bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Potent Activity of an Anti-ICAM1 Antibody–Drug Conjugate against Multiple Myeloma
Authors: Sherbenou Daniel W. , Su Yang , Behrens Christopher R. , Aftab Blake T. , Perez de Acha Olivia , Murnane Megan , Bearrows Shelby C. , Hann Byron C. , Wolf Jeffery L. , Martin Thomas G. , Liu Bin
Published: April 2023

AbstractPurpose:
New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody–drug conjugate (ADC).
Experimental Design:
Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state.
Results:
The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples.
Conclusions:
We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.
Data from Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial
Authors: Uppaluri Ravindra , Campbell Katie M. , Egloff Ann Marie , Zolkind Paul , Skidmore Zachary L. , Nussenbaum Brian , Paniello Randal C. , Rich Jason T. , Jackson Ryan , Pipkorn Patrik , Michel Loren S. , Ley Jessica , Oppelt Peter , Dunn Gavin P. , Barnell Erica K. , Spies Nicholas C. , Lin Tianxiang , Li Tiantian , Mulder David T. , Hanna Youstina , Cirlan Iulia , Pugh Trevor J. , Mudianto Tenny , Riley Rachel , Zhou Liye , Jo Vickie Y. , Stachler Matthew D. , Hanna Glenn J. , Kass Jason , Haddad Robert , Schoenfeld Jonathan D. , Gjini Evisa , Lako Ana , Thorstad Wade , Gay Hiram A. , Daly Mackenzie , Rodig Scott J. , Hagemann Ian S. , Kallogjeri Dorina , Piccirillo Jay F. , Chernock Rebecca D. , Griffith Malachi , Griffith Obi L. , Adkins Douglas R.
Published: April 2023

AbstractPurpose:
Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)–unrelated HNSCC.
Patients and Methods:
Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%–49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684).
Results:
Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3–4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%–41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.
Conclusions:
Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.
Data from Molecular Engineering of Ultrasmall Silica Nanoparticle–Drug Conjugates as Lung Cancer Therapeutics
Authors: Madajewski Brian , Chen Feng , Yoo Barney , Turker Melik Z. , Ma Kai , Zhang Li , Chen Pei-Ming , Juthani Rupa , Aragon-Sanabria Virginia , Gonen Mithat , Rudin Charles M. , Wiesner Ulrich , Bradbury Michelle S. , Brennan Cameron
Published: April 2023

AbstractPurpose:
Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects.
Experimental Design:
Ultrasmall (<8 nm) core-shell silica nanoparticles, C′ dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib–dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively.
Results:
Gefitinib-bound C′ dots (DFO-Gef-C′ dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11–56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 μmol/L, respectively). In human non–small cell lung cancer mice, efficacious Gef-C′ dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 μmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C′ dot–treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug.
Conclusions:
Results underscore the clinical potential of DFO-Gef-C′ dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.
Data from First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer
Authors: Dunphy Mark P.S. , Pressl Christina , Pillarsetty Nagavarakishore , Grkovski Milan , Modi Shanu , Jhaveri Komal , Norton Larry , Beattie Bradley J. , Zanzonico Pat B. , Zatorska Danuta , Taldone Tony , Ochiana Stefan O. , Uddin Mohammad M. , Burnazi Eva M. , Lyashchenko Serge K. , Hudis Clifford A. , Bromberg Jacqueline , Schöder Heiko M. , Fox Josef J. , Zhang Hanwen , Chiosis Gabriela , Lewis Jason S. , Larson Steven M.
Published: April 2023

AbstractPurpose:
124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging.
Experimental Design:
Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays.
Results:
124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects.
Conclusions:
Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.
Data from Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2− Advanced Breast Cancer
Authors: Bardia Aditya , Modi Shanu , Oliveira Mafalda , Cortes Javier , Campone Mario , Ma Brigette , Dirix Luc , Weise Amy , Hewes Becker , Diaz-Padilla Ivan , Han Yu , Deshpande Priya , Samant Tanay S. , Lorenc Karen Rodriguez , He Wei , Su Fei , Chavez-MacGregor Mariana
Published: April 2023

AbstractPurpose:
Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).
Patients and Methods:
Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.
Results:
Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.
Conclusions:
Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.
Data from Phase Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions (APL) of the Head and Neck
Authors: Shin Dong M. , Nannapaneni Sreenivas , Patel Mihir R. , Shi Qiuying , Liu Yuan , Chen Zhengjia , Chen Amy Y. , El-Deiry Mark W. , Beitler Jonathan J. , Steuer Conor E. , Roser Steven M. , Klein Adam M. , Owonikoko Taofeek K. , Ramalingam Suresh S. , Khuri Fadlo R. , Chen Zhuo G. , Saba Nabil F.
Published: April 2023

AbstractPurpose:
On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR–tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx.
Patients and Methods:
Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation.
Results:
Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment.
Conclusions:
Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.
Data from Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia
Authors: Wei Hui , Wang Ying , Gale Robert Peter , Lin Dong , Zhou Chunlin , Liu Bingcheng , Qiu Shaowei , Gu Runxia , Li Yan , Zhao Xingli , Wei Shuning , Gong Benfa , Liu Kaiqi , Gong Xiaoyuan , Liu Yuntao , Zhang Guangji , Song Zhen , Wang Yang , Li Wei , Mi Yingchang , Wang Jianxiang
Published: April 2023

AbstractPurpose:
Cytarabine, 100–200 mg/mE+2/day, is commonly used in induction therapy of acute myelogenous leukemia (AML). Whether a higher dose of cytarabine would be more effective is unknown. Also, there is controversy whether high-dose cytarabine is better than an intermediate-dose combined with other drugs for post-remission therapy. In this open-label, randomized controlled, parallel group study, roles of intermediate-dose cytarabine were investigated.
Patients and Methods:
Subjects with AML age 15–55 years were randomized to receive daunorubicin, omacetaxine mepesuccinate, and conventional- or intermediate-dose cytarabine. Subjects achieving complete remission were randomized to receive 3 courses of high-dose cytarabine or 2 courses of intermediate-dose cytarabine with daunorubicin in the 1st and mitoxantrone in the 2nd course. The primary endpoint was disease-free survival (DFS).
Results:
591 subjects were randomized to intermediate- (N = 295) or conventional-dose (N = 296) cytarabine group. Three-year DFSs were 67% [95% confidence interval (CI), 61–73] in the intermediate-dose cohort compared with 54% (95% CI, 48–61) in the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, 0.51–0.89; P = 0.005). Three-year survivals were 68% (95%CI, 63–74) and 59% (95%CI, 53–65; HR, 0.720; 95%CI, 0.56–0.94; P = 0.014). Two courses of intermediate-dose cytarabine with daunorubicin or mitoxantrone resulted in similar DFS and survival as three courses of high-dose cytarabine when used for post-remission therapy.
Conclusions:
Induction therapy with intermediate-dose cytarabine with daunorubicin and omacetaxine mepesuccinate increases DFS and survival in persons with AML ages 15–55 years compared with conventional-dose cytarabine.

See related commentary by Watts and Bradley, p. 3073
Data from Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Authors: Liu Chen , Lu Hengyu , Wang Hongyun , Loo Alice , Zhang Xiamei , Yang Guizhi , Kowal Colleen , Delach Scott , Wang Ye , Goldoni Silvia , Hastings William D. , Wong Karrie , Gao Hui , Meyer Matthew J. , Moody Susan E. , LaMarche Matthew J. , Engelman Jeffrey A. , Williams Juliet A. , Hammerman Peter S. , Abrams Tinya J. , Mohseni Morvarid , Caponigro Giordano , Hao Huai-Xiang
Published: April 2023

AbstractPurpose:
SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.
Experimental Design:
The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined.
Results:
In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody.
Conclusions:
Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
Data from Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics
Authors: Topham James T. , Karasinska Joanna M. , Lee Michael K.C. , Csizmok Veronika , Williamson Laura M. , Jang Gun Ho , Denroche Robert E. , Tsang Erica S. , Kalloger Steve E. , Wong Hui-li , O'Kane Grainne M. , Moore Richard A. , Mungall Andrew J. , Notta Faiyaz , Loree Jonathan M. , Wilson Julie M. , Bathe Oliver , Tang Patricia A. , Goodwin Rachel , Knox Jennifer J. , Gallinger Steven , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Renouf Daniel J. , Schaeffer David F.
Published: April 2023

AbstractPurpose:
RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice.
Experimental Design:
Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival.
Results:
Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001).
Conclusions:
Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.
Data from Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non–small Cell Lung Cancer
Authors: Yu Helena A. , Paz-Ares Luis G. , Yang James Chih-Hsin , Lee Ki Hyeong , Garrido Pilar , Park Keunchil , Kim Joo-Hang , Lee Dae Ho , Mao Huzhang , Wijayawardana Sameera R. , Gao Ling , Hozak Rebecca R. , Chao Bo H. , Planchard David
Published: April 2023

AbstractPurpose:
We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non–small cell lung cancer (NSCLC).
Patients and Methods:
This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.
Results:
Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6–21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5–19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.
Conclusions:
Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

See related commentary by Garon, p. 905
Data from Artificial Intelligence–Assisted Amphiregulin and Epiregulin IHC Predicts Panitumumab Benefit in RAS Wild-Type Metastatic Colorectal Cancer
Authors: Williams Christopher J.M. , Seligmann Jenny F. , Elliott Faye , Shires Michael , Richman Susan D. , Brown Sarah , Zhang Liping , Singh Shalini , Pugh Judith , Xu Xiao-Meng , Muranyi Andrea , Guetter Christoph , Lorsakul Auranuch , Kurkure Uday , Zhao Zuo , Martin Jim , Wang Xingwei , Nguyen Kien , Liu Wen-Wei , Yan Dongyao , West Nicholas P. , Barrett Jennifer H. , Barnes Michael , Bai Isaac , Seymour Matthew T. , Quirke Philip , Shanmugam Kandavel
Published: April 2023

AbstractPurpose:
High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab.
Experimental Design:
Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL).
Results:
High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37–0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74–1.49; P = 0.78). The ligand-treatment interaction was significant (Pinteraction = 0.02) and remained significant after adjustment for BRAF-mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P < 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; Pinteraction = 0.01). The effect on OS was similar but not statistically significant.
Conclusions:
AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice.
Data from Angiokines Associated with Targeted Therapy Outcomes in Patients with Non–Clear Cell Renal Cell Carcinoma
Authors: Armstrong Andrew J. , Nixon Andrew B. , Carmack Andrea , Yang Qian , Eisen Tim , Stadler Walter M. , Jones Robert J. , Garcia Jorge A. , Vaishampayan Ulka N. , Picus Joel , Hawkins Robert E. , Hainsworth John D. , Kollmannsberger Christian K. , Logan Theodore F. , Puzanov Igor , Pickering Lisa M. , Ryan Christopher W. , Protheroe Andrew , George Daniel J. , Halabi Susan
Published: April 2023

AbstractPurpose:
Biomarkers are needed in patients with non–clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib.
Patients and Methods:
ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS).
Results:
We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib.
Conclusions:
In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
Data from Eribulin Plus Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer (ENHANCE 1): A Phase Ib/II Study
Authors: Tolaney Sara M. , Kalinsky Kevin , Kaklamani Virginia G. , D'Adamo David R. , Aktan Gursel , Tsai Michaela L. , O'Regan Ruth M. , Kaufman Peter A. , Wilks Sharon T. , Andreopoulou Eleni , Patt Debra A. , Yuan Yuan , Wang Grace , Savulsky Claudio , Xing Dongyuan , Kleynerman Ella , Karantza Vassiliki , Diab Sami
Published: April 2023

AbstractPurpose:
As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.
Patients and Methods:
In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.
Results:
The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)].
Conclusions:
Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.
Data from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
Authors: Parsons Heather A. , Rhoades Justin , Reed Sarah C. , Gydush Gregory , Ram Priyanka , Exman Pedro , Xiong Kan , Lo Christopher C. , Li Tianyu , Fleharty Mark , Kirkner Gregory J. , Rotem Denisse , Cohen Ofir , Yu Fangyan , Fitarelli-Kiehl Mariana , Leong Ka Wai , Hughes Melissa E. , Rosenberg Shoshana M. , Collins Laura C. , Miller Kathy D. , Blumenstiel Brendan , Trippa Lorenzo , Cibulskis Carrie , Neuberg Donna S. , DeFelice Matthew , Freeman Samuel S. , Lennon Niall J. , Wagle Nikhil , Ha Gavin , Stover Daniel G. , Choudhury Atish D. , Getz Gad , Winer Eric P. , Meyerson Matthew , Lin Nancy U. , Krop Ian , Love J. Christopher , Makrigiorgos G. Mike , Partridge Ann H. , Mayer Erica L. , Golub Todd R. , Adalsteinsson Viktor A.
Published: April 2023

AbstractPurpose:
Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.
Experimental Design:
We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2− metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.
Results:
Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2–346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3–58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4–39.2 months).
Conclusions:
Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
Data from A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer
Authors: Bhatia Smita , Palomares Melanie R. , Hageman Lindsey , Chen Yanjun , Landier Wendy , Smith Kandice , Umphrey Heidi , Reich Caroline A. , Zamora Kathryn W. , Armenian Saro H. , Bevers Therese B. , Blaes Anne , Henderson Tara , Hodgson David , Hudson Melissa M. , Korde Larissa A. , Melin Susan A. , Merajver Sofia D. , Overholser Linda , Pruthi Sandhya , Wong F. Lennie , Garber Judy E.
Published: April 2023

AbstractPurpose:
Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk.
Patients and Methods:
We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints.
Results:
Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen.
Conclusions:
In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.
Data from The B7-H3–Targeting Antibody–Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models
Authors: Kendsersky Nathan M. , Lindsay Jarrett , Kolb E. Anders , Smith Malcolm A. , Teicher Beverly A. , Erickson Stephen W. , Earley Eric J. , Mosse Yael P. , Martinez Daniel , Pogoriler Jennifer , Krytska Kateryna , Patel Khushbu , Groff David , Tsang Matthew , Ghilu Samson , Wang Yifei , Seaman Steven , Feng Yang , Croix Brad St. , Gorlick Richard , Kurmasheva Raushan , Houghton Peter J. , Maris John M.
Published: April 2023

AbstractPurpose:
Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line–derived xenograft (CDX) models.
Experimental Design:
B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.
Results:
The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.
Conclusions:
m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
Data from Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial
Authors: Xu Jianming , Shen Jie , Gu Shanzhi , Zhang Yun , Wu Lihua , Wu Jian , Shao Guoliang , Zhang Yanqiao , Xu Li , Yin Tao , Liu Jingfeng , Ren Zhenggang , Xiong Jianping , Mao Xianhai , Zhang Ling , Yang Jiayin , Li Lequn , Chen Xiaoming , Wang Zhiming , Gu Kangsheng , Chen Xi , Pan Zhanyu , Ma Kuansheng , Zhou Xinmin , Yu Zujiang , Li Enxiao , Yin Guowen , Zhang Xiao , Wang Shuni , Wang Quanren
Published: April 2023

AbstractPurpose:
We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).
Patients and Methods:
This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1.
Results:
Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.
Conclusions:
Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.

See related commentary by Pinato et al., p. 908
Data from TIGIT Expression Is Associated with T-cell Suppression and Exhaustion and Predicts Clinical Outcome and Anti–PD-1 Response in Follicular Lymphoma
Authors: Yang Zhi-Zhang , Kim Hyo Jin , Wu Hongyan , Jalali Shahrzad , Tang Xinyi , Krull Jordan E. , Ding Wei , Novak Anne J. , Ansell Stephen M.
Published: April 2023

AbstractPurpose:
T-cell immunoglobulin and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma is largely unknown.
Experimental Design:
Biopsy specimens from a cohort of 82 patients with follicular lymphoma were analyzed using mass cytometry to explore the phenotype and biological and clinical significance of TIGIT+ T cells.
Results:
TIGIT is highly expressed on intratumoral T cells and its expression alters T-cell phenotype in follicular lymphoma. TIGIT is abundantly expressed on Treg cells, resulting in an enhanced suppressive property. TIGIT expression on non-Treg/TFH T cells defines a population that exhibits an exhausted phenotype. Clinically, increased numbers of TIGIT+ T cells are associated with inferior patient outcomes and poor survival. We observe that anti–PD-1 therapy with pembrolizumab alters the phenotype of TIGIT+ T subsets and identifies a role for CD28 expression on TIGIT+ T cells in treatment response.
Conclusions:
The current study provides a comprehensive analysis of the phenotypic profile of intratumoral TIGIT+ T subsets and their prognostic relevance in follicular lymphoma. Inhibition of TIGIT signaling may be an additional mechanism to prevent T-cell suppression and exhaustion in B-cell lymphoma.
Data from 177Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer
Authors: Thakur Shilpa , Daley Brianna , Millo Corina , Cochran Craig , Jacobson Orit , Lu Huiyan , Wang Zhantong , Kiesewetter Dale , Chen Xiaoyuan , Vasko Vasyl , Klubo-Gwiezdzinska Joanna
Published: April 2023

AbstractPurpose:
The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues.
Experimental Design:
We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUVmax) of SSTR2 analogue, 68Ga-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional in vitro studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy in vivo.
Results:
Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest 68Ga-DOTA-TATE uptake [median SUVmax, 16.5 (7.9–29)] than other types of thyroid cancers. In vivo studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE (P < 0.001) and DOTA-JR11 (P < 0.001). Treatment with 177Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUVmax, 15.16 ± 4.34), but had no effects in a model with low SST analogues uptake (SUVmax, 4.8 ± 0.27).
Conclusions:
A novel SST analogue, 177Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.
Data from Inotuzumab Ozogamicin for Relapsed/Refractory Acute Lymphoblastic Leukemia in the INO-VATE Trial: CD22 Pharmacodynamics, Efficacy, and Safety by Baseline CD22
Authors: Kantarjian Hagop M. , Stock Wendy , Cassaday Ryan D. , DeAngelo Daniel J. , Jabbour Elias , O'Brien Susan M. , Stelljes Matthias , Wang Tao , Paccagnella M. Luisa , Nguyen Kevin , Sleight Barbara , Vandendries Erik , Neuhof Alexander , Laird A. Douglas , Advani Anjali S.
Published: April 2023

AbstractPurpose:
We assessed the relationship between cluster of differentiation-22 (CD22) expression and outcomes of inotuzumab ozogamicin versus standard of care (SC) in INO-VATE (NCT01564784).
Patients and Methods:
Adults with relapsed/refractory B-cell precursor CD22-positive (by local or central laboratory) acute lymphoblastic leukemia were randomized to inotuzumab ozogamicin (n = 164) or SC (n = 162). Outcomes were analyzed by baseline CD22 positivity (percentage of leukemic blasts CD22 positive, ≥90% vs. <90%) and CD22 receptor density [molecules of equivalent soluble fluorochrome (MESF), quartile analysis].
Results:
Most patients had high (≥90%) CD22 positivity per central laboratory. The response rate was significantly higher with inotuzumab ozogamicin versus SC. Minimal/measurable residual disease negativity, duration of remission (DoR), progression-free survival, and overall survival (OS) were significantly better with inotuzumab ozogamicin versus SC in patients with CD22 positivity ≥90%. Fewer patients had CD22 positivity <90%; for whom, response rates were higher with inotuzumab ozogamicin versus SC, but DoR and OS appeared similar. Similar trends were evident in quartile analyses of CD22 MESF and CD22 positivity per local laboratory. Among inotuzumab ozogamicin–responding patients with subsequent relapse, decrease in CD22 positivity and receptor density was evident, but not the emergence of CD22 negativity. Rates of grade ≥3 hematologic adverse events (AEs) were similar and hepatobiliary AEs rate was higher for inotuzumab ozogamicin versus SC. No apparent relationship was observed between the rates of hematologic and hepatic AEs and CD22 expression.
Conclusions:
Inotuzumab ozogamicin demonstrated a favorable benefit–risk profile versus SC in patients with higher and lower CD22 expression. Patients with high CD22 expression and normal cytogenetics benefited the most from inotuzumab ozogamicin therapy.
Data from Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312)
Authors: Cole Kristina A. , Pal Sharmistha , Kudgus Rachel A. , Ijaz Heba , Liu Xiaowei , Minard Charles G. , Pawel Bruce R. , Maris John M. , Haas-Kogan Daphne A. , Voss Stephan D. , Berg Stacey L. , Reid Joel M. , Fox Elizabeth , Weigel Brenda J.
Published: April 2023

AbstractPurpose:
Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.
Patients and Methods:
Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.
Results:
Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.
Conclusions:
Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.