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Purpose: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells., Patients & Methods: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion., Results: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1., Conclusion: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20μL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue., Competing Interests: All authors have read and understand PLOS ONE’s policies. The below commercial interests did not fund and have no association with the work performed in this study; therefore, this does not alter our adherence to PLOS ONE’s policies on sharing data and materials. The authors of this manuscript have the following competing interests: A.G.C. received research funding from Juno Therapeutics, a Bristol Myers Squibb Company. E.K. received research funding from Juno Therapeutics, a Bristol Myers Squibb Company. A.V.H. has received research funding from Juno Therapeutics, a Bristol Myers Squibb Company, and Nektar Therapeutics; has received honoraria from Bristol Myers Squibb. C.J.T. has received research funding from Juno Therapeutics/BMS, Nektar Therapeutics. C.J.T. is on the scientific advisory board for Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Celgene/BMS Cell Therapy. C.J.T. is a DSMB member for Kyverna. C.J.T. ad hoc advisory boards/consulting (last 12 months) include: Nektar Therapeutics, Century Therapeutics, Legend Biotech, Allogene, Sobi, Syncopation Life Sciences, Prescient Therapeutics, Orna Therapeutics, IGM Biosciences, Abbvie. C.J.T. stock options: Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics. C.J.T. has the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy C.Y. has received research funding from Minerva, Lonza. C.Y. consults for TwinStrand Biosciences., (Copyright: © 2024 Pullarkat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As the proportion of women diagnosed with invasive breast cancer increases, the role of imaging for staging and surveillance purposes should be determined based on evidence-based guidelines. It is important to understand the indications for extent of disease evaluation and staging, as unnecessary imaging can delay care and even result in adverse outcomes. In asymptomatic patients that received treatment for curative intent, there is no role for imaging to screen for distant recurrence. Routine surveillance with an annual 2-D mammogram and/or tomosynthesis is recommended to detect an in-breast recurrence or a new primary breast cancer in women with a history of breast cancer, and MRI is increasingly used as an additional screening tool in this population, especially in women with dense breasts. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein., Methods: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032., Findings: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event., Interpretation: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile., Funding: Pfizer and Celcuity., Competing Interests: Declaration of interests RML received medical writing support and institutional research funding from Celcuity and Pfizer; institutional research funding from Novartis, Eli Lilly, Puma, Zentalis, Arvinas, and Accutar Biotechnology; and consulting fees from or participation on advisory boards for Celcuity, Pfizer, Novartis, Eli Lilly, Gilead, and Biotheryx. HSH received institutional research funding from Abbvie, Arvinas, Celcuity, Department of Defense, G1 Therapeutics, GlaxoSmith Kline, Horizon Oncology Research, Marker Therapeutics, Mersana, Novartis, Pfizer, Phoenix Pharmaceuticals, Pyonr, QuantumLeap Health, and Seagen, Zymeworks; consulting fees from or participation on advisory boards for Daiichi Sankyo–Astra Zeneca, Immunomedics–Gilead, and Novartis; and Speaker's Bureau fees for Eli Lilly. HSR received institutional research funding from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F Hoffmann-La Roche–Genentech, Gilead Sciences, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr; consulting fees from or participation on advisory boards for Napo Pharmaceutical, Puma Biotechnology, Blueprint, Scorpion Therapeutics, and Daiichi Sankyo; and honoraria from Blueprint, Mylan, and Puma Biotechnology. EMS-R received research funding from Susan G Komen, V Foundation, NIH, and Breast Cancer Research Foundation; consulting fees from or participation on advisory boards for Lilly, SeaGen, Immunomedics, Tersera, AstraZeneca, Merck, Novartis, and Mylan; other payments or honoraria from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, American Association for Cancer Research–Bristol Myers Squibb–Winn Clinical Trials Workshop. JMS received institutional research funding from Celcuity, Pfizer, Merck, Seagen, Seattle Genetics, Minerva, Myriad Pharmaceuticals, Novartis, Genentech, Cascadian Therapeutics, Abbvie, and Nektar; consulting fees from Volastra and GE Healthcare; royalties or licenses from UW Comotion as a donation to the UW Breast Program; honoraria from Binaytara Foundation, Washington State Medical Oncology Society, and Hong Kong International Oncology Symposium; meeting or travel support from ECOG ACRIN, A2 Biotherapeutics, IwCAR-T, the Society of Nuclear Medicine and Molecular Imaging, and Translational Breast Cancer Research Consortium; and is a member of data safety monitoring or advisory boards for GE Healthcare, Sensei Biotherapeutics, and GlaxoSmithKline. ECD received institutional research funding from Merck, Novartis, Meryx, H3 Biomedicine, and G1 Therapeutics and participated on the data safety monitoring board for Sanofi. PK received institutional research funding from AstraZeneca, Hibercell, Sanofi, Eli Lilly, Zymeworks, and Genentech. SS is a full-time employee of Celcuity receiving a salary and holding shares in Celcuity; and received consulting fees from Celcuity (before employment), Artiva Biotherapeutics, Elevation Oncology, Kartos Therapeutics, Tellios Pharma, and Direct Biologics. SCM, BFS, and IG are full-time employees of Celcuity receiving a salary and holding shares in Celcuity. RW received institutional research funding from Celcuity and Pfizer, is a member of advisory boards for Celcuity and Seagen, and is a member of the investigational steering committee for this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose ( 18 F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases., Methods: For this study, nine patients with 38 bone lesions were imaged with 18 F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18 F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18 F-FDG before and after standard-of-care therapy for response assessment., Results: The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and - 16.3% for SUVmax, and 21.2% and - 17.5% for SULpeak. 18 F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak., Conclusion: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18 F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18 F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response., (© 2024. The Author(s).)

Objectives: Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment., Methods: Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as "one primary only." Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival., Results: Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period ( P =0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P <0.001) and 23% received chemotherapy (vs. 45% for PBA, P =0.11)., Conclusions: We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma., Competing Interests: E.T.L.—Clinical trial funding from BioAtla, Ayala, and SpringWorks. L.D.C.—Clinical trial funding from Eli Lilly, AADi, BluePrint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma. Honoraria or has served on advisory boards for Daaichi Sankyo. M.J.W.—Clinical trial support from Deciphera, Adaptimmune, GSK, Athenex, Foghorn Therapeutics, Shaqsi, Presage Biosciences, Inhibrx, and Incyte. Consulting fees from Adaptimmune, Epizyme, Aadi, and Deciphera. H.M.L.—Research funding from Tolmar, EliLilly, GE Healthcare, Sanofi, and Zymeworks. Consulting for GE Healthcare, Novartis, Sanofi, and Eli Lilly. J.M.S.—Research funding from Celcuity, Genentech, Xencor, Pfizer, SeaGen, Merck, Carisma, and Lyell. Consultant/advisory boards: A2 Biotherapeutics, Volastra Therapeutics, GE Healthcare, Sensei Therapeutics, and GlaxoSmithKline. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate combined MRI and 18 F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer., Methods: Patients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18 F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K 1 ) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated., Results: Thirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31-66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18 F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18 F-FDG PET (K 1 ) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS., Conclusion: Mid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18 F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome., (© 2023. The Author(s).)

Objective: When multiple surveillance mammograms are performed within an annual interval, the current guidance for one-year follow-up to determine breast cancer status results in shared follow-up periods in which a single breast cancer diagnosis can be attributed to multiple preceding examinations, posing a challenge for standardized performance assessment. We assessed the impact of using follow-up periods that eliminate the artifactual inflation of second breast cancer diagnoses., Materials and Methods: We evaluated surveillance mammograms from 2007-2016 in women with treated breast cancer linked with tumor registry and pathology outcomes. Second breast cancers included ductal carcinoma in situ or invasive breast cancer diagnosed during one-year follow-up. The cancer detection rate, interval cancer rate, sensitivity, and specificity were compared using different follow-up periods: standard one-year follow-up per the American College of Radiology versus follow-up that was shortened at the next surveillance mammogram if less than one year (truncated follow-up). Performance measures were calculated overall and by indication (screening, evaluation for breast problem, and short interval follow-up)., Results: Of 117971 surveillance mammograms, 20% (n = 23533) were followed by another surveillance mammogram within one year. Standard follow-up identified 1597 mammograms that were associated with second breast cancers. With truncated follow-up, the breast cancer status of 179 mammograms (11.2%) was revised, resulting in 1418 mammograms associated with unique second breast cancers. The interval cancer rate decreased with truncated versus standard follow-up (3.6 versus 4.9 per 1000 mammograms, respectively), with a difference (95% confidence interval [CI]) of -1.3 (-1.6, -1.1). The overall sensitivity increased to 70.4% from 63.7%, for the truncated versus standard follow-up, with a difference (95% CI) of 6.6% (5.6%, 7.7%). The specificity remained stable at 98.1%., Conclusion: Truncated follow-up, if less than one year to the next surveillance mammogram, enabled second breast cancers to be associated with a single preceding mammogram and resulted in more accurate estimates of diagnostic performance for national benchmarks., Competing Interests: The authors have no potential conflicts of interest related to this study to disclose. Potential conflicts of interest unrelated to this study: Janie M. Lee grant from GE Healthcare; Jennifer M. Specht payment to author for consultancies from Daiichii Sankyo, GE Healthcare, GSK-Glaxosmithkline; grants from Merck, Cascadian Therapeutics, Pfizer, Genentech, Xencor, Abbvie, Seattle Genetics, Celcuity Inc; Karla Kerlikowske unpaid consultant to Grail for STRIVE study; Diana L. Miglioretti royalties from Elsevier; Kathryn P. Lowry grants from GE Healthcare; and Diana S. M. Buist payment for participation in review activities from Women Informed to Screen Depending on Measures of Risk Data Safety and Monitoring Board. All other authors declare no conflict of interest., (Copyright © 2023 The Korean Society of Radiology.)

Background: In women with previously treated breast cancer, occurrence and timing of second breast cancers have implications for surveillance. The authors examined the timing of second breast cancers by primary cancer estrogen receptor (ER) status in the Breast Cancer Surveillance Consortium., Methods: Women who were diagnosed with American Joint Commission on Cancer stage I-III breast cancer were identified within six Breast Cancer Surveillance Consortium registries from 2000 to 2017. Characteristics collected at primary breast cancer diagnosis included demographics, ER status, and treatment. Second breast cancer events included subsequent ipsilateral or contralateral breast cancers diagnosed >6 months after primary diagnosis. The authors examined cumulative incidence and second breast cancer rates by primary cancer ER status during 1-5 versus 6-10 years after diagnosis., Results: At 10 years, the cumulative second breast cancer incidence was 11.8% (95% confidence interval [CI], 10.7%-13.1%) for women with ER-negative disease and 7.5% (95% CI, 7.0%-8.0%) for those with ER-positive disease. Women with ER-negative cancer had higher second breast cancer rates than those with ER-positive cancer during the first 5 years of follow-up (16.0 per 1000 person-years [PY]; 95% CI, 14.2-17.9 per 1000 PY; vs. 7.8 per 1000 PY; 95% CI, 7.3-8.4 per 1000 PY, respectively). After 5 years, second breast cancer rates were similar for women with ER-negative versus ER-positive breast cancer (12.1 per 1000 PY; 95% CI, 9.9-14.7; vs. 9.3 per 1000 PY; 95% CI, 8.4-10.3 per 1000 PY, respectively)., Conclusions: ER-negative primary breast cancers are associated with a higher risk of second breast cancers than ER-positive cancers during the first 5 years after diagnosis. Further study is needed to examine the potential benefit of more intensive surveillance targeting these women in the early postdiagnosis period., (© 2023 American Cancer Society.)

In the past 5 years, the treatment options available to patients with HER2+ breast cancer brain metastasis (BCBM) have expanded. The longer survival of patients with HER2+ BCBM renders understanding the toxicities of local therapies even more important to consider. After reviewing the available literature for HER2 targeted systemic therapies as well as local therapies, we present a simplified algorithm for when to prioritize systemic therapies over local therapies in patients with HER2+ BCBM.

Introduction: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC., Methods: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m 2 IV weekly ×12 followed by doxorubicin 24 mg/m 2 IV weekly + cyclophosphamide 60 mg/m 2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade)., Results: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER + disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue., Conclusions: Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC., Competing Interests: Disclosure The following authors report they have conflicts of interest to disclose: JRG: Roche/Genentech (DSMC, Steering committee), Astra Zeneca (DSMC, consultant), Novartis (DSMC), Puma (advisory board), Immunomedics (DSMC), Radia (DSMC), Pfizer (advisory board), InBiomotion (advisory board), Sandoz/Hexal (Consultant), Genomic Health (advisory board) VG: SEngine Precision Medicine (ownership), AmunBio (Ownership), New Equilibrium Biosciences (Ownership), Seagen (Honoria/Consulting), Puma (Honoraria, Consulting), Sanofi (Honoraria/Consulting), Roche (research funding) BK: eResearch Technologies (Employer) AS: Amgen (grant funding/honoraria), AstraZeneca (consulting), Athenex (consulting) The remaining authors have no conflicts of interest to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Lessons Learned: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination., Background: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors., Methods: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab., Results: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation., Conclusion: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)