bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations
Authors: Zhang Daniel Y. , Dmello Crismita , Chen Li , Arrieta Victor A. , Gonzalez-Buendia Edgar , Kane J. Robert , Magnusson Lisa P. , Baran Aneta , James C. David , Horbinski Craig , Carpentier Alexandre , Desseaux Carole , Canney Michael , Muzzio Miguel , Stupp Roger , Sonabend Adam M.
Published: April 2023

AbstractPurpose:
Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood–brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models.
Experimental Design:
The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice.
Results:
Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated.
Conclusions:
Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.
Data from Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study
Authors: Strosberg Jonathan , Mizuno Nobumasa , Doi Toshihiko , Grande Enrique , Delord Jean-Pierre , Shapira-Frommer Ronnie , Bergsland Emily , Shah Manisha , Fakih Marwan , Takahashi Shunji , Piha-Paul Sarina A. , O'Neil Bert , Thomas Sajeve , Lolkema Martijn P. , Chen Menghui , Ibrahim Nageatte , Norwood Kevin , Hadoux Julien
Published: April 2023

AbstractPurpose:
KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET).
Patients and Methods:
Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary).
Results:
A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29–80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1–positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6–33.4). ORR was 3.7% (95% CI, 1.0–9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1–negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5–5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8–32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3–5 AEs.
Conclusions:
Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.
Data from Preclinical Activity of SAR408701: A Novel Anti-CEACAM5–maytansinoid Antibody–drug Conjugate for the Treatment of CEACAM5-positive Epithelial Tumors
Authors: Decary Stéphanie , Berne Pierre-François , Nicolazzi Céline , Lefebvre Anne-Marie , Dabdoubi Tarik , Cameron Béatrice , Rival Pierrick , Devaud Catherine , Prades Catherine , Bouchard Hervé , Cassé Alhassan , Henry Christophe , Amara Céline , Brillac Claire , Ferrari Paul , Maçon Laetitia , Lacoste Eric , Combeau Cecile , Beys Eric , Naimi Souad , García-Echeverría Carlos , Mayaux Jean-François , Blanc Véronique
Published: April 2023

AbstractPurpose:
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody–drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker.
Experimental Design:
The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey.
Results:
SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone.
Conclusions:
On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors.
Data from Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors
Authors: Centanni Maddalena , Krishnan Sreenath M. , Friberg Lena E.
Published: April 2023

AbstractPurpose:
Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of “real-life” comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker.
Experimental Design:
Models describing relations between sunitinib exposure, adverse events (hand–foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3–adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation.
Results:
The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling.
Conclusions:
Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.
Data from A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy
Authors: El Sissy Carine , Kirilovsky Amos , Van den Eynde Marc , Muşină Ana-Maria , Anitei Maria-Gabriela , Romero Alfredo , Marliot Florence , Junca Audelaure , Doyen Jérôme , Mlecnik Bernhard , Haicheur Nacilla , Fredriksen Tessa , Lagorce Christine , Jouret-Mourin Anne , Leonard Daniel , Bibeau Frédéric , Iseas Soledad , Roca Enrique L. , Cabanne Ana M. , Vaccaro Carlos A. , Santino Juan P. , Huertas Eduardo , Tougeron David , Carvalho Carlos , Figueiredo Nuno , Perez Rodrigo O. , Habr-Gama Angelita , Scripcariu Viorel , Gerard Jean-Pierre , Galon Jérôme , Zeitoun Guy , Pagès Franck
Published: April 2023

AbstractPurpose:
No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy (“Watch-and-Wait”).
Experimental Design:
Biopsies from two independent cohorts (n1 = 131, n2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3+ and CD8+ T cells and quantified by digital pathology to determine ISB. The expression of immune-related genes post-nT was investigated (n = 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The ISB prognostic performance was further assessed in a multicentric cohort (n = 73 patients) treated by Watch-and-Wait.
Results:
ISB positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P = 0.006). ISB high identified patients at lower risk of relapse or death compared with ISB low [HR, 0.21; 95% confidence interval (CI), 0.06–0.78; P = 0.009]. Prognostic performance of ISB for DFS was confirmed in a validation cohort. ISB was an independent parameter, more informative than pre- (P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. ISB combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the “Watch-and-Wait” cohort (n = 73), no relapse was observed in patients with ISB high (23.3%).
Conclusions:
ISB predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.
Data from Synthetic Lethal Screens Reveal Cotargeting FAK and MEK as a Multimodal Precision Therapy for GNAQ-Driven Uveal Melanoma
Authors: Paradis Justine S. , Acosta Monica , Saddawi-Konefka Robert , Kishore Ayush , Lubrano Simone , Gomes Frederico , Arang Nadia , Tiago Manoela , Coma Silvia , Wu Xingyu , Ford Kyle , Day Chi-Ping , Merlino Glenn , Mali Prashant , Pachter Jonathan A. , Sato Takami , Aplin Andrew E. , Gutkind J. Silvio
Published: April 2023

AbstractPurpose:
Uveal melanoma is the most common eye cancer in adults. Approximately 50% of patients with uveal melanoma develop metastatic uveal melanoma (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. Uveal melanoma is characterized by gain-of-function mutations in GNAQ/GNA11, encoding Gαq proteins. We have recently shown that the Gαq–oncogenic signaling circuitry involves a noncanonical pathway distinct from the classical activation of PLCβ and MEK–ERK. GNAQ promotes the activation of YAP1, a key oncogenic driver, through focal adhesion kinase (FAK), thereby identifying FAK as a druggable signaling hub downstream from GNAQ. However, targeted therapies often activate compensatory resistance mechanisms leading to cancer relapse and treatment failure.
Experimental Design:
We performed a kinome-wide CRISPR-Cas9 sgRNA screen to identify synthetic lethal gene interactions that can be exploited therapeutically. Candidate adaptive resistance mechanisms were investigated by cotargeting strategies in uveal melanoma and mUM in vitro and in vivo experimental systems.
Results:
sgRNAs targeting the PKC and MEK–ERK signaling pathways were significantly depleted after FAK inhibition, with ERK activation representing a predominant resistance mechanism. Pharmacologic inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in uveal melanoma cells and exerted cytotoxic effects, leading to tumor collapse in uveal melanoma xenograft and liver mUM models in vivo.
Conclusions:
Coupling the unique genetic landscape of uveal melanoma with the power of unbiased genetic screens, our studies reveal that FAK and MEK–ERK cotargeting may provide a new network-based precision therapeutic strategy for mUM treatment.

See related commentary by Harbour, p. 2967
Data from DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors
Authors: Chung Jin-Sung , Ramani Vijay , Kobayashi Masato , Fattah Farjana , Popat Vinita , Zhang Song , Cruz Ponciano D. , Gerber David E. , Ariizumi Kiyoshi
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.
Experimental Design:
Plasma samples were collected from patients with advanced non–small cell lung carcinoma (NSCLC) (n = 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-DC-HIL gene, injection of DC-HIL–expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.
Results:
Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (n = 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL+MDSC or induction of sDC-HIL expression.
Conclusions:
sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.
Data from BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia
Authors: Ramsey Haley E. , Greenwood Dalton , Zhang Susu , Childress Merrida , Arrate Maria P. , Gorska Agnieszka E. , Fuller Londa , Zhao Yue , Stengel Kristy , Fischer Melissa A. , Stubbs Matthew C. , Liu Phillip C.C. , Boyd Kelli , Rathmell Jeffrey C. , Hiebert Scott W. , Savona Michael R.
Published: April 2023

AbstractPurpose:
The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity.
Experimental Design:
INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models.
Results:
INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity.
Conclusions:
Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
Data from Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer
Authors: Hong David S. , Concin Nicole , Vergote Ignace , de Bono Johann S. , Slomovitz Brian M. , Drew Yvette , Arkenau Hendrik-Tobias , Machiels Jean-Pascal , Spicer James F. , Jones Robert , Forster Martin D. , Cornez Nathalie , Gennigens Christine , Johnson Melissa L. , Thistlethwaite Fiona C. , Rangwala Reshma A. , Ghatta Srinivas , Windfeld Kristian , Harris Jeffrey R. , Lassen Ulrik Niels , Coleman Robert L.
Published: April 2023

AbstractPurpose:
Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).
Patients and Methods:
Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.
Results:
Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%−37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.
Conclusions:
Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.
Data from Predominance of Central Memory T Cells with High T-Cell Receptor Repertoire Diversity is Associated with Response to PD-1/PD-L1 Inhibition in Merkel Cell Carcinoma
Authors: Spassova Ivelina , Ugurel Selma , Terheyden Patrick , Sucker Antje , Hassel Jessica C. , Ritter Cathrin , Kubat Linda , Habermann Daniel , Farahpour Farnoush , Saeedghalati Mohammadkarim , Peiffer Lukas , Kumar Rajiv , Schrama David , Hoffmann Daniel , Schadendorf Dirk , Becker Jürgen C.
Published: April 2023

AbstractPurpose:
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, which can be effectively controlled by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. However, a significant proportion of patients are characterized by primary therapy resistance. Predictive biomarkers for response to immunotherapy are lacking.
Experimental Design:
We applied Bayesian inference analyses on 41 patients with MCC testing various clinical and biomolecular characteristics to predict treatment response. Further, we performed a comprehensive analysis of tumor tissue–based immunologic parameters including multiplexed immunofluorescence for T-cell activation and differentiation markers, expression of immune-related genes and T-cell receptor (TCR) repertoire analyses in 18 patients, seven objective responders, and 11 nonresponders.
Results:
Bayesian inference analyses demonstrated that among currently discussed biomarkers only unimpaired overall performance status and absence of immunosuppression were associated with response to therapy. However, in responders, a predominance of central memory T cells and expression of genes associated with lymphocyte attraction and activation was evident. In addition, TCR repertoire usage of tumor-infiltrating lymphocytes (TILs) demonstrated low T-cell clonality, but high TCR diversity in responding patients. In nonresponders, terminally differentiated effector T cells with a constrained TCR repertoire prevailed. Sequential analyses of tumor tissue obtained during immunotherapy revealed a more pronounced and diverse clonal expansion of TILs in responders indicating an impaired proliferative capacity among TILs of nonresponders upon checkpoint blockade.
Conclusions:
Our explorative study identified new tumor tissue–based molecular characteristics associated with response to anti–PD-1/PD-L1 therapy in MCC. These observations warrant further investigations in larger patient cohorts to confirm their potential value as predictive markers.
Data from MET Exon 14–altered Lung Cancers and MET Inhibitor Resistance
Authors: Guo Robin , Offin Michael , Brannon A. Rose , Chang Jason , Chow Andrew , Delasos Lukas , Girshman Jeffrey , Wilkins Olivia , McCarthy Caroline G. , Makhnin Alex , Falcon Christina , Scott Kerry , Tian Yuan , Cecchi Fabiola , Hembrough Todd , Alex Deepu , Shen Ronglai , Benayed Ryma , Li Bob T. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Rekhtman Natasha , Paik Paul , Zehir Ahmet , Drilon Alexander
Published: April 2023

AbstractPurpose:
MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14–altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.
Experimental Design:
We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14–altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.
Results:
Seventy-five of 168 MET exon 14–altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N = 15) or immunochemistry (N = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P = 0.02).
Conclusions:
In MET exon 14–altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
Data from Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells
Authors: Lemm Elizabeth A. , Valle-Argos Beatriz , Smith Lindsay D. , Richter Johanna , Gebreselassie Yohannes , Carter Matthew J. , Karolova Jana , Svaton Michael , Helman Karel , Weston-Bell Nicola J. , Karydis Laura , Williamson Chris T. , Lenz Georg , Pettigrew Jeremy , Harwig Curtis , Stevenson Freda K. , Cragg Mark , Forconi Francesco , Steele Andrew J. , Cross Jennifer , Mackenzie Lloyd , Klener Pavel , Packham Graham
Published: April 2023

AbstractPurpose:
PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5′-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies.
Experimental Design:
In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models.
Results:
Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti–IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti–IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition.
Conclusions:
Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.
Data from Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia
Authors: Zeidner Joshua F. , Lee Daniel J. , Frattini Mark , Fine Gil D. , Costas Judy , Kolibaba Kathryn , Anthony Stephen P. , Bearss David , Smith B. Douglas
Published: April 2023

AbstractPurpose:
Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy.
Patients and Methods:
A multiinstitutional phase I dose-escalation study of alvocidib on days 1–3 followed by 7+3 (cytarabine 100 mg/m2/day i.v. infusion days 5–12 and daunorubicin 60 mg/m2 i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded.
Results:
There was no MTD on this study; the recommended phase II dose of alvocidib was 30 mg/m2 i.v. over 30 minutes followed by 60 mg/m2 i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively).
Conclusions:
Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.
Data from Local and Systemic Immune Dysregulation Alters Glioma Growth in Hyperglycemic Mice
Authors: Zhang Ian Y. , Zhou Hui , Liu Huili , Zhang Leying , Gao Hang , Liu Shunan , Song Yanyan , Alizadeh Darya , Yin Hongwei Holly , Pillai Raju , Badie Behnam
Published: April 2023

AbstractPurpose:
Unlike most cancers, no clear epidemiological correlation between diabetes (Db) and malignant glioma progression exists. Because hyperglycemia activates proinflammatory pathways through the receptor for advanced glycation endproducts (RAGE), we hypothesized that Db can also promote malignant glioma progression.
Experimental Design:
We compared the growth of two phenotypically diverse syngeneic glioma models in control and diabetic mice. Tumor growth and antitumor immune responses were evaluated in orthotopic and heterotopic models and correlated to RAGE and RAGE ligand expression.
Results:
Irrespective of tumor implantation site, growth of a “classical” glioma model, GL261, increased in hyperglycemic mice and was mediated by upregulation of RAGE and its ligand, HMGB1. However, growth of a “mesenchymal” glioma subtype, K-Luc, depended on tumor implantation site. Whereas heterotopic K-Luc tumors progressed rapidly in Db mice, intracranial K-Luc tumors grew slower. We further showed that hyperglycemia inhibited the innate antitumor inflammatory responses in both models. Although this contributed to the accelerated growth of heterotopic tumors, suppression of tumor inflammatory responses dampened the growth of orthotopic K-Luc gliomas.
Conclusions:
Hyperglycemia may enhance glioma growth through promotion of RAGE expression and suppression of antitumor immune responses. However, abrogation of the proinflammatory milieu in tumors may also dampen the growth of inflammatory glioma subtypes in the brains of diabetic mice. This dichotomy in glioma growth response to hyperglycemia may partly explain why conflicting epidemiological studies show both an increased risk and a protective effect of Db in patients with malignant gliomas.
Data from Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET
Authors: Wang Sinan , Li Jun , Hua Jun , Su Yang , Beckford-Vera Denis R. , Zhao Walter , Jayaraman Mayuri , Huynh Tony L. , Zhao Ning , Wang Yung-hua , Huang Yangjie , Qin Fujun , Shen Sui , Gioeli Daniel , Dreicer Robert , Sriram Renuka , Egusa Emily A. , Chou Jonathan , Feng Felix Y. , Aggarwal Rahul , Evans Michael J. , Seo Youngho , Liu Bin , Flavell Robert R. , He Jiang
Published: April 2023

AbstractPurpose:
We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models.
Experimental Design:
[89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR−, CD46+, prostate-specific membrane antigen–negative (PSMA−)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545.
Results:
[89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection).
Conclusions:
[89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.
Data from First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas
Authors: Gopal Ajay K. , Levy Ronald , Houot Roch , Patel Sandip P. , Popplewell Leslie , Jacobson Caron , Mu Xinmeng J. , Deng Shibing , Ching Keith A. , Chen Ying , Davis Craig B. , Huang Bo , Fly Kolette D. , Thall Aron , Woolfson Adrian , Bartlett Nancy L.
Published: April 2023

AbstractPurpose:
In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL).
Patients and Methods:
Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D).
Results:
Sixty-seven patients received utomilumab (0.03–10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%–33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function.
Conclusions:
Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.
Data from A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer
Authors: Kazmi Farasat , Nicum Shibani , Roux Rene L. , Spiers Laura , Gnanaranjan Chat , Sukumaran Ajithkumar , Gabra Hani , Ghazaly Essam , McCracken Nigel W. , Harrison David J. , Blagden Sarah P.
Published: April 2023

AbstractPurpose:
NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer.
Patients and Methods:
NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles. Four dose cohorts of NUC-1031 (500, 625, and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was recommended phase II combination dose (RP2CD). Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetics.
Results:
A total of 25 women with recurrent ovarian cancer, a mean of 3.8 prior lines of chemotherapy, and a median platinum-free interval of 5 months (range: 7–451 days) were enrolled; 15 of 25 (60%) were platinum resistant, 9 (36%) were partially platinum sensitive, and 1 (4%) was platinum sensitive. Of the 23 who were response evaluable, there was 1 confirmed complete response (4%), 5 partial responses (17%), and 8 (35%) stable disease. The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin.
Conclusions:
NUC-1031 combined with carboplatin is well tolerated in recurrent ovarian cancer. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 and 8 with AUC5 carboplatin day 1, every 3 weeks for six cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.
Data from Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors
Authors: Vidula Neelima , Rich Thereasa A. , Sartor Oliver , Yen Jennifer , Hardin Aaron , Nance Tracy , Lilly Michael B. , Nezami Mohammad Amin , Patel Sandip P. , Carneiro Benedito A. , Fan Alice C. , Brufsky Adam M. , Parker Barbara A. , Bridges Benjamin B. , Agarwal Neeraj , Maughan Benjamin L. , Raymond Victoria M. , Fairclough Stephen R. , Lanman Richard B. , Bardia Aditya , Cristofanilli Massimo
Published: April 2023

AbstractPurpose:
PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.
Experimental Design:
Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion–deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.
Results:
Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.
Conclusions:
cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
Data from Circulating Tumor Cells and Early Relapse in Node-positive Melanoma
Authors: Lucci Anthony , Hall Carolyn S. , Patel Sapna P. , Narendran Boomadevi , Bauldry Jessica B. , Royal Richard E. , Karhade Mandar , Upshaw Joshua R. , Wargo Jennifer A. , Glitza Isabella C. , Wong Michael K.K. , Amaria Rodabe N. , Tawbi Hussein A. , Diab Adi , Davies Michael A. , Gershenwald Jeffrey E. , Lee Jeffrey E. , Hwu Patrick , Ross Merrick I.
Published: April 2023

AbstractPurpose:
There is a need for sensitive, reproducible biomarkers for patients with stage III melanoma to guide clinical decision making. Circulating tumor cells (CTCs) can be detected in patients with melanoma; however, there are limited data regarding their significance in stage III disease. The aim of this study was to determine whether CTCs are associated with early relapse in stage III melanoma.
Experimental Design:
We prospectively assessed CTCs at first presentation in clinic (baseline) for 243 patients with stage III melanoma. CTCs were measured using the CellSearch System. Relapse-free survival (RFS) was compared between patients with one or more baseline CTC versus those with no CTCs. Log-rank test and Cox regression analysis were applied to establish associations of CTCs with RFS.
Results:
At least one baseline CTC was identified in 90 of 243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. CTC detection was not associated with substage, or primary tumor characteristics. Multivariable analysis demonstrated that the detection of ≥1 baseline CTC was significantly associated with decreased 6-month RFS [log-rank, P < 0.0001; HR, 3.62, 95% confidence interval (CI), 1.78–7.36; P < 0.0001] and 54-month RFS (log-rank, P = 0.01; HR, 1.69; 95% CI, 1.13–2.54; P = 0.01).
Conclusions:
≥1 CTC was independently associated with melanoma relapse, suggesting that CTC assessment may be useful to identify patients at risk for relapse who could derive benefit from adjuvant therapy.
Data from A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers
Authors: Paik Paul K. , Kim Rachel K. , Ahn Linda , Plodkowski Andrew J. , Ni Ai , Donoghue Mark T.A. , Jonsson Philip , Villalona-Calero Miguel , Ng Kenneth , McFarland Daniel , Fiore John J. , Iqbal Afsheen , Eng Juliana , Kris Mark G. , Rudin Charles M.
Published: April 2023

AbstractPurpose:
Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs.
Patients and Methods:
This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy.
Results:
Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%–74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7–10.5) months. There were no unexpected toxicities.
Conclusions:
Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.
Data from Transcriptional Subtypes Resolve Tumor Heterogeneity and Identify Vulnerabilities to MEK Inhibition in Lung Adenocarcinoma
Authors: Daemen Anneleen , Cooper Jonathan E. , Myrta Szymon , Wongchenko Matthew J. , Lin Eva , Long Jason E. , Foreman Oded , Modrusan Zora , Tremayne Jarrod R. , de la Cruz Cecile C. , Merchant Mark , Martin Scott E. , Yan Yibing , Junttila Melissa R.
Published: April 2023

AbstractPurpose:
Lung adenocarcinomas comprise the largest fraction of non–small cell lung cancer, which is the leading cause of cancer-related deaths. Seventy-five percent of adenocarcinomas lack targeted therapies because of scarcity of druggable drivers. Here, we classified tumors on the basis of signaling similarities and discovered subgroups within this unmet patient population.
Experimental Design:
We leveraged transcriptional data from >800 early- and advanced-stage patients.
Results:
We identified three robust subtypes dubbed mucinous, proliferative, and mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers, including KRAS and EGFR. The subtypes capture heterogeneity even among tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrated unified subtypes despite divergently evolved prooncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity among in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof of concept, we identified differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial.
Conclusions:
Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment.

See related commentary by Skoulidis, p. 913