bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Pan-Tumor Landscape of Targetable Kinase Fusions in Circulating Tumor DNA
Authors: Lee Jessica K. , Hazar-Rethinam Mehlika , Decker Brennan , Gjoerup Ole , Madison Russell W. , Lieber Daniel S. , Chung Jon H. , Schrock Alexa B. , Creeden James , Venstrom Jeffrey , Alexander Brian , Oxnard Geoffrey R.
Published: April 2023

AbstractPurpose:
Oncogenic kinase fusions are targetable with approved and investigational therapies and can also mediate acquired resistance (AR) to targeted therapy. We aimed to understand the clinical validity of liquid biopsy comprehensive genomic profiling (CGP) to detect kinase fusions pan tumor.
Experimental Design:
CGP was performed on plasma and tissue samples during clinical care. All exons plus selected introns of 16 kinases involved in oncogenic fusions (ALK, BRAF, EGFR, ERBB2, FGFR1/2/3, MET, NTRK1/2/3, PDGFRA/B, RAF1, RET, and ROS1) were sequenced to capture fusions, including well-characterized and novel breakpoints. Plasma circulating tumor DNA (ctDNA) fraction was estimated to inform sensitivity.
Results:
Of 36,916 plasma cases, 32,492 (88%) had detectable ctDNA. Kinase fusions were detected in 1.8% of ctDNA-positive cases (571/32,492) and were most prevalent in patients with cholangiocarcinoma (4.2%), bladder cancer (3.6%), and non–small cell lung cancer (NSCLC; 3.1%). Of the 63 paired patient samples that had tissue and ctDNA specimens collected within 1 year and with estimated plasma ctDNA fraction >1%, fusions were detected in 47 of 51 (92%) liquid specimens with a fusion in the tissue sample. In 32 patients with fusions detected in liquid but not in tissue, 21 (66%) had evidence of putative acquired resistance.
Conclusions:
Targetable kinase fusions are identified in ctDNA across cancer types. In pairs with tissue-identified fusions, fusion detection in ctDNA is reliable with elevated ctDNA fraction. These data support the validity of CGP to enable ctDNA-based fusion detection for informing clinical care in patients with advanced cancer.
Data from Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: Pang John , Nguyen Nam , Luebeck Jens , Ball Laurel , Finegersh Andrey , Ren Shuling , Nakagawa Takuya , Flagg Mitchell , Sadat Sayed , Mischel Paul S. , Xu Guorong , Fisch Kathleen , Guo Theresa , Cahill Gabrielle , Panuganti Bharat , Bafna Vineet , Califano Joseph
Published: April 2023

AbstractPurpose:
Human papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.
Experimental Design:
Forty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets.
Results:
Our analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human–viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition.
Conclusions:
Nonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.
Data from Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer
Authors: Schmitd Ligia B. , Perez-Pacheco Cindy , Bellile Emily L. , Wu Weisheng , Casper Keith , Mierzwa Michelle , Rozek Laura S. , Wolf Gregory T. , Taylor Jeremy M.G. , D'Silva Nisha J.
Published: April 2023

AbstractPurpose:
Perineural invasion (PNI), a common occurrence in oral squamous cell carcinomas, is associated with poor survival. Consequently, these tumors are treated aggressively. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. To address these knowledge gaps, we investigated spatial and transcriptomic profiles of PNI-positive and PNI-negative nerves.
Experimental Design:
Tissue sections from 142 patients were stained with S100 and cytokeratin antibodies. Nerves were identified in two distinct areas: tumor bulk and margin. Nerve diameter and nerve-to-tumor distance were assessed; survival analyses were performed. Spatial transcriptomic analysis of nerves at varying distances from tumor was performed with NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas.
Results:
PNI is an independent predictor of poor prognosis among patients with metastasis-free lymph nodes. Patients with close nerve-tumor distance have poor outcomes even if diagnosed as PNI negative using current criteria. Patients with large nerve(s) in the tumor bulk survive poorly, suggesting that even PNI-negative nerves facilitate tumor progression. Diagnostic criteria were supported by spatial transcriptomic analyses of >18,000 genes; nerves in proximity to cancer exhibit stress and growth response changes that diminish with increasing nerve-tumor distance. These findings were validated in vitro and in human tissue.
Conclusions:
This is the first study in human cancer with high-throughput gene expression analysis in nerves with striking correlations between transcriptomic profile and clinical outcomes. Our work illuminates nerve-cancer interactions suggesting that cancer-induced injury modulates neuritogenesis, and supports reclassification of PNI based on nerve-tumor distance rather than current subjective criteria.
Data from Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer
Authors: Batalini Felipe , Xiong Niya , Tayob Nabihah , Polak Madeline , Eismann Julia , Cantley Lewis C. , Shapiro Geoffrey I. , Adalsteinsson Viktor , Winer Eric P. , Konstantinopoulos Panagiotis A. , D'Andrea Alan , Swisher Elizabeth M. , Matulonis Ursula A. , Wulf Gerburg M. , Mayer Erica L.
Published: April 2023

AbstractPurpose:
We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here, we report on the breast cancer cohort from that study.
Patients and Methods:
Eligible patients had recurrent triple-negative breast cancer (TNBC) or recurrent breast cancer of any subtype with a germline BRCA mutation and were enrolled to a dose-escalation or -expansion cohort. After definition of the RP2D, secondary end points included safety and objective response rate (ORR). Exploratory analyses were performed using circulating-free DNA (cfDNA).
Results:
Seventeen patients with TNBC were enrolled with a median of three prior lines of chemotherapy. The most common treatment-related grade 3–4 adverse events were hyperglycemia (18%) and rash (12%). The ORR was 18% (23% for patients treated at the RP2D) and 59% had disease control. The median duration of response was 7.4 months. Analysis of cfDNA tumor fractions (TFx) revealed that patients with TFx < 15% after completion of the first cycle had a longer progression-free survival compared with those with TFx ≥ 15% (6.0 vs. 0.9 months; P = 0.0001).
Conclusions:
Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA carriers. cfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3K inhibitor to sensitize HR-proficient (BRCA wild-type) TNBC to PARP inhibition and suggest the potential to expand the use of PARP inhibition beyond BRCA-mutant tumors.
Data from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
Authors: Wagner Michael J. , Zhang Yuzheng , Cranmer Lee D. , Loggers Elizabeth T. , Black Graeme , McDonnell Sabrina , Maxwell Shannon , Johnson Rylee , Moore Roxanne , Hermida de Viveiros Pedro , Aicher Lauri , Smythe Kimberly S. , He Qianchuan , Jones Robin L. , Pollack Seth M.
Published: April 2023

AbstractPurpose:
Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti–PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma.
Patients and Methods:
A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression.
Results:
33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01).
Conclusions:
Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
Data from Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma
Authors: Denize Thomas , Hou Yue , Pignon Jean-Christophe , Walton Emily , West Destiny J. , Freeman Gordon J. , Braun David A. , Wu Catherine J. , Gupta Saurabh , Motzer Robert J. , Atkins Michael B. , McDermott David , Choueiri Toni K. , Shukla Sachet A. , Signoretti Sabina
Published: April 2023

AbstractPurpose:
PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy.
Experimental Design:
RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes.
Results:
In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune- and cell proliferation–related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation–related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13–0.83) and higher objective response rate (30% vs. 0%, P = 0.04) on nivolumab compared with everolimus.
Conclusions:
Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation–related) mechanisms are likely intertwined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC.
Data from Clinical Outcomes and Immune Markers by Race in a Phase I/II Clinical Trial of Durvalumab Concomitant with Neoadjuvant Chemotherapy in Early-Stage TNBC
Authors: Foldi Julia , Kahn Adriana , Silber Andrea , Qing Tao , Reisenbichler Emily , Fischbach Neal , Persico Justin , Adelson Kerin , Katoch Anamika , Chagpar Anees , Park Tristen , Blanchard Adam , Blenman Kim , Rimm David L. , Pusztai Lajos
Published: April 2023

AbstractPurpose:
The incidence of triple-negative breast cancer (TNBC) is higher among Black or African American (AA) women, yet they are underrepresented in clinical trials. To evaluate safety and efficacy of durvalumab concurrent with neoadjuvant chemotherapy for stage I–III TNBC by race, we enrolled additional AA patients to a Phase I/II clinical trial.
Patients and Methods:
Our study population included 67 patients. The primary efficacy endpoint was pathologic complete response (pCR; ypT0/is, N0) rate. χ2 tests were used to evaluate associations between race and baseline characteristics. Cox proportional hazards models were used to assess association between race and overall survival (OS) and event-free survival (EFS). Multivariate logistic regression analyses were used to evaluate associations between race and pCR, immune-related adverse events (irAE) and recurrence.
Results:
Twenty-one patients (31%) self-identified as AA. No significant associations between race and baseline tumor stage (P = 0.40), PD-L1 status (0.92), and stromal tumor–infiltrating lymphocyte (sTIL) count (P = 0.57) were observed. pCR rates were similar between AA (43%) and non-AA patients (48%; P = 0.71). Three-year EFS rates were 78.3% and 71.4% in non-AA and AA patients, respectively [HR, 1.451; 95% confidence interval (CI), 0.524–4.017; P = 0.474]; 3-year OS was 87% and 81%, respectively (HR, 1.72; 95% CI, 0.481–6.136; P = 0.405). The incidence of irAEs was similar between AA and non-AA patients and no significant associations were found between irAEs and pathologic response.
Conclusions:
pCR rates, 3-year OS and EFS after neoadjuvant immunotherapy and chemotherapy were similar in AA and non-AA patients. Toxicities, including the frequency of irAEs, were also similar.
Data from Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Authors: Konopleva Marina , Thirman Michael J. , Pratz Keith W. , Garcia Jacqueline S. , Recher Christian , Pullarkat Vinod , Kantarjian Hagop M. , DiNardo Courtney D. , Dail Monique , Duan Yinghui , Chyla Brenda , Potluri Jalaja , Miller Catherine L. , Wei Andrew H.
Published: April 2023

AbstractPurpose:
To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia.
Patients and Methods:
Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates.
Results:
In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc; complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group.
Conclusions:
When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD.

See related commentary by Perl and Vyas, p. 2719
Data from Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection
Authors: Ramaswami Ramya , Polizzotto Mark N. , Lurain Kathryn , Wyvill Kathleen M. , Widell Anaida , George Jomy , Goncalves Priscila , Steinberg Seth M. , Whitby Denise , Uldrick Thomas S. , Yarchoan Robert
Published: April 2023

AbstractPurpose:
Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.
Patients and Methods:
Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.
Results:
Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%–87%. Twelve of 18 HIV-positive (67%; 95% CI, 41–87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%–97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6–15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.
Conclusions:
Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.
Data from Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction
Authors: Zhu Mojun , Chen Chunhua , Foster Nathan R. , Hartley Christopher , Mounajjed Taofic , Salomao Marcela A. , Fruth Briant F. , Beamer Staci E. , Kim Yohan , Harrington Susan M. , Pitot Henry C. , Sanhueza Cristobal T. , Feng Yening , Herrmann Joerg , McWilliams Robert R. , Lucien Fabrice , Huang Bing Q. , Ma Wen Wee , Bekaii-Saab Tanios S. , Dong Haidong , Wigle Dennis , Ahn Daniel H. , Hallemeier Chris L. , Blackmon Shanda , Yoon Harry H.
Published: April 2023

AbstractPurpose:
This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma.
Patients and Methods:
Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma.
Results:
We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS < 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR.
Conclusions:
Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
Data from Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy
Authors: Girardi Daniel M. , Niglio Scot A. , Mortazavi Amir , Nadal Rosa , Lara Primo , Pal Sumanta K. , Saraiya Biren , Cordes Lisa , Ley Lisa , Ortiz Olena Sierra , Cadena Jacqueline , Diaz Carlos , Bagheri Hadi , Redd Bernadette , Steinberg Seth M. , Costello Rene , Chan Keith S. , Lee Min-Jung , Lee Sunmin , Yu Yunkai , Gurram Sandeep , Chalfin Heather J. , Valera Vladimir , Figg William D. , Merino Maria , Toubaji Antoun , Streicher Howard , Wright John J. , Sharon Elad , Parnes Howard L. , Ning Yang-Min , Bottaro Donald P. , Cao Liang , Trepel Jane B. , Apolo Andrea B.
Published: April 2023

AbstractPurpose:
This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI).
Patients and Methods:
A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability.
Results:
Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS.
Conclusions:
CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.
Data from Single-cell Characterization of the Cellular Landscape of Acral Melanoma Identifies Novel Targets for Immunotherapy
Authors: Li Jiannong , Smalley Inna , Chen Zhihua , Wu Jheng-Yu , Phadke Manali S. , Teer Jamie K. , Nguyen Thanh , Karreth Florian A. , Koomen John M. , Sarnaik Amod A. , Zager Jonathan S. , Khushalani Nikhil I. , Tarhini Ahmad A. , Sondak Vernon K. , Rodriguez Paulo C. , Messina Jane L. , Chen Y. Ann , Smalley Keiran S.M.
Published: April 2023

AbstractPurpose:
Acral melanoma is a rare subtype of melanoma that arises on the non–hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets.
Experimental Design:
We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell–cell interactions were inferred and compared with those in nonacral cutaneous melanoma.
Results:
Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells.
Conclusions:
Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation.
Data from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study
Authors: Herrera Alex F. , Patel Manish R. , Burke John M. , Advani Ranjana , Cheson Bruce D. , Sharman Jeff P. , Penuel Elicia , Polson Andrew G. , Liao Chen Di , Li Chunze , Schuth Eva , Vaze Anjali , Samineni Divya , Elstrom Rebecca , Cooper James , Diefenbach Catherine
Published: April 2023

AbstractPurpose:
Targeting CD79B using antibody–drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast with ADCs with heterogeneous loads.
Patients and Methods:
This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following ≥1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3–4.8 mg/kg); 9 received combination therapy (3.6–4.8 mg/kg) with rituximab.
Results:
Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses ≥1.2 mg/kg. Response rate in all-treated patients (N = 60) was 47% (n = 28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n = 28) and patients with DLBCL (n = 20).
Conclusions:
DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging antitumor activity advocates continuation of investigations into novel ADC technologies.
Data from Distinct Immune Gene Programs Associated with Host Tumor Immunity, Neoadjuvant Chemotherapy, and Chemoimmunotherapy in Resectable NSCLC
Authors: Rocha Pedro , Zhang Jiexin , Laza-Briviesca Raquel , Cruz-Bermúdez Alberto , Bota-Rabassedas Neus , Sanchez-Espiridon Beatriz , Yoshimura Katsuhiro , Behrens Carmen , Lu Wei , Tang Ximing , Pataer Apar , Parra Edwin R. , Haymaker Cara , Fujimoto Junya , Swisher Stephen G. , Heymach John V. , Gibbons Don L. , Lee J. Jack , Sepesi Boris , Cascone Tina , Solis Luisa M. , Provencio Mariano , Wistuba Ignacio I. , Kadara Humam
Published: April 2023

AbstractPurpose:
Our understanding of the immunopathology of resectable non–small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Experimental Design:
Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21). Tumor immune microenvironment (TIME) phenotypes were based on the location of CD8+ T cells (inflamed, cold, excluded), tumoral PD-L1 expression (<1% and ≥1%), and tumor-infiltrating lymphocytes (TIL). Immune programs and signatures were statistically analyzed on the basis of tumoral PD-L1 expression, immune phenotypes, and pathologic response and were cross-compared across the three cohorts.
Results:
PD-L1–positive tumors exhibited increased signature scores for various lymphoid and myeloid cell subsets (P < 0.05). TIME phenotypes exhibited disparate frequencies by stage, PD-L1 expression, and mutational burden. Inflamed and PD-L1+/TILs+ NSCLCs displayed overall significantly heightened levels of immune signatures, with the excluded group representing an intermediate state. A cytotoxic T-cell signature was associated with favorable survival in neoadjuvant chemotherapy–treated NSCLCs (P < 0.05). Pathologic response to chemoimmunotherapy was positively associated with higher expression of genes involved in immune activation, chemotaxis, as well as T and natural killer cells (P < 0.05 for all). Among the three cohorts, chemoimmunotherapy-treated NSCLCs exhibited the highest scores for various immune cell subsets including T effector and B cells (P < 0.05).
Conclusions:
Our findings highlight immune gene programs that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC.
Data from Targeted Analysis of Cell-free Circulating Tumor DNA is Suitable for Early Relapse and Actionable Target Detection in Patients with Neuroblastoma
Authors: Lodrini Marco , Graef Josefine , Thole-Kliesch Theresa M. , Astrahantseff Kathy , Sprüssel Annika , Grimaldi Maddalena , Peitz Constantin , Linke Rasmus B. , Hollander Jan F. , Lankes Erwin , Künkele Annette , Oevermann Lena , Schwabe Georg , Fuchs Jörg , Szymansky Annabell , Schulte Johannes H. , Hundsdörfer Patrick , Eckert Cornelia , Amthauer Holger , Eggert Angelika , Deubzer Hedwig E.
Published: April 2023

AbstractPurpose:
Treating refractory or relapsed neuroblastoma remains challenging. Monitoring body fluids for tumor-derived molecular information indicating minimal residual disease supports more frequent diagnostic surveillance and may have the power to detect resistant subclones before they give rise to relapses. If actionable targets are identified from liquid biopsies, targeted treatment options can be considered earlier.
Experimental Design:
Droplet digital PCR assays assessing MYCN and ALK copy numbers and allelic frequencies of ALK p.F1174L and ALK p.R1275Q mutations were applied to longitudinally collected liquid biopsies and matched tumor tissue samples from 31 patients with high-risk neuroblastoma. Total cell-free DNA (cfDNA) levels and marker detection were compared with data from routine clinical diagnostics.
Results:
Total cfDNA concentrations in blood plasma from patients with high-risk neuroblastoma were higher than in healthy controls and consistently correlated with neuron-specific enolase levels and lactate dehydrogenase activity but not with 123I-meta-iodobenzylguanidine scores at relapse diagnosis. Targeted cfDNA diagnostics proved superior for early relapse detection to all current diagnostics in 2 patients. Marker analysis in cfDNA indicated intratumor heterogeneity for cell clones harboring MYCN amplifications and druggable ALK alterations that were not detectable in matched tumor tissue samples in 17 patients from our cohort. Proof of concept is provided for molecular target detection in cerebrospinal fluid from patients with isolated central nervous system relapses.
Conclusions:
Tumor-specific alterations can be identified and monitored during disease course in liquid biopsies from pediatric patients with high-risk neuroblastoma. This approach to cfDNA surveillance warrants further prospective validation and exploitation for diagnostic purposes and to guide therapeutic decisions.
Data from Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
Authors: Yoshida Kosuke , Yokoi Akira , Yamamoto Tomofumi , Hayashi Yusuke , Nakayama Jun , Yokoi Tsuyoshi , Yoshida Hiroshi , Kato Tomoyasu , Kajiyama Hiroaki , Yamamoto Yusuke
Published: April 2023

AbstractPurpose:
Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.
Experimental Design:
Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis (IPA) was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines.
Results:
We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The IPA revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression.
Conclusions:
We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anticancer effect. Therefore, cell-cycle–related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.
Data from Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI–Treated Patients with EGFR-Mutant NSCLC (SWOG S1403)
Authors: Mack Philip C. , Miao Jieling , Redman Mary W. , Moon James , Goldberg Sarah B. , Herbst Roy S. , Melnick Mary Ann , Walther Zenta , Hirsch Fred R. , Politi Katerina , Kelly Karen , Gandara David R.
Published: April 2023

AbstractPurpose:
Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome.
Experimental Design:
Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor—naïve, EGFR mutation tissue–positive non–small cell lung cancer.
Results:
EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), 0.12–0.45; P < 0.0001], with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6–17.5) months in the group with clearance of ctDNA versus 4.6 (1.7–7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21–0.90), P = 0.02; median overall survival (OS): 32.6 (23.5–not estimable) versus 15.6 (4.9–28.3) months.
Conclusions:
Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.
Data from Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis
Authors: Palazón-Carrión Natalia , Martín García-Sancho Alejandro , Nogales-Fernández Esteban , Jiménez-Cortegana Carlos , Carnicero-González Fernando , Ríos-Herranz Eduardo , de la Cruz-Vicente Fátima , Rodríguez-García Guillermo , Fernández-Álvarez Rubén , Martínez-Banaclocha Natividad , Gumà-Padrò Josep , Gómez-Codina José , Salar-Silvestre Antonio , Rodríguez-Abreu Delvys , Gálvez-Carvajal Laura , Labrador Jorge , Guirado-Risueño María , García-Domínguez Daniel J. , Hontecillas-Prieto Lourdes , Espejo-García Pablo , Fernández-Román Isabel , Provencio-Pulla Mariano , Sánchez-Beato Margarita , Navarro Marta , Marylene Lejeune , Álvaro-Naranjo Tomás , Casanova-Espinosa Maria , Sánchez-Margalet Victor , Rueda-Domínguez Antonio , de la Cruz-Merino Luis
Published: April 2023

AbstractPurpose:
New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma.
Patients and Methods:
In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1–14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1–3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1–21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29).
Results:
After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3–4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells.
Conclusions:
R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.
Data from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
Authors: Li Yimei , Hwang Wei-Ting , Maude Shannon L. , Teachey David T. , Frey Noelle V. , Myers Regina M. , Barz Leahy Allison , Liu Hongyan , Porter David L. , Grupp Stephan A. , Shaw Pamela A.
Published: April 2023

Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.
Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial
Authors: Tesileanu C. Mircea S. , Sanson Marc , Wick Wolfgang , Brandes Alba A. , Clement Paul M. , Erridge Sara C. , Vogelbaum Michael A. , Nowak Anna K. , Baurain Jean-Francois , Mason Warren P. , Wheeler Helen , Chinot Olivier L. , Gill Sanjeev , Griffin Matthew , Rogers Leland , Taal Walter , Rudà Roberta , Weller Michael , McBain Catherine , van Linde Myra E. , Aldape Kenneth , Jenkins Robert B. , Kros Johan M. , Wesseling Pieter , von Deimling Andreas , Hoogstrate Youri , de Heer Iris , Atmodimedjo Peggy N. , Dubbink Hendrikus J. , Brouwer Rutger W.W. , van IJcken Wilfred F.J. , Cheung Kin Jip , Golfinopoulos Vassilis , Baumert Brigitta G. , Gorlia Thierry , French Pim J. , van den Bent Martin J.
Published: April 2023

AbstractPurpose:
In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors].
Patients and Methods:
From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.
Results:
Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.
Conclusions:
In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Data from Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma
Authors: Yurchenko Andrey A. , Pop Oltin T. , Ighilahriz Meriem , Padioleau Ismael , Rajabi Fatemeh , Sharpe Hayley J. , Poulalhon Nicolas , Dreno Brigitte , Khammari Amir , Delord Marc , Alberti Antonio , Soufir Nadem , Battistella Maxime , Mourah Samia , Bouquet Fanny , Savina Ariel , Besse Andrej , Mendez-Lopez Max , Grange Florent , Monestier Sandrine , Mortier Laurent , Meyer Nicolas , Dutriaux Caroline , Robert Caroline , Saiag Philippe , Herms Florian , Lambert Jerome , de Sauvage Frederic J. , Dumaz Nicolas , Flatz Lukas , Basset-Seguin Nicole , Nikolaev Sergey I.
Published: April 2023

AbstractPurpose:
Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms.
Experimental Design:
Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC).
Results:
We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate.
Conclusions:
IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.