencing and evaluation of the impact of drug exposure on the EWS::FLI1 transcriptome. Conclusions: T+I exhibited anti-tumor activity in heavily pretreated pts with ES and met its prespecified ORR with 5 PRs in 16 evaluable patients, all of which are ongoing at data cutoff. There were no unexpected safety signals. The combination of T given as a 1h infusion and low-dose I demonstrated meaningful clinical benefit and is worthy of further study in ES pts. Analysis of biological correlates is ongoing. Clinical trial information: NCT04067115 .
Phase IB/II trial of durvalumab plus doxorubicin combination in patients with advanced soft-tissue sarcoma.
Authors: Hee Jin Cho, Nam Suk Sim, Su-Jin Shin, Kum-Hee Yun, Young Han Lee, Hyun Jung Jun, Sun Young Rha, Hyo Song Kim
Journal: Journal of Clinical Oncology (2024)

11552 Background: We conducted an open-label, phase IB/II study to determine the activity and safety of the standard-of-care, doxorubicin in combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in patients with anthracycline-naïve soft tissue sarcoma (STS) and identified patients who would likely benefit from combination treatment. Methods: In this trial (NCT03798106), we enrolled patients with metastatic and/or recurrent STS had not received anthracycline chemotherapy and PD-L1/PD-1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin [level 1 (75mg/m 2 ) and level -1 (60 mg/m 2 )] in combination with durvalumab 1500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II assessed the efficacy, with the primary endpoint to detect a difference in objective response between 5% and 20%. Results: No DLTs were observed during the phase IB (n=3), therefore recommended phase II dose was defined at doses of 75/m 2 doxorubicin and proceed the phase II part. Of 41 evaluable patients, 1 (2.4%) achieved complete response, 12 (29.3%) achieved confirmed partial response, yielding an objective response rate of 31.7%. The median progression free survival was 8.2 months (95% CI, 7.3-9.0) and median overall survival was 24.1 months (95% CI, 7.6-40.3). Treatment-related adverse events of grade 3 or 4 occurred in neutropenia (n = 23, 53.4%), thrombocytopenia (n=6, 13.9%), and anemia (n=5, 11.6%). The prespecified genomic analysis with targeted and transcriptomic sequencing will be available at the meeting. Conclusions: Durvalumab combined with doxorubicin demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. Clinical trial information: NCT03798106 .
Phase 2a results of SQ3370, a doxorubicin-based click chemistry therapeutic in patients with advanced STS: Planned interim analysis.
Authors: Nam Bui, Vineet Kwatra, Christopher W. Ryan, Erlinda Maria Gordon, Masa Aleckovic, Sangeetha Srinivasan, Tri-Hung Nguyen, Jose Manuel Mejia Oneto, Esteban Abella-Dominicis, Sant P. Chawla
Journal: Journal of Clinical Oncology (2024)

11555 Background: Shasqi is a clinical stage biotech that uses click chemistry, a Nobel Prize winning technology, to selectively activate cancer treatments at the tumor. The Click Activated Protodrugs Against Cancer (CAPAC) platform comprises of 1) tumor targeting agents, which carry an activator, and 2) attenuated cancer drugs, which are selectively activated at the tumor by the targeting agent through click chemistry, maximizing therapeutic index and minimizing toxicities. We have demonstrated clinical proof of concept with SQ3370, which uses an intratumorally injected SQL70 biopolymer (bp) with a doxorubicin (Dox) protodrug (SQP33) injected systemically. As previously reported RP2D of SQP33=12x Dox. (NCT04106492). Methods: Dox naïve patients (pts) received 10/20 mL bp and protodrug IV QD x 3 or 5. Key eligibility: locally advanced or metastatic soft tissue sarcomas (STS). The objective was to explore bp dose and schedule of the RDP2 (same dose per cycle) in advanced or metastatic STS. Results: Fourteen patients with predominantly metastatic (11/14) STS, all unresectable, were enrolled at the 1st interim analysis. Median age 58 years (32-89), ECOG=1 (11/14). Therapy was well tolerated. The most common TEAE was nausea and fatigue (all grade ≤ 2), with 1 subject in each group having a manageable grade ≤ 3 TEAE-related discontinuations. The majority of subjects did not suffer clinical myelosuppression grade ≤ 1 neutropenia (10/14), anemia (13/14), or thrombocytopenia (13/14), with DCR 71% (CI 95% 44-92%) and ORR 14.3% (CI 95%1.7-40%). Detailed PK, immune assessment and safety findings will be presented. Conclusions: SQ3370 is the first clinical click chemistry-based cancer therapy, and this is the 1st clinical trial to explore doses greater than 3x Dox in STS patients. The results show that the bp activates protodrug, which is not a vesicant, and releases Dox in patients. Click chemistry favorably alters PK and safety of the Dox payload. At 12x Dox, using the commonly administered 3-week schedule, Dox was very well tolerated. Click-chemistry maintains expected clinical activity, and preliminary data suggest enhanced safety (reduced myelosuppression) as well as unlocking immunological effects (intratumoral and systemic), without the myelosuppressive effects typically seen with Dox. Clinical trial information: NCT04106492 . [Table: see text]
Analysis of the time to progression in patients who underwent metastasectomy plus isolated lung chemoperfusion for disease recurrence after metastasectomy alone.
Authors: Evgeny Levchenko, Aleksandr Mikhnin, Konstantin Senchik, Oleg Mamontov, Stepan Ergnyan, Nikita Levchenko, Roman Yurin, Nikolay Khandogin, Evgeny Nyukhlov, Evgeny Imyanitov
Journal: Journal of Clinical Oncology (2024)

11568 Background: The combination of pulmonary metastasectomy (ME) with isolated lung chemoperfusion (ILuP) has shown promising results, however, a direct comparison of the clinical outcomes obtained by ME plus ILuP versus ME alone is complicated. The heterogeneity of patients in terms of cancer types, number of metastases and composition of prior systemic therapy adds to the difficulties of this analysis. Methods: Patients who initially received ME alone, and then ME plus normothermic ILuP after the disease relapse, were considered. The aim of the study was to compare the time to pulmonary disease progression (TTP) after the first and second interventions (TTP1 and TTP2, respectively) in the same subjects. Results: Of 225 patients who underwent ME plus ILuP in 2007 - 2020, we selected 48 patients who received this treatment due to pulmonary disease progression after ME alone. There were 16 patients with soft tissue sarcoma, 8 patients with osteosarcoma, 14 colorectal cancer cases and 10 patients with other tumor types. The mean number of metastases was 2.94 before ME alone and 4.33 before ME plus ILuP. Cisplatin was used in 30 patients at a mean dose of 191.8 mg, and melphalan was utilized in 18 subjects at a mean dose of 44.1 mg. The median follow-up was 31.1 months. The median TTP1 was 6.9 months, and the median TTP2 was 19.0 months (p &lt;0.0001). TTP2/TTP1 ratio equal or above 1.5 was observed in 34 out of 48 patients (71%). Conclusions: This is the first study comparing the results of ILuP plus ME versus ME alone in the same patients. The data obtained strongly support the feasibility of adding isolated lung chemoperfusion to surgery in patients amenable to excision of lung metastases.
A signal-finding study of nivolumab and relatlimab in patients with advanced chordoma.
Authors: Aaron Burkenroad, Arun S. Singh, Bartosz Chmielowski, Sandra Brackert, Noah Federman, Anahis Hagopian, John A Glaspy, Joseph Kendal, Lauren E Wessel, Francis J. Hornicek, Nicholas M. Bernthal
Journal: Journal of Clinical Oncology (2024)

11578 Background: Chordomas are derived from notochordal remnants and are typically treated with surgery and radiation therapy. For advanced chordomas, there are no approved systemic therapies. Preclinical evidence and anecdotal reports have indicated that the immune system is active in chordomas and that there may be a role for immunomodulation in treating this disease. Methods: This study is a single-arm, signal-finding trial in patients with advanced chordoma treated with the anti PD-1 antibody nivolumab (480 mg Q4 weeks up to 2 years) and the anti-LAG3 antibody relatlimab (160 mg Q4 weeks up to 2 years). The primary objective of this study was to assess the safety of nivolumab and relatlimab in subjects with progressive metastatic or locally advanced/unresectable chordoma. Secondary objectives were to ascertain the median progression free survival (PFS), response rate (RR), and the 4- and 6-month PFS by RECIST 1.1. Results: Out of a planned enrollment of 20 patients, 10 patients (8 Male, 2 Female) were consented and treated on trial. Enrolled patients had the following sites of involvement: 5 clival/c-spine, 4 sacral, and 1 thoracic. Nine had conventional subtype chordoma and 1 had chondroid subtype. Eight of the 10 patients had previous surgery, 6 had previous radiation therapy and 5 had 1-2 lines of prior systemic therapy, including one who received pembrolizumab. Pretreatment biopsies were obtained from 9 out of 10 patients and blood has been collected on all patients. Nine patients were evaluable for study outcomes. A total of 64 AEs (Grades 1-4) have been noted to date, with 6 events being classified as grade 3-4: nausea, facial pain, headache, and pulmonary embolism. Five serious adverse events (SAEs) were noted in patients on treatment: headache (2), asthma (1), myocarditis (1), and sepsis (1). The median PFS of the 9 evaluable patients was 21.4 weeks. At 4 months, 7 out of 9 patients were progression free (77.7%). At 6 months, 4 out of 9 patients remained progression free (44.4%) and had continued progression-free survival at 1 year. One out of 9 (9.1%) patients had a PR via RECIST 1.1. One patient discontinued treatment due to an adverse event (grade 1 myocarditis). Conclusions: This signal-finding study indicated that some patients with advanced chordomas can receive benefit with relatlimab in combination with nivolumab. The combination was well-tolerated and no new safety signals were found in this rare patient population. Correlative studies are ongoing. The study was closed for slow accrual. Clinical trial information: NCT03623854 .
Preliminary results from FLAGSHP-1: A phase 1 study of ERAS-601 as a monotherapy or in combination with cetuximab in patients (pts) previously treated for advanced chordoma.
Authors: Mrinal M. Gounder, Ezra Rosen, Aparna Raj Parikh, Anthony Paul Conley, David S. Hong, Siddharth Sheth, Nicholas Mai, Erica Sgroe, Ryan Mitchell, Roxana Picard, Les H. Brail, Gregory Michael Cote
Journal: Journal of Clinical Oncology (2024)

11522 Background: SHP2 is an oncogenic tyrosine phosphatase that transduces receptor tyrosine kinase signaling in the RAS/MAPK pathway via phosphatase-mediated regulation of guanine nucleotide exchange factors. SHP2 signaling has recently been identified as a genetic dependency for chordoma, a rare tumor type with no approved therapies (1), and preclinical studies with SHP2 inhibitors have demonstrated activity in chordoma models. Methods: As part of the FLAGSHP-1 study, patients (pts) with advanced or metastatic chordoma were enrolled in either the monotherapy or cetuximab combination cohort to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-601. Chordoma pts previously treated with an EGFR inhibitor were allowed to enroll. Results: As of 31 Oct 2023, a total of 11 pts with previously treated advanced or metastatic chordoma received ERAS-601. Two pts received ERAS-601 as monotherapy: one at 40 mg BID (continuous) and the other at 80 mg TIW (three times a week). An additional 9 pts received the combination of ERAS-601 (40 mg BID 3 weeks on and 1 week off every 28 days [3/1]) in combination with cetuximab (500 mg/m2 Q2W). The treatment-emergent adverse events (TEAEs) occurring in &gt;20% of pts (Grade [Gr] 1-2 unless noted) were: dermatitis acneiform (2 pts-Gr 3), paronychia, dry skin, skin fissures, skin infection (1 pt-Gr. 3), diarrhea, nausea, vomiting, stomatitis, peripheral oedema, fatigue, thrombocytopenia, and AST elevation. No patients discontinued therapy due to TEAEs related to ERAS-601. Out of the 9 pts receiving the combination of ERAS-601 and cetuximab, by RECIST 1.1 there was 1 PR and 8 pts with a best response of SD. Of the 8 pts who had a best response of SD, 7 had some tumor shrinkage. The median time on combination treatment was 5.06 months, with 8 out of 9 pts remaining on the study. Conclusions: The most common toxicities observed for the ERAS-601 + cetuximab combination were dermatologic, which were reversible. Encouraging preliminary activity was seen in advanced, refractory chordoma. 1. Sharifina et al., 2023, Nat. Commun. Clinical trial information: NCT04670679 .
Molecular characterization of long-term and short-term survivors of metastatic uterine leiomyosarcoma.
Authors: Tiffany Y. Sia, David N Brown, Kathryn M Miller, Mario M. Leitao, Nadeem Abu-Rustum, Sarah Chiang, Britta Weigelt, Martee Leigh Hensley
Journal: Journal of Clinical Oncology (2024)

11542 Background: While some metastatic uterine leiomyosarcomas (uLMS) are clinically aggressive, others have a more indolent disease pace, suggesting biologic heterogeneity. Our objective was to determine whether the molecular characteristics of metastatic uLMS tumors differed between long-term survivors (LS) and short-term survivors (SS). Methods: Patients with metastatic uLMS between 1/1/2000 – 11/31/2020 who received care at our institution and had tumor tissue available were included. uLMSs were subjected to a targeted DNA next-generation sequencing panel of up to 505 cancer-related genes. Metastatic overall survival (mOS) was calculated from the date of diagnosis of metastatic disease until the date of death or last follow-up. LS was defined as mOS &gt;2 years and SS as mOS &lt;2 years. Appropriate statistical tests were used. Results: Our cohort included 17 LS and 10 SS (Table). uLMSs from LS harbored TP53 alterations in 58% of cases compared to 90% of SS (P&lt;0.001). Rate of RB1 alterations in LS was 76% compared to 50% in SS (P&lt;0.001). Rates of somatic genetic alterations affecting ATRX(11% LS vs. 20% SS) and BRCA2(47% LS vs. 50% SS) were similar between groups (P&gt;0.05 for both). Most BRCA2alterations (92%) were homozygous deletions. Levels of chromosomal instability as quantified by the fraction of genome altered was similar between groups (median 27.3% in LS versus 22.9% in SS, p=0.26). Tumor mutational burden was low in both groups. Conclusions: While uLMS from LS and SS have similar levels of chromosomal instability and tumor mutational burden, uLMS in LS have lower rates of TP53 alterations compared to SS patients, as well as compared to previously reported rates in uLMS. Rates of RB1alterations were higher in LS compared to SS. Interestingly, the rate of BRCA2alterations in both LS and SS is higher than previously reported and provides rationale for next-generation sequencing in patients with metastatic uLMS. Further studies in larger cohorts to validate these findings are warranted. [Table: see text]