bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Safety, Efficacy, and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03
Authors: Sheng Xinan , Chen Haige , Hu Bin , Yao Xudong , Liu Ziling , Yao Xin , Guo Hongqian , Hu Yi , Ji Zhigang , Luo Hong , Shi Benkang , Liu Jiyan , Wu Jin , Zhou FangJian , He Zhisong , Fan Jinhai , Wang Weifeng , Feng Hui , Yao Sheng , Keegan Patricia , Huang Yiran , Guo Jun
Published: April 2023

AbstractPurpose:
Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC.
Patients and Methods:
Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated.
Results:
Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1− patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P < 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group.
Conclusions:
Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.
Data from Whole-exome Sequencing in Penile Squamous Cell Carcinoma Uncovers Novel Prognostic Categorization and Drug Targets Similar to Head and Neck Squamous Cell Carcinoma
Authors: Chahoud Jad , Gleber-Netto Frederico O. , McCormick Barrett Z. , Rao Priya , Lu Xin , Guo Ming , Morgan Maggaret B. , Chu Randy A. , Martinez-Ferrer Magaly , Eterovic Agda Karina , Pickering Curtis R. , Pettaway Curtis A.
Published: April 2023

AbstractPurpose:
Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets.
Experimental Design:
PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC-enriched mutational patterns based on their association with the Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies.
Results:
We identified that most PSCC samples showed enrichment for Notch pathway (n = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased tumor mutation burden (TMB; CC, 0.71; P < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13–92.9); P = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC–enriched subset [HR, 2.41 (1.11–6.77); P = 0.042].
Conclusions:
This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications.

See related commentary by McGregor and Sonpavde, p. 2375
Data from FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with RET Gene Mutations or Fusions
Authors: Bradford Diana , Larkins Erin , Mushti Sirisha L. , Rodriguez Lisa , Skinner Amy M. , Helms Whitney S. , Price Lauren S.L. , Zirkelbach Jeanne Fourie , Li Yangbing , Liu Jiang , Charlab Rosane , Turcu Francisca Reyes , Liang Dun , Ghosh Soma , Roscoe Donna , Philip Reena , Zack-Taylor Autumn , Tang Shenghui , Kluetz Paul G. , Beaver Julia A. , Pazdur Richard , Theoret Marc R. , Singh Harpreet
Published: April 2023

Abstract
On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic RET fusion–positive non–small cell lung cancer (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 granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had RET alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54–73] in prior platinum-treated RET fusion–positive NSCLC to 100% (95% CI, 63–100) in systemic therapy–naïve RET fusion–positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months. The product label includes warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. This is the first approval of a drug specifically for patients with RET alterations globally.
Data from Impact of Broadening Trial Eligibility Criteria for Patients with Advanced Non–Small Cell Lung Cancer: Real-World Analysis of Select ASCO-Friends Recommendations
Authors: Harvey R. Donald , Bruinooge Suanna S. , Chen Li , Garrett-Mayer Elizabeth , Rhodes Whitney , Stepanski Edward , Uldrick Thomas S. , Ison Gwynn , Khozin Sean , Rubinstein Wendy S. , Schenkel Caroline , Miller Robert S. , Komatsoulis George A. , Schilsky Richard L. , Kim Edward S.
Published: April 2023

AbstractPurpose:
Cancer clinical trials often accrue slowly or miss enrollment targets. Strict eligibility criteria are a major reason. Restrictive criteria also limit opportunities for patient participation while compromising external validity of trial results. We examined the impact of broadening select eligibility criteria on characteristics and number of patients eligible for trials, using recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research.
Experimental Design:
A retrospective, observational analysis used electronic health record data from ASCO’s CancerLinQ Discovery database. Study cohort included patients with advanced non–small cell lung cancer treated from 2011 to 2018. Patients were grouped by traditional criteria [no brain metastases, no other malignancies, and creatinine clearance (CrCl) ≥ 60 mL/minute] and broadened criteria (including brain metastases, other malignancies, and CrCl ≥ 30 mL/minute).
Results:
The analysis cohort included 10,500 patients. Median age was 68 years, and 73% of patients were White. Most patients had stage IV disease (65%). A total of 5,005 patients (48%) would be excluded from trial participation using the traditional criteria. The broadened criteria, however, would allow 98% of patients (10,346) to be potential participants. Examination of patients included by traditional criteria (5,495) versus those added (4,851) by broadened criteria showed that the number of women, patients aged 75+ years, and those with stage IV cancer was significantly greater using broadened criteria.
Conclusions:
This analysis of real-world data demonstrated that broadening three common eligibility criteria has the potential to double the eligible patient population and include trial participants who are more representative of those encountered in practice.

See related commentary by Giantonio, p. 2369
Data from Anlotinib Induces a T Cell–Inflamed Tumor Microenvironment by Facilitating Vessel Normalization and Enhances the Efficacy of PD-1 Checkpoint Blockade in Neuroblastoma
Authors: Su Yudong , Luo Bingying , Lu Yao , Wang Daowei , Yan Jie , Zheng Jian , Xiao Jun , Wang Yangyang , Xue Zhenyi , Yin Jie , Chen Peng , Li Long , Zhao Qiang
Published: April 2023

AbstractPurpose:
Anlotinib has achieved good results in clinical trials of a variety of cancers. However, the effects of anlotinib on the tumor microenvironment (TME) and systemic immunity have not been reported. There is an urgent need to identify the underlying mechanism to reveal new opportunities for its application in neuroblastoma (NB) and other cancers. Understanding the mechanism will hopefully achieve the goal of using the same method to treat different cancers.
Experimental Design:
This study used bioinformatics, NB syngeneic mouse models, flow cytometry, RNA-seq, and immunofluorescence staining to explore the mechanisms of anlotinib on the TME, and further explored anlotinib-containing combination treatment strategies.
Results:
We proved that anlotinib facilitates tumor vessel normalization at least partially through CD4+ T cells, reprograms the immunosuppressive TME into an immunostimulatory TME, significantly inhibits tumor growth, and effectively prevents systemic immunosuppression. Moreover, the combination of anlotinib with a PD-1 checkpoint inhibitor counteracts the immunosuppression caused by the upregulation of PD-L1 after monotherapy, extends the period of vascular normalization, and finally induces NB regression.
Conclusions:
To our knowledge, this study is the first to dynamically evaluate the effect of a multitarget antiangiogenic tyrosine kinase inhibitor on the TME. These findings have very important clinical value in guiding the testing of related drugs in NB and other cancers. Based on these findings, we are conducting a phase II clinical study (NCT04842526) on the efficacy and safety of anlotinib, irinotecan, and temozolomide in the treatment of refractory or relapsed NB, and hopefully we will observe patient benefit.
Data from Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program
Authors: Bychkovsky Brittany L. , Li Tianyu , Sotelo Jilliane , Tayob Nabihah , Mercado Joanna , Gomy Israel , Chittenden Anu , Kane Sarah , Stokes Samantha , Hughes Melissa E. , Kim Ji Seok , Umeton Renato , Awad Mark M. , Konstantinopoulos Panagiotis A. , Yurgelun Matthew B. , Wolpin Brian M. , Taplin Mary-Ellen , Newmark Randall E. , Johnson Bruce E. , Lindeman Neal I. , MacConaill Laura E. , Garber Judy E. , Lin Nancy U.
Published: April 2023

AbstractPurpose:
Tumor-only genomic testing can uncover somatic and germline pathogenic variants [pathogenic/likely pathogenic (P/LP)] in cancer predisposition genes. We describe the prevalence of P/LPs in BRCA1/2 and PALB2 (B1B2P2) across malignancies and the frequency of clinical germline testing (CGT) in patients with P/LPs in B1B2P2 identified on tumor-only testing.
Experimental Design:
Among 7,575 patients with cancer tested between 2016 and 2018 with the OncoPanel tumor-only sequencing assay, we characterized P/LP frequencies by tumor type, receipt of CGT prior to or within 12 months after OncoPanel, and factors associated with CGT.
Results:
272 (3.6%) patients had OncoPanel-detected P/LPs in B1B2P2: 37.5% of P/LPs were in BRCA-related cancers; the remainder were in non-BRCA tumors. P/LPs were detected in ≥5% of breast, pancreatic, prostate, ovarian, nonmelanoma skin, endometrial, small cell lung, and colorectal cancers. 37.9% of patients with P/LPs received CGT prior to OncoPanel; an additional 10.7% underwent CGT within 12 months of OncoPanel. Among 132 with CGT, 88.6% had ≥1 clinical factor for CGT compared with 47.1% who did not undergo CGT. Patients with BRCA tumors were more likely to have CGT compared with those without (81.4% vs. 29.0%, P < 0.0001). Among patients with CGT, 70.5% (93/132) of P/LPs were germline.
Conclusions:
Tumor-only genomic testing identified P/LPs in B1B2P2 in 3.6% of patients. 52.9% of patients with tumor-detected P/LPs and without CGT did not meet personal or family history criteria for CGT. In addition, some patients with tumor-detected P/LPs were not referred for CGT, especially those with non-BRCA tumors. Given implications for treatment selection and familial cancer risk, processes to reliably trigger CGT from tumor-genomic findings are needed.
Data from Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy
Authors: Guix Ines , Liu Qi , Pujana Miquel Angel , Ha Patrick , Piulats Josep , Linares Isabel , Guedea Ferran , Mao Jian-Hua , Lazar Ann , Chapman Jocelyn , Yom Sue S. , Ashworth Alan , Barcellos-Hoff Mary Helen
Published: April 2023

AbstractPurpose:
Loss of TGFβ signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFβ and alt-EJ gene expression signatures, which we showed are anticorrelated across cancer types. A score representing anticorrelation, βAlt, predicts patient outcome in response to genotoxic therapy. Here we sought to verify this biology in live specimens and additional datasets.
Experimental Design:
Human head and neck squamous carcinoma (HNSC) explants were treated in vitro to test whether the signatures report TGFβ signaling, indicated by SMAD2 phosphorylation, and unrepaired DNA damage, indicated by persistent 53BP1 foci after irradiation or olaparib. A custom NanoString assay was implemented to analyze the signatures’ expression in explants. Each signature gene was then weighted by its association with functional responses to define a modified score, βAltw, that was retested for association with response to genotoxic therapies in independent datasets.
Results:
Most genes in each signature were positively correlated with the expected biological response in tumor explants. Anticorrelation of TGFβ and alt-EJ signatures measured by NanoString was confirmed in explants. βAltw was significantly (P < 0.001) better than βAlt in predicting overall survival in response to genotoxic therapy in The Cancer Genome Atlas (TCGA) pancancer patients and in independent HNSC and ovarian cancer patient datasets.
Conclusions:
Association of the TGFβ and alt-EJ signatures with their biological response validates TGFβ competency as a key mediator of DNA repair that can be readily assayed by gene expression. The predictive value of βAltw supports its development to assist in clinical decision making.
Data from Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition
Authors: Zhang Pu , Brinton Lindsey T. , Williams Katie , Sher Steven , Orwick Shelley , Tzung-Huei Lai , Mims Alice S. , Coss Christopher C. , Kulp Samuel K. , Youssef Youssef , Chan Wing Keung , Mitchell Shaneice , Mustonen Allison , Cannon Matthew , Phillips Hannah , Lehman Amy M. , Kauffman Tierney , Beaver Larry , Canfield Daniel , Grieselhuber Nicole R. , Alinari Lapo , Sampath Deepa , Yan Pearlly , Byrd John C. , Blachly James S. , Lapalombella Rosa
Published: April 2023

AbstractPurpose:
Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274.
Experimental Design:
Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model.
Results:
We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells.
Conclusions:
Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel–novel combination-based treatment for AML.
Data from A Paradigm of Cancer Immunotherapy Based on 2-[18F]FDG and Anti–PD-L1 mAb Combination to Enhance the Antitumor Effect
Authors: Wen Xuejun , Shi Changrong , Zeng Xinying , Zhao Liang , Yao Lanlin , Liu Zhida , Feng Lixia , Zhang Deliang , Huang Jinxiong , Li Yesen , Lin Qin , Chen Haojun , Zhuang Rongqiang , Chen Xiaoyuan , Zhang Xianzhong , Guo Zhide
Published: April 2023

AbstractPurpose:
Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emission tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy.
Experimental Design:
We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti–PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by Western blot, transcriptomics study, and flow-cytometric analysis.
Results:
PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB was used. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from “cold” to “hot,” to make low immunoactivity tumors sensitive to ICB therapy.
Conclusions:
In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. 2-[18F]FDG-based ICB immunotherapy is highly significant in enhancing antitumor effect. A research of 2-[18F]FDG-based ICB immunotherapy has been proposed to enhance the antitumor effect.
Data from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
Authors: Johnson Melissa , Dudek Arkadiusz Z. , Sukari Ammar , Call Justin , Kunk Paul R. , Lewis Karl , Gainor Justin F. , Sarantopoulos John , Lee Patrice , Golden Adele , Harney Allison , Rothenberg S. Michael , Zhang Yuanyuan , Goldman Jonathan W.
Published: April 2023

AbstractPurpose:
ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors.
Patients and Methods:
This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W.
Results:
Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200–400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382–related adverse events were increased transaminases (10.5%–83.3%) and increased creatine phosphokinase (18.2%–50.0%).
Conclusions:
Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
Data from Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma
Authors: Patel Krina K. , Shah Jatin J. , Feng Lei , Lee Hans C. , Manasanch Elisabet M. , Olsem Jasper , Morphey Ashley , Huo Xiao Jiao , Thomas Sheeba K. , Bashir Qaiser , Qazilbash Muzaffar H. , Weber Donna M. , Orlowski Robert Z.
Published: April 2023

AbstractPurpose:
In this study, the addition of ixazomib to lenalidomide maintenance post-autologous stem cell transplant (ASCT) in 64 patients with newly diagnosed multiple myeloma was evaluated on the basis of the observed benefit of lenalidomide-only maintenance in prior studies.
Patients and Methods:
Patients were started on maintenance therapy with lenalidomide and ixazomib within 60–180 days of stem cell infusion.
Results:
Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 43% and median overall survival was not reached with a median follow-up of 62 months (range, 25–82 months). Median PFS (mPFS) for all patients was 73 months and has not been reached for those with International Staging System (ISS) stage 1 disease. mPFS in 9 patients who had ISS stage 3 disease and 14 patients who had high-risk cytogenetics was 34 and 25 months, respectively. Twenty-two patients had progressive disease, while 19 patients continue to receive dual maintenance. The most common grade 3/4 adverse events included neutropenia, leukopenia, thrombocytopenia, lung infections, diarrhea, and maculopapular rash. Second primary malignancies occurred in 9 patients. Toxicity led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to toxicity occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients.
Conclusions:
The addition of ixazomib to lenalidomide maintenance demonstrated a better than expected PFS compared with historical data using lenalidomide alone and was safe and tolerable.
Data from RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Authors: Hunihan Lisa , Zhao Dejian , Lazowski Heather , Li Man , Qian Yuping , Abriola Laura , Surovtseva Yulia V. , Muthusamy Viswanathan , Tanoue Lynn T. , Rothberg Bonnie E. Gould , Schalper Kurt A. , Herbst Roy S. , Wilson Frederick H.
Published: April 2023

AbstractPurpose:
The identification of actionable oncogenic alterations has enabled targeted therapeutic strategies for subsets of patients with advanced malignancies, including lung adenocarcinoma (LUAD). We sought to assess the frequency of known drivers and identify new candidate drivers in a cohort of LUAD from patients with minimal smoking history.
Experimental Design:
We performed genomic characterization of 103 LUADs from patients with ≤10 pack-year smoking history. Tumors were subjected to targeted molecular profiling and/or whole-exome sequencing and RNA sequencing in search of established and previously uncharacterized candidate drivers.
Results:
We identified an established oncogenic driver in 98 of 103 tumors (95%). From one tumor lacking a known driver, we identified a novel gene rearrangement between OCLN and RASGRF1. The encoded OCLN-RASGRF1 chimera fuses the membrane-spanning portion of the tight junction protein occludin with the catalytic RAS-GEF domain of the RAS activator RASGRF1. We identified a similar SLC4A4-RASGRF1 fusion in a pancreatic ductal adenocarcinoma cell line lacking an activating KRAS mutation and an IQGAP1-RASGRF1 fusion from a sarcoma in The Cancer Genome Atlas. We demonstrate these fusions increase cellular levels of active GTP-RAS, induce cellular transformation, and promote in vivo tumorigenesis. Cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway in vitro and in vivo.
Conclusions:
Our findings credential RASGRF1 fusions as a therapeutic target in multiple malignancies and implicate RAF-MEK-ERK inhibition as a potential treatment strategy for advanced tumors harboring these alterations.

See related commentary by Moorthi and Berger, p. 2983
Data from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Authors: Voss Martin H. , Azad Arun A. , Hansen Aaron R. , Gray Jhanelle E. , Welsh Sarah J. , Song Xuyang , Kuziora Michael , Meinecke Lina , Blando Jorge , Achour Ikbel , Wang Yi , Walcott Farzana L. , Oosting Sjoukje F.
Published: April 2023

AbstractPurpose:
MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy.
Patients and Methods:
Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles.
Results:
Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% [7/42; 95% confidence interval (CI), 7.0–31.4] with combination treatment and 23.8% (5/21; 95% CI, 8.2–47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm.
Conclusions:
MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy.
Data from Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer
Authors: Sowalsky Adam G. , Figueiredo Ines , Lis Rosina T. , Coleman Ilsa , Gurel Bora , Bogdan Denisa , Yuan Wei , Russo Joshua W. , Bright John R. , Whitlock Nichelle C. , Trostel Shana Y. , Ku Anson T. , Patel Radhika A. , True Lawrence D. , Welti Jonathan , Jimenez-Vacas Juan M. , Rodrigues Daniel Nava , Riisnaes Ruth , Neeb Antje , Sprenger Cynthia T. , Swain Amanda , Wilkinson Scott , Karzai Fatima , Dahut William L. , Balk Steven P. , Corey Eva , Nelson Peter S. , Haffner Michael C. , Plymate Stephen R. , de Bono Johann S. , Sharp Adam
Published: April 2023

AbstractPurpose:
Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied.
Experimental Design:
We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome.
Results:
In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy.
Conclusions:
This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study
Authors: Stephens Deborah M. , Huang Ying , Ruppert Amy S. , Walker Janek S. , Canfield Daniel , Cempre Casey B. , Fu Qiang , Baker Sharyn , Hu Boyu , Shah Harsh , Vadeboncoeur Renee , Rogers Kerry A. , Bhat Seema , Jaglowski Samantha M. , Lockman Hank , Lapalombella Rosa , Byrd John C. , Woyach Jennifer A.
Published: April 2023

AbstractPurpose:
Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).
Patients and Methods:
In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.
Results:
Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively.
Conclusions:
The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.
Data from Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models
Authors: Li Fuyang , Bondra Kathryn M. , Ghilu Samson , Studebaker Adam , Liu Qianqian , Michalek Joel E. , Kogiso Mari , Li Xiao-Nan , Kalapurakal John A. , James C. David , Burma Sandeep , Kurmasheva Raushan T. , Houghton Peter J.
Published: April 2023

AbstractPurpose:
We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes.
Experimental Design:
Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized.
Results:
In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell–intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance.
Conclusions:
In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.
Data from Perioperative ctDNA-Based Molecular Residual Disease Detection for Non–Small Cell Lung Cancer: A Prospective Multicenter Cohort Study (LUNGCA-1)
Authors: Xia Liang , Mei Jiandong , Kang Ran , Deng Senyi , Chen Yaohui , Yang Ying , Feng Gang , Deng Yulan , Gan Fanyi , Lin Yidan , Pu Qiang , Ma Lin , Lin Feng , Yuan Yong , Hu Yang , Guo Chenglin , Liao Hu , Liu Chengwu , Zhu Yunke , Wang Wenping , Liu Zheng , Xu Yuyang , Li Kaidi , Li Chuan , Li Qingyun , He Ji , Chen Weizhi , Zhang Xiaolong , Kou Yingli , Wang Yun , Wu Zhu , Che Guowei , Chen Longqi , Liu Lunxu
Published: April 2023

AbstractPurpose:
We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer (NSCLC).
Experimental Design:
Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I–III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis.
Results:
Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P < 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P < 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P < 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283).
Conclusions:
Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.
Data from Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma
Authors: Aragon-Sanabria Virginia , Aditya Anusha , Zhang Li , Chen Feng , Yoo Barney , Cao Tianye , Madajewski Brian , Lee Rachel , Turker Melik Z. , Ma Kai , Monette Sebastien , Chen Peiming , Wu Jing , Ruan Shutian , Overholtzer Michael , Zanzonico Pat , Rudin Charles M. , Brennan Cameron , Wiesner Ulrich , Bradbury Michelle S.
Published: April 2023

AbstractPurpose:
Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C′ dots), for the efficacious treatment of high-grade gliomas.
Experimental Design:
This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C′ dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models.
Results:
Optimal drug-per-particle ratios of as-developed nanoparticle–drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor–driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model.
Conclusions:
Ultrasmall C′ dot–drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
Data from Circulating Tumor DNA Is Associated with Response and Survival in Patients with Advanced Leiomyosarcoma
Authors: Madanat-Harjuoja Laura M. , Klega Kelly , Lu Yao , Shulman David S. , Thorner Aaron R. , Nag Anwesha , Tap William D. , Reinke Denise K. , Diller Lisa , Ballman Karla V. , George Suzanne , Crompton Brian D.
Published: April 2023

AbstractPurpose:
We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival.
Experimental Design:
Using ultra–low-passage whole-genome sequencing (ULP-WGS) of plasma cell-free DNA from patients treated on a prospective clinical trial, we tested whether detection of ctDNA evaluated prior to the start of therapy and after two cycles of chemotherapy was associated with treatment response and outcome. Associations between detection of ctDNA and pathologic measures of disease burden were evaluated.
Results:
We found that ctDNA was detectable by ULP-WGS in 49% patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pretreatment ctDNA was significantly associated with a lower overall survival [HR, 1.55; 95% confidence interval (CI), 1.03–2.31; P = 0.03] and a significantly lower likelihood of objective response [odds ratio (OR), 0.21; 95% CI, 0.06–0.59; P = 0.005]. After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR, 1.77; 95% CI, 1–3.14; P = 0.05) and were unlikely to experience an objective response (OR, 0.05; 95% CI, 0–0.39; P = 0.001).
Conclusions:
Our results demonstrate that detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy.

See related commentary by Kasper and Wilky, p. 2480
Data from Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma
Authors: Sudha Parvathi , Ahsan Aarif , Ashby Cody , Kausar Tasneem , Khera Akhil , Kazeroun Mohammad H. , Hsu Chih-Chao , Wang Lin , Fitzsimons Evelyn , Salminen Outi , Blaney Patrick , Czader Magdalena , Williams Jonathan , Abu Zaid Mohammad I. , Ansari-Pour Naser , Yong Kwee L. , van Rhee Frits , Pierceall William E. , Morgan Gareth J. , Flynt Erin , Gooding Sarah , Abonour Rafat , Ramasamy Karthik , Thakurta Anjan , Walker Brian A.
Published: April 2023

AbstractPurpose:
We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards.
Experimental Design:
The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations).
Results:
Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849.
Conclusions:
In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies.
Data from Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity
Authors: Orr Brian , Mahdi Haider , Fang Yusi , Strange Mary , Uygun Ibrahim , Rana Mainpal , Zhang Lixin , Suarez Mora Adria , Pusateri Alexandra , Elishaev Esther , Kang Chaeryon , Tseng George , Gooding William , Edwards Robert P. , Kalinski Pawel , Vlad Anda M.
Published: April 2023

AbstractPurpose:
Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), whereas the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFNα, and COX-2 blockers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmunotherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC.
Patients and Methods:
Twelve patients were enrolled in phase I portion of the trial NCT02432378, and treated with intraperitoneal cisplatin, intraperitoneal rintatolimod (dsRNA, TLR3 ligand), and oral celecoxib (COX-2 blocker). Patients in cohorts 2, 3, and 4 also received intraperitoneal IFNα at 2, 6, and 18 million units (MU), respectively. Primary objectives were to evaluate safety, identify phase 2 recommended dose (P2RD), and characterize changes in the immune TME. Peritoneal resident cells and intraperitoneal wash fluid were profiled via NanoString and Meso Scale Discovery (MSD) multiplex assay, respectively.
Results:
The P2RD of IFNα was 6 MU. Median progression-free survival and overall survival were 8.4 and 30 months, respectively. Longitudinal sampling of the peritoneal cavity via intraperitoneal washes demonstrated local upregulation of IFN-stimulated genes (ISG), including CTL-attracting chemokines (CXCL-9, -10, -11), MHC I/II, perforin, and granzymes. These changes were present 2 days after chemokine modulation and subsided within 1 week.
Conclusions:
The chemokine-modulating intraperitoneal-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a phase II trial.

See related commentary by Aranda et al., p. 1993