bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer
Authors: Goyal Lipika , Sirard Cynthia , Schrag Michael , Kagey Michael H. , Eads Jennifer R. , Stein Stacey , El-Khoueiry Anthony B. , Manji Gulam A. , Abrams Thomas A. , Khorana Alok A. , Miksad Rebecca , Mahalingam Devalingam , Zhu Andrew X. , Duda Dan G.
Published: April 2023

AbstractPurpose:
Dickkopf-1 (DKK1) modulates Wnt signaling, promoting tumor growth, metastasis, and immunosuppression. High DKK1 expression has been detected in various tumor types—including biliary tract cancer (BTC)—and is associated with poor prognosis. DKN-01—a humanized mAb targeting DKK1—was evaluated in a phase I multicenter study in combination with gemcitabine and cisplatin in patients with unresectable or metastatic BTC with no prior systemic therapy for advanced disease.
Patients and Methods:
This study included a dose-escalation phase assessing DKN-01 at two dose levels (150 mg and 300 mg) combined with gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) followed by dose expansion. Primary endpoints evaluated safety and tolerability; secondary endpoints evaluated efficacy, pharmacokinetics, and circulating biomarkers.
Results:
Fifty-one patients with intrahepatic cholangiocarcinoma (63%), extrahepatic cholangiocarcinoma (8%), and gallbladder cancer (29%) were enrolled. No dose-limiting toxicities were seen, and the expansion phase proceeded with DKN-01 300 mg (N = 47). The most frequent grade 3/4 treatment-emergent adverse events included neutropenia (60%), thrombocytopenia (34%), and anemia (23%). The objective response rate was 21.3% and median progression-free survival was 8.7 months (95% confidence interval, 5.4–10.3 months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL6 and decreased TNFα).
Conclusions:
DKN-01 300 mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/chemotherapy and the need for increased dose/intensity. A study with DKN-01 600 mg in combination with a PD-1 inhibitor in BTC is ongoing.
Data from Development and Validation of a Prognostic Model for Patients with Advanced Lung Cancer Treated with the Immune Checkpoint Inhibitor Atezolizumab
Authors: Hopkins Ashley M. , Kichenadasse Ganessan , Garrett-Mayer Elizabeth , Karapetis Christos S. , Rowland Andrew , Sorich Michael J.
Published: April 2023

AbstractPurpose:
Immune checkpoint inhibitors (ICI) are a significant advance to the treatment of advanced non–small cell lung cancer (NSCLC); however, their initiation is associated with heterogeneity in outcomes. This study aimed to develop and validate a prognostic tool of survival in patients with advanced NSCLC treated with ICIs.
Experimental Design:
A pretreatment prognostic model was developed and validated using clinicopathologic data. Development data consisted of patients with advanced NSCLC treated with atezolizumab from the randomised trials OAK and POPLAR (n = 751). Data from the single-arm atezolizumab trials BIRCH and FIR (n = 797) were used for external validation. Prognostic scores were categorized into low, intermediate-low, intermediate, intermediate-high, and high-risk prognostic groups. The primary outcome was overall survival (OS), with progression-free survival (PFS) secondary.
Results:
Pretreatment C-reactive protein (CRP) was the most predictive variable for OS. The prognostic tool was optimally defined by CRP, lactate dehydrogenase, derived neutrophil-to-lymphocyte ratio, albumin, PD-L1 expression, performance status, time since metastatic diagnosis, and metastatic site count. Prognostic groups had significantly different OS (c-statistic = 0.72), with median OS ranging from >24 to 3 months for the low- to high-risk groups. Performance was maintained on validation (c = 0.76). These findings were similar for PFS, with median PFS ranging from 5 months to 1 month for the low- to high-risk groups. Benefit of atezolizumab (vs. docetaxel) was greatest in the low-risk group (>3 months median OS improvement), with little benefit apparent for the highest risk group.
Conclusions:
A prognostic tool was developed and validated to identify patient groups with distinctly different survival following atezolizumab initiation for advanced NSCLC.
Data from Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer
Authors: Merz Valeria , Zecchetto Camilla , Santoro Raffaela , Simionato Francesca , Sabbadini Fabio , Mangiameli Domenico , Piro Geny , Cavaliere Alessandro , Deiana Michela , Valenti Maria Teresa , Bazan Diana , Fedele Vita , Lonardi Sara , Melisi Davide
Published: April 2023

AbstractPurpose:
Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting.
Experimental Design:
In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics.
Results:
Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39–4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84–6.68; P = 4.9e−05). These results were confirmed in a validation cohort of 50 patients.
Conclusions:
Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.
Data from Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study
Authors: Shi Yuankai , Cai Qiqing , Jiang Yu , Huang Gang , Bi Minghong , Wang Baocheng , Zhou Yuhong , Wang Guowen , Ying Hongyan , Tao Zhiwei , Shi Chunmei , Guo Qian , Gao Chao
Published: April 2023

AbstractPurpose:
Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS.
Patients and Methods:
We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18–75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population.
Results:
Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5–55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0–not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2–95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4+ T cells was adversely associated with patient response (P = 0.031).
Conclusions:
Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.
Data from CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes
Authors: Leuci Valeria , Donini Chiara , Grignani Giovanni , Rotolo Ramona , Mesiano Giulia , Fiorino Erika , Gammaitoni Loretta , D'Ambrosio Lorenzo , Merlini Alessandra , Landoni Elisa , Medico Enzo , Capellero Sonia , Giraudo Lidia , Cattaneo Giulia , Iaia Ilenia , Pignochino Ymera , Basiricò Marco , Vigna Elisa , Pisacane Alberto , Fagioli Franca , Ferrone Soldano , Aglietta Massimo , Dotti Gianpietro , Sangiolo Dario
Published: April 2023

AbstractPurpose:
No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes in vitro and in immunodeficient mice.
Experimental Design:
The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored in vitro, in two- and three-dimensional STS cultures, and in three in vivo STS xenograft models.
Results:
CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by in silico analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior in vitro cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in vivo in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK.
Conclusions:
This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes in vitro and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting.
Data from Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer
Authors: Crosby Erika J. , Acharya Chaitanya R. , Haddad Anthony-Fayez , Rabiola Christopher A. , Lei Gangjun , Wei Jun-Ping , Yang Xiao-Yi , Wang Tao , Liu Cong-Xiao , Wagner Kay U. , Muller William J. , Chodosh Lewis A. , Broadwater Gloria , Hyslop Terry , Shepherd Jonathan H. , Hollern Daniel P. , He Xiaping , Perou Charles M. , Chai Shengjie , Ashby Benjamin K. , Vincent Benjamin G. , Snyder Joshua C. , Force Jeremy , Morse Michael A. , Lyerly Herbert K. , Hartman Zachary C.
Published: April 2023

AbstractPurpose:
Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.
Experimental Design:
Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination.
Results:
We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.
Conclusions:
Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
Data from Multiplex Immunofluorescence in Formalin-Fixed Paraffin-Embedded Tumor Tissue to Identify Single-Cell–Level PI3K Pathway Activation
Authors: Stopsack Konrad H. , Huang Ying , Tyekucheva Svitlana , Gerke Travis A. , Bango Clyde , Elfandy Habiba , Bowden Michaela , Penney Kathryn L. , Roberts Thomas M. , Parmigiani Giovanni , Kantoff Philip W. , Mucci Lorelei A. , Loda Massimo
Published: April 2023

AbstractPurpose:
Identifying cancers with high PI3K pathway activity is critical for treatment selection and eligibility into clinical trials of PI3K inhibitors. Assessments of tumor signaling pathway activity need to consider intratumoral heterogeneity and multiple regulatory nodes.
Experimental Design:
We established a novel, mechanistically informed approach to assessing tumor signaling pathways by quantifying single-cell–level multiplex immunofluorescence using custom algorithms. In a proof-of-concept study, we stained archival formalin-fixed, paraffin-embedded (FFPE) tissue from patients with primary prostate cancer in two prospective cohort studies, the Health Professionals Follow-up Study and the Physicians’ Health Study. PTEN, stathmin, and phospho-S6 were quantified on 14 tissue microarrays as indicators of PI3K activation to derive cell-level PI3K scores.
Results:
In 1,001 men, 988,254 tumor cells were assessed (median, 743 per tumor; interquartile range, 290–1,377). PI3K scores were higher in tumors with PTEN loss scored by a pathologist, higher Gleason grade, and a new, validated bulk PI3K transcriptional signature. Unsupervised machine-learning approaches resulted in similar clustering. Within-tumor heterogeneity in cell-level PI3K scores was high. During long-term follow-up (median, 15.3 years), rates of progression to metastases and death from prostate cancer were twice as high in the highest quartile of PI3K activation compared with the lowest quartile (hazard ratio, 2.04; 95% confidence interval, 1.13–3.68).
Conclusions:
Our novel pathway-focused approach to quantifying single-cell–level immunofluorescence in FFPE tissue identifies prostate tumors with PI3K pathway activation that are more aggressive and may respond to pathway inhibitors.
Data from PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype
Authors: Guarneri Valentina , Dieci Maria Vittoria , Bisagni Giancarlo , Brandes Alba A. , Frassoldati Antonio , Cavanna Luigi , Musolino Antonino , Giotta Francesco , Rimanti Anita , Garrone Ornella , Bertone Elena , Cagossi Katia , Nanni Oriana , Piacentini Federico , Orvieto Enrico , Griguolo Gaia , Curtarello Matteo , Urso Loredana , Paré Laia , Chic Nuria , D'Amico Roberto , Prat Aleix , Conte Pierfranco
Published: April 2023

AbstractPurpose:
We explored the prognostic effect of PIK3CA mutation in HER2+ patients enrolled in the ShortHER trial.
Patients and Methods:
The ShortHER trial randomized 1,253 patients with HER2+ breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform.
Results:
A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56–1.27; P = 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n = 232): 5-year DFS 91.8% versus 76.1% (log-rank P = 0.049; HR, 0.46; 95% CI, 0.21–1.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68–0.99; P = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65–0.99; P = 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53–0.99; P = 0.042 for MYBL2 expression).
Conclusions:
PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes.
Data from Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
Authors: Glisson Bonnie S. , Leidner Rom S. , Ferris Robert L. , Powderly John , Rizvi Naiyer A. , Keam Bhumsuk , Schneider Reva , Goel Sanjay , Ohr James P. , Burton Jennifer , Zheng Yanan , Eck Steven , Gribbin Matthew , Streicher Katie , Townsley Danielle M. , Patel Sandip Pravin
Published: April 2023

AbstractPurpose:
Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.
Patients and Methods:
In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.
Results:
In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells.
Conclusions:
MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
Data from Radiation-induced Adaptive Response: New Potential for Cancer Treatment
Authors: Coleman C. Norman , Eke Iris , Makinde Adeola Y. , Chopra Sunita , Demaria Sandra , Formenti Silvia C. , Martello Shannon , Bylicky Michelle , Mitchell James B. , Aryankalayil Molykutty J.
Published: April 2023

Abstract
Radiotherapy is highly effective due to its ability to physically focus the treatment to target the tumor while sparing normal tissue and its ability to be combined with systemic therapy. This systemic therapy can be utilized before radiotherapy as an adjuvant or induction treatment, during radiotherapy as a radiation “sensitizer,” or following radiotherapy as a part of combined modality therapy. As part of a unique concept of using radiation as “focused biology,” we investigated how tumors and normal tissues adapt to clinically relevant multifraction (MF) and single-dose (SD) radiation to observe whether the adaptations can induce susceptibility to cell killing by available drugs or by immune enhancement. We identified an adaptation occurring after MF (3 × 2 Gy) that induced cell killing when AKT-mTOR inhibitors were delivered following cessation of radiotherapy. In addition, we identified inducible changes in integrin expression 2 months following cessation of radiotherapy that differ between MF (1 Gy × 10) and SD (10 Gy) that remain targetable compared with preradiotherapy. Adaptation is reflected across different “omics” studies, and thus the range of possible molecular targets is not only broad but also time, dose, and schedule dependent. While much remains to be studied about the radiation adaptive response, radiation should be characterized by its molecular perturbations in addition to physical dose. Consideration of the adaptive effects should result in the design of a tailored radiotherapy treatment plan that accounts for specific molecular changes to be targeted as part of precision multimodality cancer treatment.
Data from A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors
Authors: Tolaney Sara M. , Do Khanh T. , Eder Joseph P. , LoRusso Patricia M. , Weekes Colin D. , Chandarlapaty Sarat , Chang Ching-Wei , Chen Shang-Chiung , Nazzal Denise , Schuth Eva , Brunstein Flavia , Carrasco-Triguero Montserrat , Darbonne Walter C. , Giltnane Jennifer M. , Flanagan William M. , Commerford S. Renee , Ungewickell Alexander , Shapiro Geoffrey I. , Modi Shanu
Published: April 2023

AbstractPurpose:
DLYE5953A is an antibody–drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors.
Patients and Methods:
This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies.
Results:
Sixty-eight patients received DLYE5953A (median, four cycles; range, 1–27). No dose-limiting toxicities were identified during dose escalation (0.2–2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non–small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg (n = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients.
Conclusions:
DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.
Data from A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
Authors: Zeidan Amer M. , Ridinger Maya , Lin Tara L. , Becker Pamela S. , Schiller Gary J. , Patel Prapti A. , Spira Alexander I. , Tsai Michaela L. , Samuëlsz Errin , Silberman Sandra L. , Erlander Mark , Wang Eunice S.
Published: April 2023

AbstractPurpose:
The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.
Patients and Methods:
Onvansertib was administered orally, in escalating doses, on days 1–5 in combination with either LDAC (20 mg/m2; days 1–10) or decitabine (20 mg/m2; days 1–5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.
Results:
Forty patients were treated with onvansertib (12–90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.
Conclusions:
The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
Data from Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays
Authors: Bouwman Peter , van der Heijden Ingrid , van der Gulden Hanneke , de Bruijn Roebi , Braspenning Merel E. , Moghadasi Setareh , Wessels Lodewyk F.A. , Vreeswijk Maaike P.G. , Jonkers Jos
Published: April 2023

AbstractPurpose:
Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway.
Experimental Design:
Two hundred thirty-eight BRCA1 VUS—comprising most BRCA1 VUS known in the Netherlands and Belgium—were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families.
Results:
All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%–100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 12 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants.
Conclusions:
We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.
Data from A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer
Authors: Romero Joan M. , Grünwald Barbara , Jang Gun-Ho , Bavi Prashant P. , Jhaveri Aaditeya , Masoomian Mehdi , Fischer Sandra E. , Zhang Amy , Denroche Robert E. , Lungu Ilinca M. , De Luca Angela , Bartlett John M.S. , Xu Jing , Li Niandong , Dhaliwal Sharon , Liang Sheng-Ben , Chadwick Dianne , Vyas Foram , Bronsert Peter , Khokha Rama , McGaha Tracy L. , Notta Faiyaz , Ohashi Pamela S. , Done Susan J. , O'Kane Grainne M. , Wilson Julie M. , Knox Jennifer J. , Connor Ashton , Wang Yifan , Zogopoulos George , Gallinger Steven
Published: April 2023

AbstractPurpose:
The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.
Experimental Design:
Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.
Results:
Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this “4-chemokine signature” positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell–inflamed phenotype across primary PDAC and PDAC liver metastases.
Conclusions:
A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.
Data from Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer
Authors: Allott Emma H. , Ebot Ericka M. , Stopsack Konrad H. , Gonzalez-Feliciano Amparo G. , Markt Sarah C. , Wilson Kathryn M. , Ahearn Thomas U. , Gerke Travis A. , Downer Mary K. , Rider Jennifer R. , Freedland Stephen J. , Lotan Tamara L. , Kantoff Philip W. , Platz Elizabeth A. , Loda Massimo , Stampfer Meir J. , Giovannucci Edward , Sweeney Christopher J. , Finn Stephen P. , Mucci Lorelei A.
Published: April 2023

AbstractPurpose:
Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms.
Experimental Design:
Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue.
Results:
During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60–0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19–0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95–1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103).
Conclusions:
Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.
Data from Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment
Authors: Chen Runzhe , Lee Won-Chul , Fujimoto Junya , Li Jun , Hu Xin , Mehran Reza , Rice David , Swisher Stephen G. , Sepesi Boris , Tran Hai T. , Chow Chi-Wan , Little Latasha D. , Gumbs Curtis , Haymaker Cara , Heymach John V. , Wistuba Ignacio I. , Lee J. Jack , Futreal P. Andrew , Zhang Jianhua , Reuben Alexandre , Tsao Anne S. , Zhang Jianjun
Published: April 2023

AbstractPurpose:
Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.
Experimental Design:
We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.
Results:
The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib–treated tumors had significantly longer survival.
Conclusions:
Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.
Data from Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study
Authors: Bagley Stephen J. , Nabavizadeh S. Ali , Mays Jazmine J. , Till Jacob E. , Ware Jeffrey B. , Levy Scott , Sarchiapone Whitney , Hussain Jasmin , Prior Timothy , Guiry Samantha , Christensen Theresa , Yee Stephanie S. , Nasrallah MacLean P. , Morrissette Jennifer J.D. , Binder Zev A. , O'Rourke Donald M. , Cucchiara Andrew J. , Brem Steven , Desai Arati S. , Carpenter Erica L.
Published: April 2023

AbstractPurpose:
The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS).
Experimental Design:
We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel.
Results:
Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, P < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, P = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, P = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, P = 0.093) and OS (median 5.5 vs. 9.2 months, P = 0.053).
Conclusions:
Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.
Data from A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients
Authors: Zeh Herbert J. , Bahary Nathan , Boone Brian A. , Singhi Aatur D. , Miller-Ocuin Jennifer Lee , Normolle Daniel P. , Zureikat Amer H. , Hogg Melissa E. , Bartlett David L. , Lee Kenneth K. , Tsung Allan , Marsh J. Wallis , Murthy Pranav , Tang Daolin , Seiser Natalie , Amaravadi Ravi K. , Espina Virginia , Liotta Lance , Lotze Michael T.
Published: April 2023

AbstractPurpose:
We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel.
Patients and Methods:
Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines.
Results:
Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival (P = 0.59) and relapse-free survival (P = 0.55) did not differ between the two arms.
Conclusions:
The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.
Data from Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer
Authors: Kang Yoon-Koo , Bang Yung-Jue , Kondo Shunsuke , Chung Hyun Cheol , Muro Kei , Dussault Isabelle , Helwig Christoph , Osada Motonobu , Doi Toshihiko
Published: April 2023

AbstractPurpose:
Patients with advanced gastric/gastroesophageal junction cancer (GC/GEJC) have limited treatment options after first-line therapy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (a TGFβ “trap”) fused to a human IgG1 antibody against programmed death ligand 1 (PD-L1), potentially offering a new treatment approach for these patients. We report results for bintrafusp alfa in GC/GEJC.
Patients and Methods:
Asian patients with recurrent GC/GEJC for whom standard therapy does not exist or for whom standard therapy has failed enrolled in this expansion cohort of an ongoing phase I trial and received bintrafusp alfa 1,200 mg once every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary objective was to assess safety/tolerability.
Results:
By July 23, 2018, 31 heavily pretreated patients received bintrafusp alfa for a median of 10.1 weeks; 3 patients remained on treatment. Six patients (19%) experienced grade 3 treatment-related adverse events (AE); no grade 4 events occurred. One on-treatment death occurred (sudden death); rupture of a preexisting thoracic aortic aneurysm was the suspected cause. Ten patients (32%) had immune-related AEs. The confirmed objective response rate per independent review committee was 16%; disease control rate was 26%. Median duration of response was 8.7 months (range, 2.4–12.4+). Responses occurred irrespective of PD-L1 expression or microsatellite instability status and appeared to correlate with high tumor TGFB1 levels.
Conclusions:
In this first evaluation in Asian patients with heavily pretreated advanced GC/GEJC, bintrafusp alfa demonstrated a manageable safety profile and clinical activity.
Data from Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy
Authors: Zhou Katherine I. , Peterson Bryan , Serritella Anthony , Thomas Joseph , Reizine Natalie , Moya Stephanie , Tan Carol , Wang Yan , Catenacci Daniel V.T.
Published: April 2023

AbstractPurpose:
Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA.
Experimental Design:
A cohort of 211 patients with stage II–IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5–15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel.
Results:
Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%–63% and 73%–75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival.
Conclusions:
PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.

See related commentary by Klempner et al., p. 6401
Data from NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response
Authors: Swain Sandra M. , Tang Gong , Brauer Heather Ann , Goerlitz David S. , Lucas Peter C. , Robidoux André , Harris Brent T. , Bandos Hanna , Ren Yuqi , Geyer Charles E. , Rastogi Priya , Mamounas Eleftherios P. , Wolmark Norman
Published: April 2023

AbstractPurpose:
In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41.
Patients and Methods:
Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization.
Results:
Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial–mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73.
Conclusions:
The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.