bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)
Authors: Hussain Maha , Corcoran Claire , Sibilla Caroline , Fizazi Karim , Saad Fred , Shore Neal , Sandhu Shahneen , Mateo Joaquin , Olmos David , Mehra Niven , Kolinsky Michael P. , Roubaud Guilhem , Özgüroǧlu Mustafa , Matsubara Nobuaki , Gedye Craig , Choi Young Deuk , Padua Charles , Kohlmann Alexander , Huisden Robert , Elvin Julia A. , Kang Jinyu , Adelman Carrie A. , Allen Allison , Poehlein Christian , de Bono Johann
Published: April 2023

AbstractPurpose:
Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies.
Patients and Methods:
An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation.
Results:
A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages >10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact.
Conclusions:
The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.
Data from Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor–Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002)
Authors: Hua Xin , Bi Xi-Wen , Zhao Jian-Li , Shi Yan-Xia , Lin Ying , Wu Zhi-Yong , Zhang Yuan-Qi , Zhang Le-Hong , Zhang An-Qing , Huang Heng , Liu Xin-Mei , Xu Fei , Guo Ying , Xia Wen , Hong Ruo-Xi , Jiang Kui-Kui , Xue Cong , An Xin , Zhong Yong-Yi , Wang Shu-Sen , Huang Jia-Jia , Yuan Zhong-Yu
Published: April 2023

AbstractPurpose:
There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy.
Patients and Methods:
We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses.
Results:
A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0–44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7–21.7)] in the ET group and 14.8 months (12.8–16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71–1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group.
Conclusions:
Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.
Data from Induction Chemotherapy with or without Erlotinib in Patients with Head and Neck Squamous Cell Carcinoma Amenable for Surgical Resection
Authors: Le Xiuning , Gleber-Netto Frederico O. , Rubin M. Laura , Qing Yun , Du Robyn , Kies Merrill , Blumenschein George , Lu Charles , Johnson Faye M. , Bell Diana , Lewis Jeff , Zhang Jiexin , Feng Lei , Wilson Kaye , Marcelo-Lewis Kathrina , Wang Jing , Ginsberg Lawrence , Gillison Maura , Lee J. Jack , Meric-Berstam Funda , Mills Gordon B. , Myers Jeffrey N. , Pickering Curtis R.
Published: April 2023

AbstractPurpose:
Neoadjuvant chemotherapy prior to definitive surgery has been used widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel versus placebo with platinum-docetaxel in patients with stage III–IVB OSCC.
Patients and Methods:
Patients with newly diagnosed stage III, IVA, and IVB (American Joint Committee on Cancer 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate; secondary endpoints included safety, overall survival (OS), and progression-free survival (PFS).
Results:
Fifty-two patients received at least 1 cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24; P = 0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n = 7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pretreatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy.
Conclusions:
The addition of erlotinib to platinum-taxane chemotherapy was well tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathologic responses had excellent clinical outcome.
Data from Evaluation of Sensitivity to Endocrine Therapy Index (SET2,3) for Response to Neoadjuvant Endocrine Therapy and Longer-Term Breast Cancer Patient Outcomes (Alliance Z1031)
Authors: Suman Vera J. , Du Lili , Hoskin Tanya , Anurag Meenakshi , Ma Cynthia , Bedrosian Isabelle , Hunt Kelly K. , Ellis Matthew J. , Symmans W. Fraser
Published: April 2023

AbstractPurpose:
To evaluate prediction of response and event-free survival (EFS) following neoadjuvant endocrine therapy by SET2,3 index of nonproliferation gene expression related to estrogen and progesterone receptors adjusted for baseline prognosis.
 Experimental Design:
A correlative study was conducted of SET2,3 measured from gene expression profiles of diagnostic tumor (Agilent microarrays) in 379 women with cStage II–III breast cancer from the American College of Surgeons Oncology Group Z1031 neoadjuvant aromatase inhibitor trial SET2,3 was dichotomized using the previously published cutoff. Fisher exact test was used to assess the association between SET2,3 and low proliferation at week 2–4 [Ki67 ≤ 10% or complete cell-cycle arrest (CCCA; Ki67 ≤ 2.7%)] and PEPI-0 rate in cohort B, and the association between SET2,3 and ypStage 0/I in all patients. Cox models were used to assess EFS with respect to SET2,3 excluding cohort B patients who switched to chemotherapy.
Results:
Patients with high SET2,3 had higher rate of pharmacodynamic response than patients with low SET2,3 (Ki67 ≤ 10% in 88.2% vs. 56.9%, P < 0.0001; CCCA in 50.0% vs. 26.2%, P = 0.0054), but rate of ypStage 0/I (24.0% vs. 20.4%, P = 0.4580) or PEPI = 0 (28.4% vs. 20.6%, P = 0.3419) was not different. Patients with high SET2,3 had longer EFS than patients with low SET2,3 (HR, 0.52, 95% confidence interval: 0.34–0.80; P = 0.0026).
Conclusions:
This exploratory analysis of Z1031 data demonstrated a higher rate of pharmacodynamic suppression of proliferation and longer EFS in high SET2,3 disease relative to low SET2,3 disease. The ypStage 0/I rate and PEPI = 0 rate were similar with respect to SET2,3.
Data from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Shah Manish A. , Shitara Kohei , Lordick Florian , Bang Yung-Jue , Tebbutt Niall C. , Metges Jean-Phillippe , Muro Kei , Lee Keun-Wook , Shen Lin , Tjulandin Sergei , Hays John L. , Starling Naureen , Xu Rui-Hua , Sturtz Keren , Fontaine Marilyn , Oh Cindy , Brooks Emily M. , Xu Bo , Li Wei , Li Chiang J. , Borodyansky Laura , Van Cutsem Eric
Published: April 2023

AbstractPurpose:
To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Patients and Methods:
In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.
Results:
Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively.
Conclusions:
Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.
Data from Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer
Authors: Xu Junfen , Fang Yifeng , Chen Kelie , Li Sen , Tang Sangsang , Ren Yan , Cen Yixuan , Fei Weidong , Zhang Bo , Shen Yuanming , Lu Weiguo
Published: April 2023

AbstractPurpose:
The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME).
Experimental Design:
The tumors of 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq).
Results:
A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models.
Conclusions:
Our transcriptomic results analyzed by scRNA-seq delineate an ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four–EMT gene model for prediction of HGSOC patient outcomes, mCAFs’ capability of enhancing ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.
Data from Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Chung Christine H. , Li Jiannong , Steuer Conor E. , Bhateja Priyanka , Johnson Matthew , Masannat Jude , Poole Maria I. , Song Feifei , Hernandez-Prera Juan C. , Molina Helen , Wenig Bruce M. , Kumar Sunil , Kuperwasser Charlotte , Stephens Philip J. , Farinhas Joaquim M. , Shin Dong M. , Kish Julie A. , Muzaffar Jameel , Kirtane Kedar , Rocco James W. , Schell Michael J. , Saba Nabil F. , Bonomi Marcelo
Published: April 2023

AbstractPurpose:
A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with a combination of cetuximab and nivolumab.
Patients and Methods:
Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 i.v. on day 14 as a lead-in followed by cetuximab 500 mg/m2 i.v. and nivolumab 240 mg i.v. on day 1 and day 15 of each 28-day cycle. Expression of p16 and programmed cell death-ligand 1 (PD-L1) in archived tumors were determined. Tumor-tissue–modified human papillomavirus (TTMV) DNA was quantified in plasma.
Results:
Ninety-five patients were enrolled, and 88 patients were evaluable for OS with a median follow-up of 15.9 months. Median OS in the 45 patients who had prior therapy for R/M HNSCC (cohort A) was 11.4 months, with a 1 year OS 50% [90% confidence interval (CI), 0.43–0.57]. Median OS in the 43 patients who had no prior therapy (cohort B) was 20.2 months, with a 1-year OS 66% (90% CI, 0.59–0.71). In the combined cohorts, the p16-negative immunostaining was associated with higher response rate (RR; P = 0.02) but did not impact survival while higher PD-L1 combined positive score was associated with higher RR (P = 0.03) and longer OS (log-rank P = 0.04). In the p16-positive patients, lower median (1,230 copies/mL) TTMV DNA counts were associated with higher RR (P = 0.01) and longer OS compared with higher median (log-rank P = 0.05).
Conclusions:
The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.
Data from Pyrotinib in Patients with HER2-Amplified Advanced Non–Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial
Authors: Song Zhengbo , Lv Dongqing , Chen Shi-Qing , Huang Jianjin , Li Yuping , Ying Shenpeng , Wu Xiaoyu , Hua Feng , Wang Wenxian , Xu Chunwei , Bei Ting , Gao Chan , Sun Zhijian , Zhang Yiping , Lu Shun
Published: April 2023

AbstractPurpose:
In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non–small cell lung cancer (NSCLC).
Patients and Methods:
In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety.
Results:
The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0–69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0–9.6 months), and median OS was 12.5 months (95% CI, 8.2–16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%−40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression.
Conclusions:
Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.
Data from Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors
Authors: Davar Diwakar , Zappasodi Roberta , Wang Hong , Naik Girish S. , Sato Takami , Bauer Todd , Bajor David , Rixe Olivier , Newman Walter , Qi Jingjing , Holland Aliya , Wong Phillip , Sifferlen Lianna , Piper Diane , Sirard Cynthia A. , Merghoub Taha , Wolchok Jedd D. , Luke Jason J.
Published: April 2023

AbstractPurpose:
TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor−related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors.
Patients and Methods:
TRX518 monotherapy was dose escalated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks. Parts C–E included dose-escalation (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLT), serious adverse events (SAE), and pharmacokinetics. Secondary endpoints were efficacy and pharmacodynamics.
Results:
A total of 109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E), respectively. A total of 67% of patients in Parts D+E had received prior anti–PD(L)1 or anti–CTLA-4. No DLTs, treatment-related SAEs, and/or grade 4 or 5 AEs were observed with TRX518 monotherapy. In Parts C–E, no DLTs were observed, although TRX518-related SAEs were reported in 3.3% (Part C) and 10.0% (Part E), respectively. Objective response rate was 3.2%, 3.8%, 4%, and 12.5% in Parts A+B, C, D, and E, respectively. TRX518 affected peripheral and intratumoral regulatory T cells (Treg) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti–PD1 combination were associated with intratumoral Treg reductions and CD8 increases and activation after treatment.
Conclusions:
TRX518 showed an acceptable safety profile with pharmacodynamic activity. Repeated dose TRX518 monotherapy and in combination resulted in limited clinical responses associated with immune activation.

See related commentary by Hernandez-Guerrero and Moreno, p. 3905
Data from Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer
Authors: Serritella Anthony V. , Shevrin Daniel , Heath Elisabeth I. , Wade James L. , Martinez Elia , Anderson Amanda , Schonhoft Joseph , Chu Yen-Lin , Karrison Theodore , Stadler Walter M. , Szmulewitz Russell Z.
Published: April 2023

AbstractPurpose:
Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC).
Patients and Methods:
One hundred and six patients with CRPC were accrued. Phase I subjects were treated with enzalutamide monotherapy at 160 mg per day for 28 days to allow steady-state accumulation. Patients then entered the dose escalation combination portion of the study. In phase II, patients were randomized 1:1 to either receive enzalutamide alone or enzalutamide plus mifepristone. The primary endpoint was PSA progression-free survival (PFS), with radiographic PFS, and PSA response rate (RR) as key secondary endpoints. Circulating tumor cells were collected before randomization for exploratory translational biomarker studies.
Results:
We determined a 25% dose reduction in enzalutamide, when added to mifepristone, resulted in equivalent drug levels compared with full-dose enzalutamide and was well tolerated. However, the addition of mifepristone to enzalutamide following a 12-week enzalutamide lead-in did not delay time to PSA, radiographic or clinical PFS. The trial was terminated early due to futility.
Conclusions:
This is the first prospective trial of dual AR–GR antagonism in CRPC. Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint. The development of more specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be explored.
Data from Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study
Authors: Nathenson Michael J. , Hu Junxiao , Ratan Ravin , Somaiah Neeta , Hsu Robert , DeMaria Peter J. , Catoe Heath W. , Pang Angela , Subhawong Ty K. , Amini Behrang , Sweet Kevin , Feister Katharina , Malik Karan , Jagannathan Jyothi , Braschi-Amirfarzan Marta , Sheren Jamie , Caldas Yupanqui , Moreno Tellez Cristiam , Rosenberg Andrew E. , Lazar Alexander J. , Maki Robert G. , Benedetto Pasquale , Cohen Jonathan , Trent Jonathan C. , Ravi Vinod , Patel Shreyaskumar , Wilky Breelyn A.
Published: April 2023

AbstractPurpose:
Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.
Experimental Design:
We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan–Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen.
Results:
A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or “other” therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations.
Conclusions:
Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated.

See related commentary by Greene and Van Tine, p. 3911
Data from Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence: a Report from the EORTC 26091 TAVAREC Trial
Authors: Draaisma Kaspar , Tesileanu C. Mircea S. , de Heer Iris , Klein Martin , Smits Marion , Reijneveld Jaap C. , Clement Paul M. , de Vos Filip Y.F. , Wick Antje , Mulholland Paul J. , Taphoorn Martin J.B. , Weller Michael , Chinot Olivier L. , Kros Johan M. , Verschuere Tina , Coens Corneel , Golfinopoulos Vassilis , Gorlia Thierry , Idbaih Ahmed , Robe Pierre A. , van den Bent Martin J. , French Pim J.
Published: April 2023

AbstractPurpose:
Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples.
Experimental Design:
Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; “Heidelberg” and “TCGA” classifier respectively).
Results:
DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence.
Conclusions:
DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
Data from Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer
Authors: Coleman Ilsa M. , DeSarkar Navonil , Morrissey Colm , Xin Li , Roudier Martine P. , Sayar Erolcan , Li Dapei , Corey Eva , Haffner Michael C. , Nelson Peter S.
Published: April 2023

AbstractPurpose:
To determine whether metastatic castration–resistant prostate cancers (mCRPC) partition into molecular phenotypes corresponding to intrinsic differentiation states and ascertain whether these subtypes exhibit specific druggable features and associate with treatment outcomes.
Experimental Design:
We used RNAseq, digital spatial profiling, and histological assessments from metastatic biopsies and patient-derived xenografts to segregate mCRPCs into subtypes defined by the PAM50 breast cancer classification algorithm. Subtype associations with treatment responses in preclinical models and patients were determined.
Results:
Using the PAM50 algorithm, we partitioned 270 mCRPC tumors into LumA (42%), LumB (24%), and Basal (34%) subtypes with classification largely driven by proliferation rates and androgen receptor (AR) activity. Most neuroendocrine tumors classified as Basal. Pathways enriched in the LumA subtype include TGFß and NOTCH signaling. LumB subtype tumors were notable for elevated MYC activity. Basal subtype tumors exhibited elevated IL6-STAT3 signaling and features of adult stem cell states. In patients where multiple tumors were evaluated, the majority had concordant PAM50 subtype determination, though a subset exhibited marked inter- and intratumor heterogeneity, including divergent classifications between primary and metastatic sites. In preclinical models, LumA subtype tumors were highly responsive to androgen deprivation and docetaxel chemotherapy whereas Basal tumors were largely resistant. In clinical cohorts patients with Basal subtype tumors demonstrated a shorter time on treatment with AR signaling inhibitors and docetaxel relative to patients with luminal subtypes.
Conclusions:
Subtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.
Data from Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy
Authors: Chida Keigo , Kawazoe Akihito , Suzuki Toshihiro , Kawazu Masahito , Ueno Toshihide , Takenouchi Kazumasa , Nakamura Yoshiaki , Kuboki Yasutoshi , Kotani Daisuke , Kojima Takashi , Bando Hideaki , Mishima Saori , Kuwata Takeshi , Sakamoto Naoya , Watanabe Jun , Mano Hiroyuki , Ikeda Masafumi , Shitara Kohei , Endo Itaru , Nakatsura Tetsuya , Yoshino Takayuki
Published: April 2023

AbstractPurpose:
Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal tumors to determine the predictors of response to PD-1 blockade.
Experimental Design:
Thirty-six patients with MSI-H/dMMR gastrointestinal tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of gastrointestinal tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of colorectal cancer.
Results:
Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial–mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFNγ pathway was enriched in responders. On the basis of the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared with those with low expression, had significantly shorter progression-free survival [PFS; median 4.8 months vs. not reached (NR), P = 0.032] and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with colorectal cancer evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3, and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4.
Conclusions:
Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. These findings can help develop predictive biomarkers or combination immunotherapies.
Data from Alpha-Fetoprotein as a Potential Surrogate Biomarker for Atezolizumab + Bevacizumab Treatment of Hepatocellular Carcinoma
Authors: Zhu Andrew X. , Dayyani Farshid , Yen Chia-Jui , Ren Zhenggang , Bai Yuxian , Meng Zhiqiang , Pan Hongming , Dillon Paul , Mhatre Shivani K. , Gaillard Vincent E. , Hernandez Sairy , Kelley Robin Kate , Sangro Bruno
Published: April 2023

AbstractPurpose:
Atezolizumab + bevacizumab is the new standard of care for systemic treatment-naïve, unresectable hepatocellular carcinoma (HCC). This exploratory study investigated on-treatment alpha-fetoprotein (AFP) response as a potential surrogate biomarker of prognosis for the combination therapy.
Experimental Design:
Data from Group A of the phase Ib GO30140 study were used to identify the optimal time for AFP measurement and AFP cutoffs to differentiate patients by their best confirmed response per independent review facility–assessed RECIST (IRF-RECIST) version 1.1: responders from nonresponders and patients with disease control from primary progressors. We applied these cutoffs to independent data from the atezolizumab + bevacizumab arm of the phase III IMbrave150 trial to distinguish patients based on (i) overall survival (OS) and progression-free survival (PFS) per IRF-RECIST 1.1 and (ii) best confirmed response per IRF-RECIST 1.1.
Results:
We derived AFP cutoffs of ≥75% decrease and ≤10% increase from baseline at 6 weeks to identify responders and those who had disease control, respectively. These cutoffs had high sensitivity and specificity in GO30140. In IMbrave150 patients, sensitivity was 0.59 and specificity was 0.86 for the ≥75% decrease AFP cutoff; the sensitivity was 0.77 and specificity was 0.44 for the ≤10% increase AFP cutoff. Both AFP cutoffs were associated with longer OS and PFS, particularly in patients with hepatitis B virus etiology (HR < 0.5; P < 0.01).
Conclusions:
AFP response at 6 weeks after initiating treatment is a potential surrogate biomarker of prognosis for patients with HCC receiving atezolizumab + bevacizumab.

See related commentary by Cappuyns and Llovet, p. 3405
Data from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial
Authors: Lu Yen-Shen , Im Seock-Ah , Colleoni Marco , Franke Fabio , Bardia Aditya , Cardoso Fatima , Harbeck Nadia , Hurvitz Sara , Chow Louis , Sohn Joohyuk , Lee Keun Seok , Campos-Gomez Saul , Villanueva Vazquez Rafael , Jung Kyung Hae , Babu K. Govind , Wheatley-Price Paul , De Laurentiis Michelino , Im Young-Hyuck , Kuemmel Sherko , El-Saghir Nagi , O'Regan Ruth , Gasch Claudia , Solovieff Nadia , Wang Craig , Wang Yongyu , Chakravartty Arunava , Ji Yan , Tripathy Debu
Published: April 2023

AbstractPurpose:
Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).
Patients and Methods:
Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods.
Results:
The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI.
Conclusions:
Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).
Data from Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study
Authors: Nowakowski Grzegorz S. , Yoon Dok Hyun , Peters Anthea , Mondello Patrizia , Joffe Erel , Fleury Isabelle , Greil Richard , Ku Matthew , Marks Reinhard , Kim Kibum , Zinzani Pier Luigi , Trotman Judith , Huang Dan , Waltl Eva E. , Winderlich Mark , Kurukulasuriya Nuwan C. , Ambarkhane Sumeet , Hess Georg , Salles Gilles
Published: April 2023

Purpose:
In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Patients and Methods:
Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes.
Results:
In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R­GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003).
Conclusions:
RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx.

See related commentary by Cherng and Westin, p. 3908
Data from Initial Phase I Safety Study of Gedatolisib plus Cofetuzumab Pelidotin for Patients with Metastatic Triple-Negative Breast Cancer
Authors: Radovich Milan , Solzak Jeffrey P. , Wang Chao J. , Hancock Bradley A. , Badve Sunil , Althouse Sandra K. , Bray Steven M. , Storniolo Anna Maria V. , Ballinger Tarah J. , Schneider Bryan P. , Miller Kathy D.
Published: April 2023

AbstractPurpose:
The PI3K pathway is dysregulated in the majority of triple-negative breast cancers (TNBC), yet single-agent inhibition of PI3K has been ineffective in TNBC. PI3K inhibition leads to an immediate compensatory upregulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a phase I clinical trial combining gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody–drug conjugate against the cell-surface PTK7 protein (Wnt pathway coreceptor) with an auristatin payload.
Patients and Methods:
Participants (pt) had metastatic TNBC or estrogen receptor (ER) low (ER and PgR < 5%, HER2-negative) breast cancer, and had received at least one prior chemotherapy for advanced disease. The primary objective was safety. Secondary endpoints included overall response rate (ORR), clinical benefit at 18 weeks (CB18), progression-free survival (PFS), and correlative analyses.
Results:
A total of 18 pts were enrolled in three dose cohorts: gedatolisib 110 mg weekly + cofetuzumab pelidotin 1.4 mg/kg every 3 weeks (n = 4), 180 mg + 1.4 mg/kg (n = 3), and 180 mg + 2.8 mg/kg (n = 11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached ≥grade 3 severity. Myelosuppression was uncommon. ORR was 16.7% (3/18). An additional 3 pts had stable disease (of these 2 had stable disease for >18 weeks); CB18 was 27.8%. Median PFS was 2.0 months (95% confidence interval for PFS: 1.2–6.2). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways.
Conclusions:
The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.
Data from Famitinib with Camrelizumab and Nab-Paclitaxel for Advanced Immunomodulatory Triple-Negative Breast Cancer (FUTURE-C-Plus): An Open-Label, Single-Arm, Phase II Trial
Authors: Chen Li , Jiang Yi-Zhou , Wu Song-Yang , Wu Jiong , Di Gen-Hong , Liu Guang-Yu , Yu Ke-Da , Fan Lei , Li Jun-Jie , Hou Yi-Feng , Hu Zhen , Chen Can-Ming , Huang Xiao-Yan , Cao A-Yong , Hu Xin , Zhao Shen , Ma Xiao-Yan , Xu Ying , Sun Xiang-Jie , Chai Wen-Jun , Guo Xiaomao , Chen Xizi , Xu Yanhui , Zhu Xiao-Yu , Zou Jian-Jun , Yang Wen-Tao , Wang Zhong-Hua , Shao Zhi-Ming
Published: April 2023

AbstractPurpose:
Camrelizumab, an mAb against programmed cell death protein 1 (PD-1), plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR, and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab, and nab-paclitaxel in advanced immunomodulatory TNBC.
Patients and Methods:
This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 IHC staining ≥10%). Eligible patients received 20 mg of oral famitinib on days 1 to 28, 200 mg of i.v. camrelizumab on days 1 and 15, and i.v. nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and exploratory biomarkers.
Results:
Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7–24.3). Confirmed ORR was 81.3% [95% confidence interval (CI), 70.2–92.3], with five complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4–18.8), and median DOR was 14.9 months [95% CI, not estimable (NE)–NE]. Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with IHC, 13 (43.3%) were programmed death-ligand 1 (PD-L1)–negative, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response.
Conclusions:
The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatory TNBC. The randomized controlled FUTURE-SUPER trial is under way to validate our findings.

See related commentary by Salgado and Loi, p. 2728
Data from Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic Leukemia/Lymphoma
Authors: Zhang Mingzhi , Chen Dan , Fu Xiaorui , Meng Huimin , Nan Feifei , Sun Zhenchang , Yu Hui , Zhang Lei , Li Ling , Li Xin , Wang Xinhua , Wang Min , You Fengtao , Li Zhaoming , Chang Yu , Zhou Zhiyuan , Yan Jiaqin , Li Jiwei , Wu Xiaolong , Wang Yu , Wang Yinyan , Xiang Shufen , Chen YuSheng , Pan Guifang , Xu Hanying , Zhang Bozhen , Yang Lin
Published: April 2023

AbstractPurpose:
Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7–chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (R/R) T-ALL/LBL, as well as its manufacturing feasibility.
Patients and Methods:
Preclinical phase was conducted in NPG mice injected with Luc+ GFP+CCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety; secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters.
Results:
CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulum/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) 3 months after CAR T-cell infusion; 1 patient with leukemia achieved minimal residual disease–negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/μL at approximately 12 days and remained detectable up to 270 days.
Conclusions:
Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.