bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of concomitant and adjuvant temozolomide for glioblastoma patients with unmethylated O6-methylguanine-DNA methyltransferase promoter regions in the United States.
Authors: Midha Manav Dev , Votruba Mark Edward 
Published: June 2021

2058 Background: Promoter region methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene has emerged as a predictive factor for longer overall (OS) and progression-free (PFS) survival response to concomitant and adjuvant temozolomide (TMZ) chemotherapy in glioblastoma. Recently, several investigators have suggested the small survival benefit of TMZ for unmethylated patients is insufficient to warrant the increased risk of adverse events and that these patients should instead be enrolled in clinical trials. This study informs the debate by estimating the incremental costs and benefits associated with TMZ use in methylated and unmethylated patients based on available published evidence. Methods: Published OS and PFS Kaplan-Meier curves were digitized, parameterized, and extrapolated to ten years. Partitioned Survival Analysis trees were constructed in TreeAge Pro 2020. Costs of TMZ, RT, and inpatient hospitalization were included, among others. It was assumed that all patients receive surgery prior to beginning radiation, and that RT and TMZ (six adjuvant cycles) dosing was standard. Published utilities associated with the progression-free and post-progression health states, subject to each treatment, were used. A 3% annual discount rate and a willingness-to-pay of $150,000/quality-adjusted life year (QALY) were assumed. Probabilistic sensitivity analysis (PSA) was conducted. Results: In methylated patients, RT + TMZ versus RT is associated with $67,622 in additional costs and 10.91 additional quality-adjusted life months (QALMs). In unmethylated patients, RT + TMZ versus RT is associated with $9,203 in additional costs and 2.24 additional QALMs. The implied incremental cost effectiveness ratios (ICERs) support TMZ use in both populations and suggest it is more favorable for unmethylated patients ($74,378/QALY and $49,302/QALY for methylated and unmethylated patients, respectively). However, the incremental net monetary benefit (INMB) associated with TMZ use is substantially smaller for unmethylated patients ($18,797 versus $68,753) due to the smaller survival gains for this population. PSA results indicate that TMZ is more likely to be cost-effective for methylated (89.3%) than unmethylated (77.4%) patients. Conclusions: Post-radiation clinical trial enrollment should be considered instead of TMZ for unmethylated glioblastoma patients. While the estimated ICER justifies the use of TMZ for unmethylated patients – in fact, does so more strongly than for methylated patients – the relatively small incremental health benefit is plausibly outweighed by the opportunity cost of not enrolling these patients in clinical trials that offer the possibility of more substantive gains to current and future glioblastoma patients.
Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.
Authors: Liu Dan , Gong Jifang , Liu Tianshu , Li KunYan , Yin Xianli , Liu Yunpeng , Wang Yongsheng , Wang Linna , Wang Wenliang , Zhang Yanyan , Shen Lin 
Published: June 2021

2503 Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence > 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence > 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.
Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Coward Jermaine , Abed Afaf , Nagrial Adnan , Markman Ben 
Published: June 2021

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.
Safety, pharmacokinetics, pharmacodynamics profiles and preliminary antitumor activity of phase 1b/2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: The phase 1b data report.
Authors: Naing Aung , Fan Jean , Lee Byung Ha , Basudhar Debashree , Pant Shubham , Chaney Marya F. , Laviada Cristina , Rajan Cynthia , Le Ngocdiep T. , Barve Minal A. 
Published: June 2021

2594 Background: NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 which can increase the number and functionality of T cells in the peripheral blood (PB) of patients (pts). The combination of NT-I7 and pembrolizumab (pembro), a PD-1 Checkpoint Inhibitor (CPI), may augment and broaden the efficacy of CPIs. Methods: This is an open-label, phase 1b/2a study in pts with relapsed/refractory (R/R) advanced solid tumors. In the phase 1b (Dose Escalation), which followed the 3+3 design, pts received NT-I7 intramuscularly (IM) at 3 dose levels (DLs): 480, 960, and 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously (IV) Q3W. The objectives of the phase 1b were to evaluate Dose Limiting Toxicity (DLT), determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity. Results: As of 12 January 2021, 12 pts were enrolled in the phase 1b: DL1 (n=3), DL2 (n=3) and DL3 (n=6). Median age 58.0 years [43-77], ECOG PS 0 (50%), PS 1 (50%), median number of prior therapies 4 [1-8]. MTD was not reached. One DLT (Grade [G] 3 ALT increased) was reported in DL3. Treatment-related adverse events (AEs) occurred in 11 (91.7%) pts, 11 (91.7%) G1-2 and 4 (33.3%) G3; no G4 or G5 AEs reported. Common treatment-emergent AEs were injection site reaction (n=8, 66.7%), chills (n=7, 58.3%), nausea (n=6, 50%) and pyrexia (n=6, 50%). Preliminary PK analysis showed Tmax = 24 hours and T1/2 = 123 hours for NT-I7 at DL3. NT-I7 + pembro induced dose-dependent lymphocyte proliferation in the PB, with ̃ 3-fold increase at DL3, and a corresponding decrease in neutrophil to lymphocyte ratio at 14 days after the 1st treatment. Importantly, increased number of T cells in the tumor microenvironment (TME) was also observed (Table). One pt with metastatic mucosal melanoma who had not responded to prior combination of nivolumab and ipilimumab had a rapid, confirmed partial response with 46% tumor reduction. Patient follow-up continues and updated data will be presented. The combination of NT-I7 1200 µg/kg IM Q6W + pembro 200 mg IV Q3W has been selected as the RP2D. Conclusions: The combination of NT-I7 + pembro was well tolerated in pts with R/R advanced solid tumors. NT-I7 + pembro significantly increased T cell numbers in both the TME and the PB, and there was encouraging antitumor activity with the combination in this pt population. These results support continued evaluation of NT-I7 in combination with pembro in pts with R/R advanced solid tumors. The phase 2a of the study is enrolling pts with either CPI-pretreated or CPI-naïve solid tumors (NCT04332653). Clinical trial information: NCT04332653. [Table: see text]
Real-world pan-cancer landscape of frameshift mutations (FSM) and their role in predicting responses to immune checkpoint inhibitors (ICI) in patients (pts) with tumors with low tumor mutational burden (TMB).
Authors: Florou Vaia , Floudas Charalampos S. , Maoz Asaf , Naqash Abdul Rafeh , Hildebrand Gregory , Sokol Ethan , Frampton Garrett M. , Puri Sonam , Swami Umang , Wilky Breelyn A. , Hosein Peter Joel , Trent Jonathan C. , Lopes Gilberto , Park Wungki , Garrido-Laguna Ignacio 
Published: June 2021

2599 Background: Pembrolizumab was recently approved in tumors with TMB ≥10 mut/Mb. FSM can complement TMB in predicting ICI responses. We obtained a real-world dataset of genomic alterations from 250,813 samples to examine the distribution of TMB and FSM across a variety of malignancies. We then conducted a multi-institutional retrospective review of pts treated with ICI. Methods: Database samples were sequenced by Foundation Medicine using hybrid capture genomic profiling to evaluate all classes of genomic alterations in at least 315 genes. The clinical cohort included pts with metastatic solid malignancies who received ICI and had undergone commercial next-generation sequencing (NGS). Pts were classified into four distinct groups: TMB-L ( < 10mut/Mb)/ FS-A (absent FSM), TMB-H (≥10mut/Mb)/ FS-A, TMB-L /FS-P (present, ≥1 FSM) and TMB-H/FS-P. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were compared between the groups. Results: 246,252 MSS and 4,561 MSI-High samples were segregated by histology and divided into four distinct groups based on the TMB and FSM. For the MSS cohort the distribution was: TMB-L/FS-A (N = 111,065, 45%), TMB-H/FS-A(N = 15,313, 6%), TMB-L /FS-P (N = 98,389, 40%) and TMB-H/FS-P (N = 21,485, 9%). In the ICI-treated clinical cohort, there were 230 pts in 12 histology groups; 212 had information on TMB and FSM. The most common primary sites were GI (N = 39), melanoma (N = 37), GU (N = 32) and H&N cancer (N = 21). 159 pts received single ICI and 53 dual ICI. 196 tumors were MSS, 11 MSI, and 5 unknown. Group distribution: TMB-L/FS-A 80 pts (38%), TMB-L/FS-P 57pts (27%), TMB-H/FS-A 36pts (17%), TMB-H/FS-P 39pts (18%). FS-P was associated with higher RR 23.81 vs. 12.8 % (p = 0.02). Regardless of TMB, the median PFS for FS-P vs. FS-A was 7.9 and 4.0 mo, respectively (p < 0.01). TMB-L/FS-P had superior PFS (5.1 mo) compared to TMB-L/FS-A (3.6 mo) group (p < 0.01). The 15-month PFS probability was 12% for TMB-L/FS-A vs. 38% for TMB-L/FS-P. No statistically significant difference was detected in OS between the groups. From the pan-cancer cohort, histologies with more than 40% of samples in the TBM-L/FS-P (MSS) group were: CRC, RCC, PDAC, biliary, breast, esophageal, and endometrial cancers. Additional genomic data will be presented. Conclusions: FSM are frequently found on commercial NGS testing in tumors that are MSS and TMB-L. The presence of FSM may complement TMB in predicting benefit from immunotherapy. If validated in additional cohorts, FSM presence could be utilized to identify pts that may benefit from ICI, particularly for tumors with low TMB.
Phase 2 study of DRD2 antagonist/ClpP agonist ONC201 in neuroendocrine tumors.
Authors: Anderson Peter Meade , Gortz Janette 
Published: June 2021

3002 Background: ONC201, an imipridone with specificity for the dopamine-like DRD2 receptor and the mitochondrial protease ClpP, imparts anti-cancer effects via up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and promotion of an integrated stress response. Select neuroendocrine tumors are known to secrete dopamine and harbor elevated DRD2 expression, which is most pronounced in pheochromocytoma-paraganglioma (PC-PG). Methods: This investigator-initiated single center trial (NCT03034200) enrolled 10 patients with metastatic PC-PG to cohort A and 12 patients with other neuroendocrine tumors to cohort B. The primary endpoint was response using MRI or CT, PET-CT and/or PET-MRI imaging defined as CR + PR + SD > 3 months by RECIST criteria assessed by investigator. Secondary endpoints included progression-free survival, overall survival and safety. ONC201 was administered at 625 mg by oral capsules once each week. CT scans and tumor markers (plasma chromogranin and metanephrines) were followed at 6 weeks, 3 months and then every 3 months. Patients with clinical benefit could receive stereotactic body radiotherapy (SBRT) for non-indicator (e.g. bone) metastases. The data cutoff for this analysis is December 1, 2020. Results: In Arm A (n = 10; all paraganglioma) 5 patients exhibited a PR and 2 additional patients exhibited SD > 3 months. Median duration of therapy for patients was 9 months (range: 1.5-33) with 5 patients > 1 year. In Arm B (n = 12) there were 1 PR and 2 SD > 3 months. Median duration of therapy was 3 months (range: 1-33). The partial response occurred in a patient with desmoplastic small round cell tumor who remains on treatment for > 2 years. There was no instance of dose modification or discontinuation due to treatment-related adverse events. Conclusions: ONC201 is well tolerated at 625mg weekly in adults with advanced neuroendocrine tumors and is associated with clinical benefit that includes tumor response, particularly in paraganglioma patients. A more intense schedule of 2 daily doses each week is under evaluation, in addition to other neuroendocrine tumors. Clinical trial information: NCT03034200.
BRCA reversion mutations in a pan-cancer cohort to reveal BRCA-dependence in select noncanonical BRCA-mutant histologies.
Authors: Murciano-Goroff Yonina R. , Schram Alison M. , Rosen Ezra , Janjigian Yelena Y. , Berger Michael F. , Donoghue Mark , Bandlamudi Chaitanya , Drilon Alexander E. 
Published: June 2021

3012 Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.
Evaluating clinical activity of MAPK targeted therapies (TT) in cancer patients (pts) with non-V600 BRAF mutations: A systematic scoping review and meta-analysis.
Authors: Dankner Matthew , Wang Yifan , Fazelzad Rouhi , Spreafico Anna , Cescon David W. , Zogopoulos George , Rose April A. N. 
Published: June 2021

3089 Background: Oncogenic nonV600 BRAF mutations (muts) can be classified according to distinct molecular characteristics. TT strategies for class 2 and 3 BRAF muts have not been established. In recent years there have been numerous reports of clinical activity for various TT in pts with nonV600 muts. We performed a systematic scoping review and meta-analysis to assess treatment outcomes with MAPK TT according to BRAF class, cancer type and TT type. Methods: An extensive literature search was conducted from 2010-20. All studies were independently reviewed and extracted by 2 reviewers and in accordance with PRISMA guidelines. Individual patient level data were collected and analyzed from studies that met the following inclusion criteria: published reports of 1) advanced cancer pts with; 2) class 2 or class 3 nonV600 BRAF muts; 3) who received MAPK TT; 4) with treatment response (TR) data available. Primary outcome was overall TR rate (TRR). To assess differences between groups, odds ratios (OR) were calculated using a multi-level mixed-effects logistic regression model. Results: 15,171 studies were screened and 168 were included for data extraction. We identified 100 studies with a total of 396 pts that met inclusion criteria. There were 17 reports (161 pts) of prospective clinical trials and 83 retrospective studies (235 pts). RECIST criteria were used for TR assessment in 183 (46%) pts. The entire study included 280 pts with class 2 and 116 pts with class 3 BRAF muts. Overall, 111 (28%) pts achieved a TR. TRR according to primary tumor type, BRAF class, and TT type is indicated in Table. TRR was lower in reports of prospective studies compared to retrospective studies (OR 0.14, P = 0.002), and in studies that employed RECIST criteria vs. those that didn’t (OR 0.29, P = 0.044). TRR was higher among pts with class 2 muts vs. those with class 3 muts (OR 2.21, P = 0.042). Conclusions: These data establish that MAPK TT have demonstrated clinical activity in cancers with oncogenic nonV600 mutations, and that BRAF mutation class may dictate responsiveness to different TT strategies. TRR may be over-estimated in the retrospective literature. This analysis will be valuable for molecular tumor boards and to guide future clinical trial design. Prospective clinical trials of TT in this pt population are warranted.[Table: see text]