bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies
Authors: Johnson Melissa , El-Khoueiry Anthony , Hafez Navid , Lakhani Nehal , Mamdani Hirva , Rodon Jordi , Sanborn Rachel E. , Garcia-Corbacho Javier , Boni Valentina , Stroh Mark , Hannah Alison L. , Wang Song , Castro Henry , Spira Alexander
Published: April 2023

AbstractPurpose:
PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody–drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody–drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target.
Patients and Methods:
This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks.
Results:
Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies.
Conclusions:
The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity.

See related commentary by Oberoi and Garralda, p. 4459
Data from Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ Specificity and Treatment Resistance
Authors: Beck Lir , Harel Michal , Yu Shun , Markovits Ettai , Boursi Ben , Markel Gal , Geiger Tamar
Published: April 2023

AbstractPurpose:
Treatment of metastatic melanoma has dramatically improved in recent years, thanks to the development of immunotherapy and BRAF-MEK–targeted therapies. However, these developments revealed marked heterogeneity in patient response, which is yet to be fully understood. In this work, we aimed to associate the proteomic profiles of metastatic melanoma with the patient clinical information, to identify protein correlates with metastatic location and prior treatments.
Experimental Design:
We performed mass spectrometry–based proteomic analysis of 185 metastatic melanoma samples and followed with bioinformatics analysis to examine the association of metastatic location, BRAF status, survival, and immunotherapy response with the tumor molecular profiles.
Results:
Bioinformatics analysis showed a high degree of functional heterogeneity associated with the site of metastasis. Lung metastases presented higher immune-related proteins, and higher mitochondrial-related processes, which were shown previously to be associated with better immunotherapy response. In agreement, epidemiological analysis of data from the National Cancer Database showed improved response to anti-programmed death 1, mainly in patients with lung metastasis. Focus on lung metastases revealed prognostic and molecular heterogeneity and highlighted potential tissue-specific biomarkers. Analysis of the BRAF mutation status and prior treatments with MAPK inhibitors proposed the molecular basis of the effect on immunotherapy response and suggested coordinated combination of immunotherapy and targeted therapy may increase treatment efficacy.
Conclusions:
Altogether, the proteomic data provided novel molecular determinants of critical clinical features, including the effects of sequential treatments and metastatic locations. These results can be the basis for development of site-specific treatments toward treatment personalization.
Data from Radium-223 Treatment Increases Immune Checkpoint Expression in Extracellular Vesicles from the Metastatic Prostate Cancer Bone Microenvironment
Authors: Vardaki Ioulia , Corn Paul , Gentile Emanuela , Song Jian H. , Madan Namrata , Hoang Anh , Parikh Nila , Guerra Leah , Lee Yu-Chen , Lin Song-Chang , Yu Guoyu , Santos Elmer , Melancon Marites P. , Troncoso Patricia , Navone Nora , Gallick Gary E. , Efstathiou Eleni , Subudhi Sumit K. , Lin Sue-Hwa , Logothetis Christopher J. , Panaretakis Theocharis
Published: April 2023

AbstractPurpose:
Radium-223 prolongs survival in a fraction of men with bone metastatic prostate cancer (PCa). However, there are no markers for monitoring response and resistance to Radium-223 treatment. Exosomes are mediators of intercellular communication and may reflect response of the bone microenvironment to Radium-223 treatment. We performed molecular profiling of exosomes and compared the molecular profile in patients with favorable and unfavorable overall survival.
Experimental Design:
We performed exosomal transcriptome analysis in plasma derived from our preclinical models (MDA-PCa 118b tumors, TRAMP-C2/BMP4 PCa) and from the plasma of 25 patients (paired baseline and end of treatment) treated with Radium-223. All samples were run in duplicate, and array data analyzed with fold changes +2 to −2 and P < 0.05.
Results:
We utilized the preclinical models to establish that genes derived from the tumor and the tumor-associated bone microenvironment (bTME) are differentially enriched in plasma exosomes upon Radium-223 treatment. The mouse transcriptome analysis revealed changes in bone-related and DNA damage repair–related pathways. Similar findings were observed in plasma-derived exosomes from patients treated with Radium-223 detected changes. In addition, exosomal transcripts detected immune-suppressors (e.g., PD-L1) that were associated with shorter survival to Radium-223. Treatment of the Myc-CaP mouse model with a combination of Radium-223 and immune checkpoint therapy (ICT) resulted in greater efficacy than monotherapy.
Conclusions:
These clinical and coclinical analyses showed that RNA profiling of plasma exosomes may be used for monitoring the bTME in response to treatment and that ICT may be used to increase the efficacy of Radium-223.
Data from Complementary Role of Circulating Tumor DNA Assessment and Tissue Genomic Profiling in Metastatic Renal Cell Carcinoma
Authors: Zengin Zeynep B. , Weipert Caroline , Salgia Nicholas J. , Dizman Nazli , Hsu Joann , Meza Luis , Chehrazi-Raffle Alexander , Muddasani Ramya , Salgia Sabrina , Malhotra Jasnoor , Chawla Neal , Philip Errol J. , Kiedrowski Lesli , Maughan Benjamin L. , Rathi Nityam , Goel Divyam , Choueiri Toni K. , Agarwal Neeraj , Pal Sumanta K.
Published: April 2023

AbstractPurpose:
The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.
Experimental Design:
Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.
Results:
ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.
Conclusions:
This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.
Data from LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors
Authors: Monaco Kelli-Ann , Delach Scott , Yuan Jing , Mishina Yuji , Fordjour Paul , Labrot Emma , McKay Daniel , Guo Ribo , Higgins Stacy , Wang Hui Qin , Liang Jinsheng , Bui Karen , Green John , Aspesi Peter , Ambrose Jessi , Mapa Felipa , Griner Lesley , Jaskelioff Mariela , Fuller John , Crawford Kenneth , Pardee Gwynn , Widger Stephania , Hammerman Peter S. , Engelman Jeffrey A. , Stuart Darrin D. , Cooke Vesselina G. , Caponigro Giordano
Published: April 2023

AbstractPurpose:
Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254.
Experimental Design:
LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.
Results:
We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive.
Conclusions:
LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.
Data from Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma
Authors: Andrews David W. , Judy Kevin D. , Scott Charles B. , Garcia Samantha , Harshyne Larry A. , Kenyon Lawrence , Talekar Kiran , Flanders Adam , Atsina Kofi-Buaku , Kim Lyndon , Martinez Nina , Shi Wenyin , Werner-Wasik Maria , Liu Haisong , Prosniak Mikhail , Curtis Mark , Kean Rhonda , Ye Donald Y. , Bongiorno Emily , Sauma Sami , Exley Mark A. , Pigott Kara , Hooper D. Craig
Published: April 2023

AbstractPurpose:
Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.
Patients and Methods:
This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.
Results:
Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted.
Conclusions:
IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Data from Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia
Authors: Hunter Anthony M. , Newman Hannah , Dezern Amy E. , Steensma David P. , Niyongere Sandrine , Roboz Gail J. , Mo Qianxing , Chan Onyee , Gerds Aaron , Sallman David A. , Dominguez-Viqueira William , Letson Christopher , Balasis Maria E. , Ball Markus , Kruer Traci , Zhang Hailing , Lancet Jeffrey E. , List Alan F. , Sekeres Mikkael A. , Komrokji Rami S. , Padron Eric
Published: April 2023

AbstractPurpose:
Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.
Patients and Methods:
A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.
Results:
The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials.
Conclusions:
Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.

See related commentary by Shastri and Adrianzen-Herrera, p. 6069
Data from Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors
Authors: Do Khanh T. , Kochupurakkal Bose , Kelland Sarah , de Jonge Adrienne , Hedglin Jennifer , Powers Allison , Quinn Nicholas , Gannon Courtney , Vuong Loan , Parmar Kalindi , Lazaro Jean-Bernard , D'Andrea Alan D. , Shapiro Geoffrey I.
Published: April 2023

AbstractPurpose:
Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition.
Patients and Methods:
This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1–5 and 15–19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments.
Results:
Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1-mutant, PARP inhibitor–resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure.
Conclusions:
Prexasertib combined with olaparib has preliminary clinical activity in BRCA-mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.
Data from Visualization of Intratumor Pharmacokinetics of [fam-] Trastuzumab Deruxtecan (DS-8201a) in HER2 Heterogeneous Model Using Phosphor-integrated Dots Imaging Analysis
Authors: Suzuki Mikiko , Yagishita Shigehiro , Sugihara Kiyoshi , Ogitani Yusuke , Nishikawa Tadaaki , Ohuchi Mayu , Teishikata Takashi , Jikoh Takahiro , Yatabe Yasushi , Yonemori Kan , Tamura Kenji , Hasegawa Kosei , Hamada Akinobu
Published: April 2023

AbstractPurpose:
We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody–drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism.
Experimental Design:
We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, and (ii) a homogeneous model in which both cell types were transplanted separately into the same mouse. PID imaging involved immunostaining using novel high-intensity fluorescent nanoparticles. The distribution of T-DXd was assessed by PID imaging targeting the parent antibody, trastuzumab, and the payload, DXd, in serial frozen sections, respectively.
Results:
After T-DXd administration in the heterogeneous model, HER2 expression tended to decrease in a time-dependent manner. The distribution of trastuzumab and DXd was observed by PID imaging along the HER2-positive area throughout the observation period. A detailed comparison of the PID distribution between trastuzumab and DXd showed that trastuzumab matched almost perfectly with the HER2-positive area. In contrast, DXd exhibited widespread distribution in the surrounding HER2-negative area as well. In the HER2-negative tumor of the homogeneous model, the PID distribution of trastuzumab and DXd remained extremely low throughout the observation period.
Conclusions:
Our results suggest that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then to adjacent HER2-negative areas. We successfully visualized the intratumor distribution of T-DXd and its mechanism of action, the so-called “bystander effect.”
Data from Clinical and Immunologic Responses to a B-Cell Epitope Vaccine in Patients with HER2/neu-Overexpressing Advanced Gastric Cancer—Results from Phase Ib Trial IMU.ACS.001
Authors: Wiedermann Ursula , Garner-Spitzer Erika , Chao Yee , Maglakelidze Marina , Bulat Iurie , Dechaphunkul Arunee , Arpornwirat Wichit , Charoentum Chaiyut , Yen Chia-Jui , Yau Thomas Cheung , Tanasanvimon Suebpong , Maneechavakajorn Jedzada , Sookprasert Aumkhae , Bai Li-Yuan , Chou Wen-Chi , Ungtrakul Teerapat , Drinic Mirjana , Tobias Joshua , Zielinski Christoph C. , Chong Leslie , Ede Nicholas J. , Marino Mark T. , Good Anthony J.
Published: April 2023

AbstractPurpose:
HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988).
Patients and Methods:
A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1.
Results:
IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses.
Conclusions:
IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.
Data from ARID1A Mutation May Define an Immunologically Active Subgroup in Patients with Microsatellite Stable Colorectal Cancer
Authors: Mehrvarz Sarshekeh Amir , Alshenaifi Jumanah , Roszik Jason , Manyam Ganiraju C. , Advani Shailesh M. , Katkhuda Riham , Verma Anuj , Lam Michael , Willis Jason , Shen John Paul , Morris Jeffrey , Davis Jennifer S. , Loree Jonathan M. , Lee Hey Min , Ajani Jaffer A. , Maru Dipen M. , Overman Michael J. , Kopetz Scott
Published: April 2023

AbstractPurpose:
AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored.
Experimental Design:
The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients.
Results:
Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δz score +1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with ARID1A mutation (P = 0.01).
Conclusions:
The immunogenicity of ARID1A-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy–based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
Data from Development and Validation of a Simplified Score to Predict Early Relapse in Newly Diagnosed Multiple Myeloma in a Pooled Dataset of 2,190 Patients
Authors: Zaccaria Gian Maria , Bertamini Luca , Petrucci Maria Teresa , Offidani Massimo , Corradini Paolo , Capra Andrea , Romano Alessandra , Liberati Anna Marina , Mannina Donato , de Fabritiis Paolo , Cascavilla Nicola , Ruggeri Marina , Mina Roberto , Patriarca Francesca , Benevolo Giulia , Belotti Angelo , Gaidano Gianluca , Nagler Arnon , Hájek Roman , Spencer Andrew , Sonneveld Pieter , Musto Pellegrino , Boccadoro Mario , Gay Francesca
Published: April 2023

AbstractPurpose:
Despite the improvement of therapeutic regimens, several patients with multiple myeloma (MM) still experience early relapse (ER). This subset of patients currently represents an unmet medical need.
Experimental Design:
We pooled data from seven European multicenter phase II/III clinical trials enrolling 2,190 patients with newly diagnosed MM from 2003 to 2017. Baseline patient evaluation included 14 clinically relevant features. Patients with complete data (n = 1,218) were split into training (n = 844) and validation sets (n = 374). In the training set, a univariate analysis and a multivariate logistic regression model on ER within 18 months (ER18) were made. The most accurate model was selected on the validation set. We also developed a dynamic version of the score by including response to treatment.
Results:
The Simplified Early Relapse in Multiple Myeloma (S-ERMM) score was modeled on six features weighted by a score: 5 points for high lactate dehydrogenase or t(4;14); 3 for del17p, abnormal albumin, or bone marrow plasma cells >60%; and 2 for λ free light chain. The S-ERMM identified three patient groups with different risks of ER18: Intermediate (Int) versus Low (OR = 2.39, P < 0.001) and High versus Low (OR = 5.59, P < 0.001). S-ERMM High/Int patients had significantly shorter overall survival (High vs. Low: HR = 3.24, P < 0.001; Int vs. Low: HR = 1.86, P < 0.001) and progression-free survival-2 (High vs. Low: HR = 2.89, P < 0.001; Int vs. Low: HR = 1.76, P < 0.001) than S-ERMM Low. The Dynamic S-ERMM (DS-ERMM) modulated the prognostic power of the S-ERMM.
Conclusions:
On the basis of simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.
Data from A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer
Authors: Jhaveri Komal , Drago Joshua Z. , Shah Payal Deepak , Wang Rui , Pareja Fresia , Ratzon Fanni , Iasonos Alexia , Patil Sujata , Rosen Neal , Fornier Monica N. , Sklarin Nancy T. , Chandarlapaty Sarat , Modi Shanu
Published: April 2023

AbstractPurpose:
Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.
Patients and Methods:
This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies.
Results:
Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways.
Conclusions:
Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.
Data from The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model
Authors: Gordon Max J. , Kaempf Andy , Sitlinger Andrea , Shouse Geoffrey , Mei Matthew , Brander Danielle M. , Salous Tareq , Hill Brian T. , Alqahtani Hamood , Choi Michael , Churnetski Michael C. , Cohen Jonathon B. , Stephens Deborah M. , Siddiqi Tanya , Rivera Xavier , Persky Daniel , Wisniewski Paul , Patel Krish , Shadman Mazyar , Park Byung , Danilov Alexey V.
Published: April 2023

AbstractPurpose:
Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.
Experimental Design:
We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset.
Results:
The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets.
Conclusions:
The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
Data from Regulation of OATP1B1 Function by Tyrosine Kinase–mediated Phosphorylation
Authors: Hayden Elizabeth R. , Chen Mingqing , Pasquariello Kyle Z. , Gibson Alice A. , Petti James J. , Shen Shichen , Qu Jun , Ong Su Sien , Chen Taosheng , Jin Yan , Uddin Muhammad Erfan , Huang Kevin M. , Paz Aviv , Sparreboom Alex , Hu Shuiying , Sprowl Jason A.
Published: April 2023

AbstractPurpose:
OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug–drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI).
Experimental Design:
OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS–based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases.
Results:
Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations.
Conclusions:
A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.
Data from Spatial Mapping and Immunomodulatory Role of the OX40/OX40L Pathway in Human Non–Small Cell Lung Cancer
Authors: Porciuncula Angelo , Morgado Micaela , Gupta Richa , Syrigos Kostas , Meehan Robert , Zacharek Sima J. , Frederick Joshua P. , Schalper Kurt A.
Published: April 2023

AbstractPurpose:
To evaluate the tissue distribution and clinical significance of OX40 and OX40L in human non–small cell lung cancer (NSCLC).
Experimental Design:
Using multiplexed quantitative immunofluorescence, we conducted simultaneous and localized measurements of OX40 and OX40L proteins, major T-cell subsets, and conventional type 1 dendritic cells (cDC1) in 614 primary NSCLCs from three independent cohorts represented in tissue microarrays. We also measured OX40L protein in samples from a phase I clinical trial of intratumor administration of a lipid nanoparticle encapsulated mRNA encoding OX40L (mRNA-2416) in human solid tumors. Finally, we studied the OX40 pathway in 212 uterine/ovarian serous carcinomas.
Results:
OX40 protein was expressed in approximately 90% of NSCLCs, and OX40L was detected in approximately 10% of cases. Increased expression of OX40 was associated with higher CD4+ and CD8+ T lymphocytes, as well as cDC1s. Elevated expression of OX40L was consistently associated with increased CD4+ tumor-infiltrating lymphocytes and longer overall survival. No association was found between OX40 or OX40L levels and oncogenic driver mutations in EGFR and KRAS in lung adenocarcinomas. Delivering OX40L mRNA using intratumor mRNA-2416 injection mediated increased local OX40L protein levels that was most prominent in a patient with ovarian serous carcinoma. Detectable OX40L protein levels were observed in 15% of primary uterine/ovarian serous malignancies and associated with longer survival.
Conclusions:
The OX40 pathway is expressed in a fraction of NSCLCs and is associated with a favorable immune contexture. Although OX40L is uncommonly expressed in NSCLC and serous malignancies, it is associated with better prognosis and can be introduced using exogenous mRNA.
Data from Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer
Authors: Parikh Aparna R. , Van Seventer Emily E. , Siravegna Giulia , Hartwig Anna V. , Jaimovich Ariel , He Yupeng , Kanter Katie , Fish Madeleine G. , Fosbenner Kathryn D. , Miao Benchun , Phillips Susannah , Carmichael John H. , Sharma Nihaarika , Jarnagin Joy , Baiev Islam , Shah Yojan S. , Fetter Isobel J. , Shahzade Heather A. , Allen Jill N. , Blaszkowsky Lawrence S. , Clark Jeffrey W. , Dubois Jon S. , Franses Joseph W. , Giantonio Bruce J. , Goyal Lipika , Klempner Samuel J. , Nipp Ryan D. , Roeland Eric J. , Ryan David P. , Weekes Colin D. , Wo Jennifer Y. , Hong Theodore S. , Bordeianou Liliana , Ferrone Cristina R. , Qadan Motaz , Kunitake Hiroko , Berger David , Ricciardi Rocco , Cusack James C. , Raymond Victoria M. , Talasaz AmirAli , Boland Genevieve M. , Corcoran Ryan B.
Published: April 2023

AbstractPurpose:
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
Experimental Design:
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Results:
Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In “landmark” plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%–36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%].
Conclusions:
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.

See related commentary by Bent and Kopetz, p. 5449
Data from Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non–Small Cell Lung Cancer
Authors: Luo Jia , Martucci Victoria L. , Quandt Zoe , Groha Stefan , Murray Megan H. , Lovly Christine M. , Rizvi Hira , Egger Jacklynn V. , Plodkowski Andrew J. , Abu-Akeel Mohsen , Schulze Isabell , Merghoub Taha , Cardenas Eduardo , Huntsman Scott , Li Min , Hu Donglei , Gubens Matthew A. , Gusev Alexander , Aldrich Melinda C. , Hellmann Matthew D. , Ziv Elad
Published: April 2023

AbstractPurpose:
Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE).
Experimental Design:
In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI.
Results:
Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52–0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08–1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit.
Conclusions:
Thyroid irAEs were associated with response to anti–PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
Data from Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma
Authors: Ewing Ailith , Meynert Alison , Churchman Michael , Grimes Graeme R. , Hollis Robert L. , Herrington C. Simon , Rye Tzyvia , Bartos Clare , Croy Ian , Ferguson Michelle , Lennie Mairi , McGoldrick Trevor , McPhail Neil , Siddiqui Nadeem , Dowson Suzanne , Glasspool Rosalind , Mackean Melanie , Nussey Fiona , McDade Brian , Ennis Darren , McMahon Lynn , Matakidou Athena , Dougherty Brian , March Ruth , Barrett J. Carl , McNeish Iain A. , Biankin Andrew V. , Roxburgh Patricia , Gourley Charlie , Semple Colin A.
Published: April 2023

AbstractPurpose:
The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated.
Experimental Design:
Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2.
Results:
In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types.
Conclusions:
These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.
Data from FDA Approval Summary: Pralsetinib for the Treatment of Lung and Thyroid Cancers With RET Gene Mutations or Fusions
Authors: Kim Janice , Bradford Diana , Larkins Erin , Pai-Scherf Lee H. , Chatterjee Somak , Mishra-Kalyani Pallavi S. , Wearne Emily , Helms Whitney S. , Ayyoub Amal , Bi Youwei , Sun Jielin , Charlab Rosane , Liu Jiang , Zhao Hong , Liang Dun , Ghosh Soma , Philip Reena , Pazdur Richard , Theoret Marc R. , Beaver Julia A. , Singh Harpreet
Published: April 2023

Abstract
The FDA granted accelerated approval for pralsetinib on September 4, 2020 for non–small cell lung cancer (NSCLC) and December 1, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion–positive NSCLC, (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was based on the results of a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385), demonstrating substantial overall response rates (ORR) and durable responses in patients with RET-altered tumors. ORRs within the approved patient populations ranged from 57% [95% confidence interval (CI), 46–68] in patients with RET fusion–positive NSCLC previously treated with platinum chemotherapy to 89% (95% CI, 52–100) in patients with RET fusion–positive thyroid cancer, with response duration of at least 6 months in most responders. The product label includes warnings and precautions for pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity. This article summarizes the major considerations during FDA review leading to the approval of pralsetinib.
Data from Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)
Authors: Roussos Torres Evanthia T. , Rafie Christine , Wang Chenguang , Lim David , Brufsky Adam , LoRusso Patricia , Eder Joseph Paul , Chung Vincent , Downs Melinda , Geare Molly , Piekarz Richard , Streicher Howard , Anforth Leslie , Rudek Michelle A. , Zhu Qingfeng , Besharati Sepideh , Cimino-Mathews Ashley , Anders Robert A. , Stearns Vered , Jaffee Elizabeth M. , Connolly Roisin M.
Published: April 2023

AbstractPurpose:
Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector:FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors.
Patients and Methods:
Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design [dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy.
Results:
Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone.
Conclusions:
The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.