Citations

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the Grading of Recommendations, Assessment, Development and Evaluation approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

Abstract Objectives The lack of uniform terminology and abbreviations for anti-synthetase syndrome has led to significant challenges in research and clinical practice. This study aimed to establish an international consensus on a standardized nomenclature and abbreviation among a diverse group of global myositis experts and patient representatives. Methods This qualitative project was approved by the International Myositis Assessment and Clinical Studies Group (IMACS). Based on the outcomes of a literature review and preliminary survey, list of terms for nomenclature and abbreviations was finalized. Subsequently, two rounds of the Delphi survey were conducted among myositis experts and patient participants to ascertain current practices and preferences. Using Nominal Group Technique (NGT), the project steering committee developed a consensus nomenclature and abbreviation. Results A total of 241 and 132 myositis experts from six continents, 35 countries and 9 specialities participated in round 1 and round 2 of the Delphi survey, respectively. The results indicated a preference for the terms anti-synthetase syndrome, antisynthetase syndrome and anti-tRNA synthetase syndrome. The abbreviations ASS, ASyS and ASSD were most used, though ASS received notable disapproval. The steering committee, including twenty-five myositis experts and three patient representatives from diverse backgrounds and geographical locations, reached a consensus on ‘anti-synthetase syndrome’ as the preferred nomenclature and ASyS as the preferred abbreviation, with 100% and 93.1% votes, respectively. Conclusion The terms anti-synthetase syndrome and ASyS should be adopted as the standard nomenclature and abbreviation in both research and clinical practice. This standardization is expected to increase consistency within the literature.

Abstract Background: Savo is an oral, potent and highly selective MET-TKI. In the Phase 2 SAVANNAH study (NCT03778229), savo + osi had a high rate of durable responses in pts with EGFRm advanced NSCLC and high MET OverExp and/or Amp levels. Early clearance of plasma EGFRm may predict outcomes. We report an exploratory analysis of plasma EGFRm clearance and its association with MET tissue biomarker status, ORR and PFS. Methods: Pts with EGFRm advanced NSCLC and MET OverExp and/or Amp with PD on 1L+ osi received savo 300 mg QD, 300 mg BID or 600 mg QD + osi 80 mg QD. MET OverExp/Amp was centrally confirmed (by IHC [Roche], 3+ intensity in ≥50% of tumor cells [MET IHC3+/≥50%]; by FISH [Abbott Molecular], MET gene copy number ≥5 or MET:CEP7 ratio ≥2 [FISH5+], or at higher thresholds of MET IHC3+/≥90% or FISH10+). Baseline (BL) and Wk 3 plasma EGFRm (Ex19del/L858R) were analyzed by ddPCR (Biodesix) as an estimate of tumor burden. MET Amp was not monitored in ctDNA due to low detection sensitivity. Clearance was defined as undetected EGFRm ctDNA at Wk 3, when detected at BL. PFS was investigator-assessed (RECIST 1.1). DCO: Aug 23, 2024. Results: Of 344 pts with evaluable BL ctDNA, 259 (75%) had detected EGFRm ctDNA. Of these, 225 had evaluable ctDNA at Wk 3 (82 [36%] had EGFRm clearance at Wk 3). Confirmed ORR was higher in pts with EGFRm Wk 3 clearance (56/82; 68%) vs non-clearance (38/143; 27%). PFS was longer in pts with vs without EGFRm clearance at Wk 3 (Table). Across all pts evaluable for ctDNA at Wk 3, clearance rates were higher in pts with vs without high MET (69/162 [43%] vs 13/63 [21%]; odds ratio [95% CI] 0.35 [0.16, 0.72]). Similar results were seen in the savo 300 mg QD + osi subgroup. Conclusions: In SAVANNAH, among pts with detected EGFRm ctDNA at BL, clearance at Wk 3 was associated with improved ORR and PFS. Plasma EGFRm clearance at Wk 3 is enriched in pts with MET IHC3+/≥90% or FISH10+ status, consistent with improved efficacy in this biomarker subgroup. Citation Format: Jonathan W. Riess, Filippo de Marinis, Benjamin Levy, Tae Min Kim, Laura Bonanno, Quincy Chu, Marcello Tiseo, Adrian Sacher, Silvia Novello, Christina Baik, Lyudmila Bazhenova, Jacques Cadranel, Giulio Metro, Cheng-Ta Yang, Tsung-Ying Yang, Gee-Chen Chang, Konstantinos Leventakos, Lorenzo Livi, James Chih-Hsin Yang, Lecia V. Sequist, John Argue, Wanning Xu, Aleksandra Markovets, Ryan Hartmaier, Myung-Ju Ahn. SAVANNAH: Clearance of plasma EGFRm in patients with EGFRm MET-overexpressed (OverExp) and/or -amplified (Amp) NSCLC post-osimertinib (osi) treated with savolitinib (savo) + osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB416.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. mainly because of late-stage diagnosis. Heritable genetic information can improve risk stratification for individuals with moderate to high-risk of PDAC for targeted screening and early detection. We aimed to develop an enhanced polygenic risk score (PRS) for PDAC using a Bayesian approach, LDpred2, that reweights risk estimates attributed to millions of polymorphisms (SNPs) estimated from genome-wide association studies (GWASs). We then compared the performance of LDpred2 with the commonly used genetic risk score (GRS) approach that is based only on genome-wide significant SNPs. Methods: GWAS summary statistics were obtained from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case Control Consortium for 9040 cases and 12496 controls and were used to compute weights for a GRS (17 SNPs) using a p-value threshold of 5e-8 and weights for an enhanced PRS (1.3 million SNPs) using LDpred2. These weights were then used to compute risk scores in an independent validation sample of 2616 cases and 45407 controls from the Mayo Clinic. We used logistic regression to test for associations of the GRS and PRS with PDAC risk, adjusting for age, sex, and the first 10 principal components of ancestry. Results: The validation sample was of mostly European ancestries (>95%). Cases were slightly older than controls (median age: 66 yrs. vs. 63 yrs.) and had a higher frequency of men than controls (57% vs. 42%). Comparisons between the GRS and the PRS are shown in Table 1. DeLong’s test comparing the AUCs between the two genetic scores showed the PRS significantly outperformed the GRS (AUC = 0.68 vs. 0.67; p = 7.6e-7). Conclusions: The LDpred2 PRS model that used a larger set of SNPs significantly improved prediction of PDAC. Comparing the top percentile of the PRS versus the rest showed that the PRS is a clinically significant risk score (OR > 3) for PDAC and could inform clinical decision making and genetic counseling of individuals identified as having a high risk of PDAC. Citation Format: Samuel O. Antwi, Brandon J. Coombes, Nicholas B. Larson, Erin E. Carlson, Kari G. Rabe, Hunter J. Atkinson, Shounak Majumder, Jun Zhong, David McKean, Pancreatic Cancer Cohort & Case Control Consortia (PanScan and PanC4), Brian M. Wolpin, Rachael Z. Stolzenberg-Solomon, Alison P. Klein, Laufey T. Amundadottir, Ann L. Oberg. Enhanced polygenic risk score for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB331.

Abstract Background: Bria-IMT™ is an allogeneic whole-cell cancer vaccine, designed to stimulate anti-tumor immunity (Chumsri et al 2024 ASCO). Bria-ABC (NCT06072612) is the multicenter, randomized, open-label trial evaluating overall survival (OS) of Bria-IMT™ regimen vs treatment of physician’s choice (PC) in patients with MBC where no meaningful therapy exists. Methods: 3 arm randomized 1:1:1 (Bria-IMT, Bria-IMT+CPI, or PC) in late stage heavily pretreated pts with MBC. Pts can be ECOG <2, Pts w/ CNS mets and/or who have received prior CPI or ADCs are allowed. The Bria-IMT™ regimen includes preconditioning w/ cyclophosphamide (300 mg/m2) on day -2/-3, intradermal SV-BR-1-GM inoculations (x4) on day 0, and interferon at inoculation sites (Days 1-3). CPI (retifanlimab 375 mg) may be given between days -2 to 2. The regimen is administered every 3 weeks (Q3W). Pts randomized to the monotherapy arm (Bria-IMT™ alone) may cross over to the combo arm upon disease progression. Response assessments are planned Q6W for the first cycle, and then Q8W thereafter. Based on prior data, an interim HR of 0.6 at 144 events will constitute early success. Overall study design anticipates 404 total pts. Results: This interim, unaudited data reflects ongoing enrollment and trial feasibility. To date, 61 pts have completed screening, with 40 pts randomized. Screened pts had a median age of 56 (range 35-82). For pts with evaluable data (n=40), median BMI was 25.6 kg/m2 (8.7-45.7) with a median of 6 (2-13) prior lines of therapy. 20 pts (50%) had HR+/HER2- breast cancer, 18 HR-/HER2- (45%), and 2 HER2+ (5%). Baseline ECOG PS were: 0 (55%), 1 (35%), 2 (10%). In biomarker-evaluable pts, circulating tumor cells were present at baseline in 30% (mean: 10.1 cells/mL; range: 0-139), while cancer-associated macrophage-like cells (CAMLs) were present in all pts (mean: 18.3 cells/mL; range: 1-154). In pts with available follow-up data, median change in CAML count from baseline to most recent cycle was -23.5%. In pts with available HLA typing, match distribution was 0 (19%), 1 (35%), 2 (26%), 3 (16%), and 4 (3%), 8 (26%) class 1, 8 (26%) class 2, and 9 (29%) matching both alleles informing potential immune response interactions with Bria-IMT™. Local injection site reaction (DTH), tumor-marker serum level, and circulating cancer cells, will be analyzed across subtypes to further characterize the pt population. The Bria-IMT™ regimen has been generally well tolerated, with no Tx D/C due to adverse events (AEs). The most frequently reported AEs include nausea (30%), constipation (22.5%), injection site rxn (22.5%), and headache (17.5%) w/ no interstitial lung disease reported. Discussion: Bria-ABC enrollment is ongoing. Future analyses will assess OS, PFS, ORR, CBR, QoL, and CNS event-free survival as data becomes available. Expected to close to enrollment by 2025, with final analyses planned for 2026. Citation Format: Saranya Chumsri, Joyce A. OShaughnessy, Azka Ali, Christopher N. Vaughn, Lawrence M. Negret, Adam Brufsky, Regina Stein, Marcela Salgado, Blaise Bayer, Giuseppe Del Priore, Sara A. Hurvitz. Bria-ABC vs physician choice in late stage MBC: Early biomarker correlates of the randomized registration trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB408.

Abstract Introduction: In a multiple myeloma mouse model (MM), we determined that subcutaneous (SC) continuous lenalidomide (Len) delivery demonstrated superior tolerability and efficacy to the active control Len given by daily i.p. over a 28 day cycle. Healthy volunteer studies showed that at a daily dose of 9.6 mg a day (400 mcg/h) the Len AUC0-24 was ∼60% less than that observed with an oral 25 mg Len dose. We hypothesized that this modality could improve Len’s therapeutic index by lowering the hematologic toxicity while maintaining or improving the efficacy. Methods: A phase 1b study in 2nd line or greater relapsed/refractory MM was performed to confirm the animal findings and determine if continuous Len can improve its therapeutic index with no negative impact on the cellular immune system. In brief, an RVd regimen was utilized wherein SC Len 9.6 mg/day was administered with an FDA registered ambulatory pump in a continuous fashion using a 28/28 day cycle. Patients were either trained to operate their pump and change the pre-filled cassettes at home or were managed in the clinic on M-W-F. All patients were seen in the clinic to receive weekly bortezomib 1.3mg/m2 and dexamethasone dosed weekly at 40/20mg, according to age. Patients who received bortezomib in a prior cycle were required to demonstrate sensitivity defined as durability for 6 months after discontinuation of the bortezomib. Results: Between September 2023 and November 2024, 6 relapsed/refractory MM patients were enrolled from 2 US community-based investigational sites in the phase 1b study. Median age was 73, male to female ratio 1/1, Caucasian 100%, and median lines of previous therapy were 2 (range 1-7). Two patients were refractory and 4 were relapsed to their prior treatment. Four patients were previously exposed to Len, one of which was discontinued from a prior regimen because of severe fatigue, and 6 had received prior bortezomib. Patients had received 3-12 cycles of study therapy. No drug-related grade 3/4 hematologic or non-hematologic toxicity occurred within cycle 1. No patients experienced drug-related anemia, neutropenia, leukopenia, or thrombocytopenia greater than grade 2 in up to 12 cycles of therapy. All 6 patients achieved an objective response (CR=1 / PR=5). One patient who achieved a partial response experienced grade 2 skin reaction during cycle 3 and withdrew from the study. Five patients are continuing treatment per protocol with a median PFS of > 10 mo. Len pharmacokinetics produced median steady-state blood levels (Cmax) of 39 ng/mL (range 26-94) (N=6) and were above the minimum target of 25 ng/mL. The Len regimen produced a median AUC0-24 of 921-1h*ng/ml (range 630-1503). Immune profiling did not show significant increases in immune checkpoint expression associated with T-cell exhaustion while CD19+ B cells were significantly depleted. Conclusion: Continuous delivery of low dose Len provides meaningful efficacy and improved tolerability with no grade >3 drug-related hematologic toxicity. Further studies in MM and chronic lymphocytic leukemia are planned. Citation Format: Nash Gabrail, Keith Lerro, Mohamad A. Hussein, Asher A. Chanan-Khan, Jamie C. Oliver. Continuous subcutaneous lenalidomide delivery improves the therapeutic index and avoids drug-related grade 3/4 hematologic toxicity in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB207.

Abstract Glioblastoma Multiforme (GBM) is a highly aggressive malignant brain tumor. Despite decades of research, the tumor is essentially incurable, primarily due to the failure of small molecule drugs to pass the blood-brain barrier (BBB). This molecular "pump" within the brain's blood vessel linings restricts effective drug delivery to the tumor. To address this challenge, we have developed an antibody targeted nanoparticle therapeutic platform, NV103. NV103 employs liposomal nanoparticles with tumor antigen targeted antibodies specifically engineered to deliver otherwise ineffective drugs like irinotecan directly to tumor. GBMs are heterogeneous, characterized by diverse genomic profiles and tumor antigen expression patterns. EGFR is a well-known example. Here we identified a novel GBM tumor antigen, CD99. CD99 is not a commonly recognized GBM biomarker, but we find that GBMs consistently express CD99. We evaluated nearly 100 GBM PDXs in the Mayo Clinic repository and found that nearly all express CD99. We then evaluated NV103's efficacy across multiple GBM tumors with varying levels of CD99 cell surface expression. Importantly, NV103 demonstrated exceptional BBB penetration in an in vitro transwell system utilizing brain endothelial cells derived from human stem cells. NV103 also exhibits prolonged plasma persistence with detectable levels present at 24 hours, compared to free drug which is undetectable within hours. This prolonged drug availability combined with the ability to penetrate the BBB and preferentially bind to tumor cells results in dramatically enhanced anti-GBM activity. In GBM mouse studies, NV103 and its payload exhibited at least 5-fold enhanced delivery to tumor vs. brain. In preclinical animal studies, NV103 extended the survival of orthotopically implanted human PDX glioblastoma (GBMPDX43)-bearing mice by at least three-fold compared to free-drug treatments. We also showed that NV103 effectively induces cytotoxicity across a broad spectrum of CD99-expressing GBMs. NV103 showed significantly enhanced anti-tumor activity, even in low CD99-expressing tumors, such as GBMPDX43. Moreover, dose-response trends in GBM-bearing animals suggest that escalating doses of CD99-targeted nanoparticles could further improve survival outcomes. This targeted approach minimizes drug exposure to normal tissues, including brain. We found no dose limiting toxicity at 50mg/kg, five times higher than the 10mg/kg used for most of the tumor bearing animal studies. These findings underscore NV103's potential to effectively target heterogeneous GBMs, including those with variable CD99 expression levels, not unlike HER2-low tumors treated with HER2-directed ADCs. Further, preclinical data suggest that NV103 dose escalation will amplify its therapeutic impact, positioning this platform as a potential groundbreaking approach to overcome treatment resistant GBM. Citation Format: HyungGyoo Kang, Bryon Upton, Jon Nagy, Jann N. Sarkaria, Timothy J. Triche. Enhancing GBM therapy with tumor-targeted nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB183.

Abstract Introduction: Glioblastoma (GBM) tumors contain distinct cell lineages, including treatment-sensitive cells (TSCs) relying on aerobic glycolysis and treatment-resistant persister cells (TRPCs) dependent on lipid metabolism. Our systems biology-based, spatial multi-omics and multi-targeted approach decodes a critical node in GBM progression, lipid acquisition in TRPCs, and validates this through a retrospective analysis of statin-treated patients, offering clinical insights into the potential benefits of targeting lipid metabolism in high TRPC signature GBM patients. Methods: We performed spatial transcriptomics and proteomics, combined with 3D rendering of the tumor microenvironment (TME) and geospatially resolved single-cell neighborhood analysis of IHC-stained GBM tissues using our custom-developed SNAQ algorithm to investigate the immune microenvironment and lipid distribution specific to TSCs and TRPCs. To characterize lipid dynamics, we employed flow cytometry, time-lapse imaging, and holotomography to track lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs. A critical node for GBM progression was identified through in vivo survival and tumor progression studies that assessed effects of genetic targeting of CCR2 and pharmacological targeting of CSF1R and FABP3. Retrospective analysis was conducted on 4,085 GBM patients to evaluate the effect of statin treatment on GBM outcomes based on their TRPC signature. Results: Our study establishes the skewed accumulation of TAMCs within the TRPC microenvironment through upregulation of the CCL2/7-CCR2 and CSF1-CSF1R pathways. TAMCs actively transfer lipids to TRPCs to fulfill their metabolic demands. Targeting elements responsible for lipid incorporation in TRPCs, such as CCR2, CSF1R, and FABP3 in vivo, resulted in tumor immune microenvironment remodeling, significant tumor growth reduction, and improved survival. This reinforces the critical role of metabolic communications via lipid trafficking in TRPCs as an essential node in GBM progression. Our retrospective study showed that GBM patients with elevated TRPC signatures, typically associated with shorter survival, had no significant survival differences when treated with lipid-lowering statins. This suggests statins may disrupt lipid metabolism in TRPCs, reducing TAMC lipid support and improving patient outcomes. Conclusion: Our study highlights lipid trafficking in TRPCs as a key mechanism in GBM progression, suggesting that targeting TAMC recruitment and lipid acquisition in TRPCs may offer a promising therapy. Additionally, our retrospective analysis highlights the potential of transcriptomic profiling for patient stratification based on TRPC signature expression levels, enabling the identification of patients to benefit from lipid metabolism-targeted therapies. Citation Format: Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Nyla T. Searl, Miruna Anica, Avinash Pittu, Illena West, Olusegun O. Sobanjo, Ethan D. Hodge, Mia K. Engelbart, Srabasti Sengupta, Nagheme Thomas, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane A. Mitchell, Loic P. Deleyrolle. Disrupting lipid metabolism in GBM: A systems biology approach to targeting treatment-resistant persister cells and tumor associated myeloid cell-mediated support [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB082.