bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
Authors: Wu Jing , Yuan Ying , Long Priel Debra A. , Fink Danielle , Peer Cody J. , Sissung Tristan M. , Su Yu-Ting , Pang Ying , Yu Guangyang , Butler Madison K. , Mendoza Tito R. , Vera Elizabeth , Ahmad Salman , Bryla Christine , Lindsley Matthew , Grajkowska Ewa , Mentges Kelly , Boris Lisa , Antony Ramya , Garren Nancy , Siegel Christine , Lollo Nicole , Cordova Christine , Aboud Orwa , Theeler Brett J. , Burton Eric M. , Penas-Prado Marta , Leeper Heather , Gonzales Javier , Armstrong Terri S. , Calvo Katherine R. , Figg William D. , Kuhns Douglas B. , Gallin John I. , Gilbert Mark R.
Published: April 2023

AbstractPurpose:
To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.
Patients and Methods:
This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.
Results:
Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.
Conclusions:
Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
Data from Bone Marrow Surveillance of Pediatric Cancer Survivors Identifies Clones that Predict Therapy-Related Leukemia
Authors: Spitzer Barbara , Rutherford Kayleigh D. , Gundem Gunes , McGovern Erin M. , Millard Nathan E. , Arango Ossa Juan E. , Cheung Irene Y. , Gao Teng , Levine Max F. , Zhang Yanming , Medina-Martínez Juan S. , Feng Yi , Ptashkin Ryan N. , Bolton Kelly L. , Farnoud Noushin , Zhou Yangyu , Patel Minal A. , Asimomitis Georgios , Cobbs Cassidy C. , Mohibullah Neeman , Huberman Kety H. , Arcilla Maria E. , Kushner Brian H. , Modak Shakeel , Kung Andrew L. , Zehir Ahmet , Levine Ross L. , Armstrong Scott A. , Cheung Nai Kong V. , Papaemmanuil Elli
Published: April 2023

AbstractPurpose:
Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children.
Experimental Design:
We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor.
Results:
We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3–32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes.
Conclusions:
These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.
Data from Circulating Protein Biomarkers for Use in Pancreatic Ductal Adenocarcinoma Identification
Authors: Lindgaard Sidsel C. , Sztupinszki Zsófia , Maag Emil , Chen Inna M. , Johansen Astrid Z. , Jensen Benny V. , Bojesen Stig E. , Nielsen Dorte L. , Hansen Carsten P. , Hasselby Jane P. , Nielsen Kaspar R. , Szallasi Zoltan , Johansen Julia S.
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals.
Experimental Design:
We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I–IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models.
Results:
Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89–0.96] in the discovery cohort and 0.92 (95% CI, 0.87–0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95–0.98) in the discovery cohort and 0.93 (95% CI, 0.90–0.96) in the replication cohort. All nine serum proteins of index I were found in index II.
Conclusions:
This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.
Data from KRASG12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma
Authors: Jones Gregory D. , Caso Raul , Tan Kay See , Mastrogiacomo Brooke , Sanchez-Vega Francisco , Liu Yuan , Connolly James G. , Murciano-Goroff Yonina R. , Bott Matthew J. , Adusumilli Prasad S. , Molena Daniela , Rocco Gaetano , Rusch Valerie W. , Sihag Smita , Misale Sandra , Yaeger Rona , Drilon Alexander , Arbour Kathryn C. , Riely Gregory J. , Rosen Neal , Lito Piro , Zhang Haiying , Lyden David C. , Rudin Charles M. , Jones David R. , Li Bob T. , Isbell James M.
Published: April 2023

AbstractPurpose:
KRASG12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant lung adenocarcinoma.
Experimental Design:
Patients who underwent resection of stage I–III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed.
Results:
In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank P = 0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3–10.8) vs. 6.1 (3.5–9.7); P = 0.021], compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort.
Conclusions:
KRASG12C mutations are associated with worse DFS after complete resection of stage I–III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.
Data from Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Authors: Wei Shiyou , Yin Delong , Yu Shengnan , Lin Xiang , Savani Milan R. , Du Kuang , Ku Yin , Wu Di , Li Shasha , Liu Hao , Tian Meng , Chen Yaohui , Bowie Michelle , Hariharan Seethalakshmi , Waitkus Matthew , Keir Stephen T. , Sugarman Eric T. , Deek Rebecca A. , Labrie Marilyne , Khasraw Mustafa , Lu Yiling , Mills Gordon B. , Herlyn Meenhard , Wu Kongming , Liu Lunxu , Wei Zhi , Flaherty Keith T. , Abdullah Kalil , Zhang Gao , Ashley David M.
Published: April 2023

AbstractPurpose:
To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas.
Experimental Design:
A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line–derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.
Results:
Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response.
Conclusions:
These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
Data from Virus-positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers
Authors: Harms Kelly L. , Zhao Lili , Johnson Bryan , Wang Xiaoming , Carskadon Shannon , Palanisamy Nallasivam , Rhodes Daniel R. , Mannan Rahul , Vo Josh N. , Choi Jae Eun , Chan May P. , Fullen Douglas R. , Patel Rajiv M. , Siddiqui Javed , Ma Vincent T. , Hrycaj Steven , McLean Scott A. , Hughes Tasha M. , Bichakjian Christopher K. , Tomlins Scott A. , Harms Paul W.
Published: April 2023

AbstractPurpose:
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage.
Experimental Design:
We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC.
Results:
A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C.
Conclusions:
MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.
Data from Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody
Authors: Harding James J. , Moreno Victor , Bang Yung-Jue , Hong Min Hee , Patnaik Amita , Trigo José , Szpurka Anna M. , Yamamoto Noboru , Doi Toshihiko , Fu Siqing , Calderon Boris , Velez de Mendizabal Nieves , Calvo Emiliano , Yu Danni , Gandhi Leena , Liu Zhuqing Tina , Galvao Violeta Regnier , Leow Ching Ching , de Miguel Maria J.
Published: April 2023

AbstractPurpose:
T-cell immunoglobulin and mucin-domain–containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.
Patients and Methods:
This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.
Results:
No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%–70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non–small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.
Conclusions:
LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
Data from Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor
Authors: García-Sáenz José Á. , Martínez-Jáñez Noelia , Cubedo Ricardo , Jerez Yolanda , Lahuerta Ainhara , González-Santiago Santiago , Ferrer Nieves , Ramos Manuel , Alonso-Romero Jose L. , Antón Antonio , Carrasco Eva , Chen Jingjing , Neuwirth Rachel , Galinsky Kevin , Vincent Sylvie , Leonard E. Jane , Slamon Dennis
Published: April 2023

AbstractPurpose:
This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant.
Patients and Methods:
Postmenopausal women with estrogen receptor–positive (ER+)/HER2-negative (HER2−) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion.
Results:
Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47–1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53–1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively).
Conclusions:
Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2− advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.
Data from Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer
Authors: Börcsök Judit , Sztupinszki Zsofia , Bekele Raie , Gao Sizhi P. , Diossy Miklos , Samant Amruta S. , Dillon Kasia M. , Tisza Viktoria , Spisák Sándor , Rusz Orsolya , Csabai Istvan , Pappot Helle , Frazier Zoë J. , Konieczkowski David J. , Liu David , Vasani Naresh , Rodrigues James A. , Solit David B. , Hoffman-Censits Jean H. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Lazaro Jean-Bernard , Taplin Mary-Ellen , Iyer Gopa , Brunak Søren , Lozsa Rita , Van Allen Eliezer M. , Szüts Dávid , Mouw Kent W. , Szallasi Zoltan
Published: April 2023

AbstractPurpose:
Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases.
Experimental Design:
We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity.
Results:
We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models.
Conclusions:
Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.

See related commentary by Jiang and Greenberg, p. 1833
Data from Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer
Authors: Grossman Joseph E. , Muthuswamy Lakshmi , Huang Ling , Akshinthala Dipikaa , Perea Sofia , Gonzalez Raul S. , Tsai Leo L. , Cohen Jonah , Bockorny Bruno , Bullock Andrea J. , Schlechter Benjamin , Peters Mary Linton B. , Conahan Catherine , Narasimhan Supraja , Lim Christine , Davis Roger B. , Besaw Robert , Sawhney Mandeep S. , Pleskow Douglas , Berzin Tyler M. , Smith Martin , Kent Tara S. , Callery Mark , Muthuswamy Senthil K. , Hidalgo Manuel
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes.
Experimental Design:
PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes.
Results:
A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients.
Conclusions:
These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC.
Data from A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non–Small Cell Lung Cancer: a Multicenter Phase I/II Study
Authors: Zhou Qing , Wu Lin , Hu Pei , An Tongtong , Zhou Jianying , Zhang Li , Liu Xiao-Qing , Luo Feng , Zheng Xin , Cheng Ying , Yang Nong , Li Junling , Feng Jifeng , Han Baohui , Song Yong , Wang Kai , Fang Jian , Zhao Hong , Shu Yongqian , Lin Xiao-Yan , Chen Zhihong , Gan Bin , Xu Wan-Hong , Tang Wei , Zhang Xiaoying , Yang Jin-Ji , Xu Xiao , Wu Yi-Long
Published: April 2023

AbstractPurpose:
To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non–small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II.
Patients and Methods:
This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II.
Results:
The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43–129). Among 209 response–evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2–59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9–92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1–9.2) and 7.5 months (95% CI: 6.0–8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4–not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related.
Conclusions:
Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.
Data from FOXM1 Variant Contributes to Gefitinib Resistance via Activating Wnt/β-Catenin Signal Pathway in Patients with Non–Small Cell Lung Cancer
Authors: Guan Shaoxing , Chen Xi , Chen Youhao , Xie Wen , Liang Heng , Zhu Xia , Yang Yunpeng , Fang Wenfeng , Huang Yan , Zhao Hongyun , Zhuang Wei , Liu Shu , Huang Min , Wang Xueding , Zhang Li
Published: April 2023

AbstractPurpose:
Although gefitinib prolonged the progression-free survival (PFS) of patients with non–small cell lung cancer (NSCLC), unpredictable resistance limited its clinical efficacy. Novel predictive biomarkers with explicit mechanisms are urgently needed.
Experimental Design:
A total of 282 patients with NSCLC with gefitinib treatment were randomly assigned in a 7:3 ratio to exploratory (n = 192) and validation (n = 90) cohorts. The candidate polymorphisms were selected with Haploview4.2 in Hapmap and genotyped by a MassARRAY system, and the feature variables were identified through Randomforest Survival analysis. Tanswell and clonogenic assays, base editing and cell-derived tumor xenograft model were performed to uncover the underlying mechanism.
Results:
We found that the germline missense polymorphism rs3742076 (A>G, S628P), located in transactivation domain of FOXM1, was associated with PFS in exploratory (median PFS: GG vs. GA&AA, 9.20 vs. 13.37 months, P = 0.00039, HR = 2.399) and validation (median PFS: GG vs. GA&AA, 8.13 vs. 13.80 months, P = 0.048, HR = 2.628) cohorts. We elucidated that rs3742076_G conferred resistance to gefitinib by increasing protein stability of FOXM1 and facilitating an aggressive phenotype in vitro and in vivo through activating wnt/β-catenin signaling pathway. Meanwhile, FOXM1 level was highly associated with prognosis in patients with EGFR-mutant NSCLC. Mechanistically, FOXM1 rs3742076_G upregulated wnt/β-catenin activity by directly binding to β-catenin in cytoplasm and promoting transcription of β-catenin in nucleus. Remarkably, inhibition of β-catenin markedly reversed rs3742076_G-induced gefitinib resistance and aggressive phenotypes.
Conclusions:
These findings characterized rs3742076_G as a gain-of-function polymorphism in mediating gefitinib resistance and tumor aggressiveness, and highlighted the variant as a predictive biomarker in guiding gefitinib treatment.
Data from Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations
Authors: Shi Qiong , Liu Lin , Chen Jianru , Zhang Weigang , Guo Weinan , Wang Xiao , Wang Huina , Guo Sen , Yue Qiao , Ma Jingjing , Liu Yu , Zhu Guannan , Zhao Tao , Zhao Jianhong , Liu Ying , Gao Tianwen , Li Chunying
Published: April 2023

AbstractPurpose:
Acral melanoma is the major subtype of melanoma seen in Asian patients with melanoma and is featured by its insidious onset and poor prognosis. The genomic study that elucidates driving mutational events is fundamental to the development of gene-targeted therapy. However, research on genomic profiles of acral melanoma in Asian patients is still sparse.
Experimental Design:
We carried out whole-exome sequencing (WES) on 60 acral melanoma lesions (with 55 primary samples involved), targeted deep sequencing in a validation cohort of 48 cases, RNA sequencing in 37 acral melanoma samples (all from the 60 undergoing WES), and FISH in 233 acral melanoma specimens (54 of the 60 undergoing WES included). All the specimens were derived from Asian populations.
Results:
BRAF, NRAS, and KIT were discerned as significantly mutated genes (SMG) in acral melanoma. The detected COSMIC signature 3 related to DNA damage repair, along with the high genomic instability score, implied corresponding pathogenesis of acral melanoma. Moreover, the copy number gains of EP300 were associated with the response of acral melanoma to targeted therapy of A485 (a p300 inhibitor) and immune checkpoint blockade treatment. In addition, the temporal order in mutational processes of the samples was reconstructed, and copy-number alterations were identified as early mutational events.
Conclusions:
Our study provided a detailed view of genomic instability, potential therapeutic targets, and intratumoral heterogeneity of acral melanoma, which might fuel the development of personalized strategies for treating acral melanoma in Asian populations.
Data from Membrane-Anchored and Tumor-Targeted IL12 (attIL12)-PBMC Therapy for Osteosarcoma
Authors: Yang Qing , Hu Jiemiao , Jia Zhiliang , Wang Qi , Wang Jing , Dao Long Hoang , Zhang Wendong , Zhang Sheng , Xia Xueqing , Gorlick Richard , Li Shulin
Published: April 2023

AbstractPurpose:
Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.
Experimental Design:
We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.
Results:
This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. Mechanistically, attIL12-PBMC treatment resulted in tumor-restricted antitumor cytokine release and accumulation of attIL12-PBMCs in tumors. It also induced terminal differentiation of osteosarcoma cells into bone-like cells to impede tumor growth.
Conclusions:
In summary, attIL12-PBMC therapy is safe and effective against osteosarcoma. Our goal is to move this treatment into a clinical trial. Owing to the convenience of the attIL12-PBMC production process, we believe it will be feasible.
Data from Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia
Authors: Yu Ming , Moinova Helen R. , Willbanks Amber , Cannon Victoria K. , Wang Ting , Carter Kelly , Kaz Andrew , Reddi Deepti , Inadomi John , Luebeck Georg , Iyer Prasad G. , Canto Marcia I. , Wang Jean S. , Shaheen Nicholas J. , Thota Prashanti N. , Willis Joseph E. , LaFramboise Thomas , Chak Amitabh , Markowitz Sanford D. , Grady William M.
Published: April 2023

AbstractPurpose:
Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE).
Experimental Design:
DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples.
Results:
Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples.
Conclusions:
A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.
Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
Authors: Vougiouklakis Theodore , Zhu Kelsey , Vasudevaraja Varshini , Serrano Jonathan , Shen Guomiao , Linn Rebecca L. , Feng Xiaojun , Chiang Sarah , Barroeta Julieta E. , Thomas Kristen M. , Schwartz Lauren E. , Shukla Pratibha S. , Malpica Anais , Oliva Esther , Cotzia Paolo , DeLair Deborah F. , Snuderl Matija , Jour George
Published: April 2023

AbstractPurpose:
Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers.
Experimental Design:
Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites.
Results:
We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors.
Conclusions:
This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
Data from Phase II Study of Ramucirumab in Advanced Biliary Tract Cancer Previously Treated By Gemcitabine-Based Chemotherapy
Authors: Lee Sunyoung , Shroff Rachna T. , Makawita Shalini , Xiao Lianchun , Danner De Armas Anaemy , Bhosale Priya , Reddy Kavitha , Shalaby Ahmed , Raghav Kanwal , Pant Shubham , Wolff Robert A. , Javle Milind
Published: April 2023

AbstractPurpose:
VEGF receptor-2 (VEGFR-2)–mediated angiogenesis contributes to pathogenesis of biliary tract cancers (BTC). We investigated ramucirumab, a mAb targeting VEGFR-2 for treatment of advanced, chemorefractory BTC.
Patients and Methods:
This is a phase II, single-arm trial for advanced, unresectable, pre-treated patients with BTC with ECOG 0/1, adequate liver, renal, and marrow functions. Ramucirumab was administered at 8 mg/kg, 2 weekly with restaging performed 8 weekly. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Exploratory endpoints included correlation of tumor mutational status with PFS and OS.
Results:
61 patients were enrolled: the median age was 58.5 years; 59 with stage IV disease; 62%, intrahepatic cholangiocarcinoma; 22%, gallbladder cancer; and 16%, extrahepatic cholangiocarcinoma. All received prior chemotherapy: 52% had 1 prior, and rest ≥2 prior lines. Median treatment duration was 10.1 weeks (range, 2.1–86). Median PFS was 3.2 months [95% confidence interval (CI), 2.1–4.8]; median OS, 9.5 months (95% CI, 5.8–13.6). One (1.7%) patient achieved partial response; 26 (43.3%), stable disease; and 25 (41.7%), disease progression; DCR, 45%. Median 6-month PFS and OS rates were 32% (95% CI, 0.22–0.46) and 58% (95% CI, 0.47–0.72). The majority of toxicities were grade 1 or 2; grade 3 proteinuria (1, 2%), hypertension (13, 22%), and pulmonary embolism (1, 2%), and grade 4 gastrointestinal bleeding (1, 2%) occurred.
Conclusions:
Ramucirumab was well tolerated and resulted in PFS similar to that achieved with other chemotherapy regimens used historically for chemorefractory BTC.
Data from Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study
Authors: Yin Wenjin , Wang Yaohui , Wu Ziping , Ye Yumei , Zhou Liheng , Xu Shuguang , Lin Yanping , Du Yueyao , Yan Tingting , Yang Fan , Zhang Jie , Liu Qiang , Lu Jinsong
Published: April 2023

AbstractPurpose:
Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy.
Patients and Methods:
The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety.
Results:
Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction <50% or >10 points drop from baseline to before surgery was reported.
Conclusions:
The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.
Data from Vaccination with Designed Neopeptides Induces Intratumoral, Cross-reactive CD4+ T-cell Responses in Glioblastoma
Authors: Wang Jian , Weiss Tobias , Neidert Marian C. , Toussaint Nora C. , Naghavian Reza , Sellés Moreno Carla , Foege Magdalena , Tomas Ojer Paula , Medici Gioele , Jelcic Ivan , Schulz Daniel , Rushing Elisabeth , Dettwiler Susanne , Schrörs Barbara , Shin Joo Heon , McKay Ron , Wu Catherine J. , Lutterotti Andreas , Sospedra Mireia , Moch Holger , Greiner Erich F. , Bodenmiller Bernd , Regli Luca , Weller Michael , Roth Patrick , Martin Roland
Published: April 2023

AbstractPurpose:
The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity.
Experimental Design:
Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T-cell receptor (TCR) contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TIL) were characterized in detail both at the bulk and clonal level.
Results:
The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100%, respectively, of the vaccine peptides. Furthermore, TIL-derived CD4+ T-cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor.
Conclusions:
Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T-cell responses in a cold tumor like glioblastoma.
Data from Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus–Driven Cancers
Authors: Ghosh Soma , Mazumdar Tuhina , Xu Wei , Powell Reid T. , Stephan Clifford , Shen Li , Shah Pooja A. , Pickering Curtis R. , Myers Jeffery N. , Wang Jing , Frederick Mitchell J. , Johnson Faye M.
Published: April 2023

AbstractPurpose:
Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers.
Experimental Design:
We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression.
Results:
Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition–induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells’ sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition–induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells.
Conclusions:
Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.
Data from Hepatocellular Carcinoma in Mongolia Delineates Unique Molecular Traits and a Mutational Signature Associated with Environmental Agents
Authors: Torrens Laura , Puigvehí Marc , Torres-Martín Miguel , Wang Huan , Maeda Miho , Haber Philipp K. , Leonel Thais , García-López Mireia , Esteban-Fabró Roger , Leow Wei Qiang , Montironi Carla , Torrecilla Sara , Varadarajan Ajay Ramakrishnan , Taik Patricia , Campreciós Genís , Enkhbold Chinbold , Taivanbaatar Erdenebileg , Yerbolat Amankyeldi , Villanueva Augusto , Pérez-del-Pulgar Sofía , Thung Swan , Chinburen Jigjidsuren , Letouzé Eric , Zucman-Rossi Jessica , Uzilov Andrew , Neely Jaclyn , Forns Xavier , Roayaie Sasan , Sia Daniela , Llovet Josep M.
Published: April 2023

AbstractPurpose:
Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated.
Experimental Design:
We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing to unveil distinct genomic and transcriptomic features associated with environmental factors in this population.
Results:
Mongolian patients were younger, with higher female prevalence, and with predominantly HBV–HDV coinfection etiology. Mongolian HCCs presented significantly higher rates of protein-coding mutations (121 vs. 70 mutations per tumor in Western), and in specific driver HCC genes (i.e., APOB and TSC2). Four mutational signatures characterized Mongolian samples, one of which was novel (SBS Mongolia) and present in 25% of Mongolian HCC cases. This signature showed a distinct substitution profile with a high proportion of T>G substitutions and was significantly associated with a signature of exposure to the environmental agent dimethyl sulfate (71%), a 2A carcinogenic associated with coal combustion. Transcriptomic-based analysis delineated three molecular clusters, two not present in Western HCC; one with a highly inflamed profile and the other significantly associated with younger female patients.
Conclusions:
Mongolian HCC has unique molecular traits with a high mutational burden and a novel mutational signature associated with genotoxic environmental factors present in this country.