bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
Authors: Bellmunt Joaquim , de Wit Ronald , Fradet Yves , Climent Miguel A. , Petrylak Daniel P. , Lee Jae-Lyun , Fong Lawrence , Necchi Andrea , Sternberg Cora N. , O'Donnell Peter H. , Powles Thomas , Plimack Elizabeth R. , Bajorin Dean F. , Balar Arjun V. , Castellano Daniel , Choueiri Toni K. , Culine Stephane , Gerritsen Winald , Gurney Howard , Quinn David I. , Vuky Jacqueline , Vogelzang Nicholas J. , Cristescu Razvan , Lunceford Jared , Saadatpour Assieh , Loboda Andrey , Ma Junshui , Rajasagi Mohini , Godwin James Luke , Homet Moreno Blanca , Grivas Petros
Published: April 2023

AbstractPurpose:
In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).
Patients and Methods:
Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05.
Results:
In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment.
Conclusions:
Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
Data from Release of IFNγ by Acute Myeloid Leukemia Cells Remodels Bone Marrow Immune Microenvironment by Inducing Regulatory T Cells
Authors: Corradi Giulia , Bassani Barbara , Simonetti Giorgia , Sangaletti Sabina , Vadakekolathu Jayakumar , Fontana Maria Chiara , Pazzaglia Martina , Gulino Alessandro , Tripodo Claudio , Cristiano Gianluca , Bandini Lorenza , Ottaviani Emanuela , Ocadlikova Darina , Piccioli Milena , Martinelli Giovanni , Colombo Mario Paolo , Rutella Sergio , Cavo Michele , Ciciarello Marilena , Curti Antonio
Published: April 2023

AbstractPurpose:
The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Treg) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFNγ released by AML cells in BM Treg induction and its impact on AML prognosis.
Experimental Design:
BM aspirates from patients with AML were subdivided according to IFNG expression. Gene expression profiles in INFγhigh and IFNγlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFNγ release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell cocultures. In mice, AML cells silenced for ifng expression were injected intrabone.
Results:
IFNγhigh AML samples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. In contrast, in patients with AML, high IFNG expression was associated with poor overall survival. Notably, IFNγ release by AML cells positively correlated with a higher BM suppressive Treg frequency. In coculture experiments, IFNγhigh AML cells modified MSC transcriptome by upregulating IFNγ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFNγ release by AML cells on MSC-derived Treg induction. In vivo, the genetic ablation of IFNγ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment.
Conclusions:
IFNγ release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunologic landscape toward Treg induction, contributing to an immunotolerant microenvironment.

See related commentary by Ferrell and Kordasti, p. 2986
Data from Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay
Authors: Hu Chunling , Susswein Lisa R. , Roberts Maegan E. , Yang Hana , Marshall Megan L. , Hiraki Susan , Berkofsky-Fessler Windy , Gupta Sounak , Shen Wei , Dunn Carolyn A. , Huang Huaizhi , Na Jie , Domchek Susan M. , Yadav Siddhartha , Monteiro Alvaro N.A. , Polley Eric C. , Hart Steven N. , Hruska Kathleen S. , Couch Fergus J.
Published: April 2023

AbstractPurpose:
The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory.
Experimental Design:
The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2.
Results:
Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS.
Conclusions:
Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.
Data from Dose Escalation Data from the Phase 1 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Japanese Patients with Advanced Solid Tumors
Authors: Sato Jun , Shimizu Toshio , Koyama Takafumi , Iwasa Satoru , Shimomura Akihiko , Kondo Shunsuke , Kitano Shigehisa , Yonemori Kan , Fujiwara Yutaka , Tamura Kenji , Suzuki Takuya , Takase Takao , Nagai Reiko , Yamaguchi Kohei , Semba Taro , Zhao Zi-Ming , Ren Min , Yamamoto Noboru
Published: April 2023

AbstractPurpose:
We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy.
Patients and Methods:
Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective.
Results:
Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4–41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased.
Conclusions:
E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing.
Data from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results
Authors: Lindeman Geoffrey J. , Fernando Tharu M. , Bowen Rebecca , Jerzak Katarzyna J. , Song Xinni , Decker Thomas , Boyle Frances , McCune Steve , Armstrong Anne , Shannon Catherine , Bertelli Gianfilippo , Chang Ching-Wei , Desai Rupal , Gupta Kushagra , Wilson Timothy R. , Flechais Aulde , Bardia Aditya
Published: April 2023

AbstractPurpose:
Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression.
Patients and Methods:
Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status.
Results:
At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status.
Conclusions:
Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial
Authors: Barlesi Fabrice , Tomasini Pascale , Karimi Maryam , Michiels Stefan , Raimbourg Judith , Daniel Catherine , Janicot Henri , Madroszyk Anne , Audigier-Valette Clarisse , Quoix Elisabeth , Mazieres Julien , Moro-Sibilot Denis , Dansin Eric , Molinier Olivier , Morel Hugues , Pichon Eric , Cortot Alexis , Otto Josiane , Chomy François , Souquet Pierre-Jean , Cloarec Nicolas , Giroux-Leprieur Etienne , Bieche Ivan , Lacroix Ludovic , Boyault Sandrine , Attignon Valery , Soubeyran Isabelle , Morel Alain , Tran-Dien Alicia , Jacquet Alexandra , Dall'Olio Filippo Gustavo , Jimenez Marta , Soria Jean-Charles , Besse Benjamin
Published: April 2023

AbstractPurpose:
Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.
Patients and Methods:
SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).
Results:
Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 <1% (n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).
Conclusions:
Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.
Data from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia
Authors: Jin Peng , Jin Qiqi , Wang Xiaoling , Zhao Ming , Dong Fangyi , Jiang Ge , Li Zeyi , Shen Jie , Zhang Wei , Wu Shishuang , Li Ran , Zhang Yunxiang , Li Xiaoyang , Li Junmin
Published: April 2023

AbstractPurpose:
The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions.
Experimental Design:
We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed.
Results:
A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling.
Conclusions:
Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.
Data from Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade
Authors: Johannet Paul , Liu Wenke , Fenyo David , Wind-Rotolo Megan , Krogsgaard Michelle , Mehnert Janice M. , Weber Jeffrey S. , Zhong Judy , Osman Iman
Published: April 2023

AbstractPurpose:
Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab.
Experimental Design:
This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915.
Results:
In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98–6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59–86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38–7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84–37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48–28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10–212.50).
Conclusions:
Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility.

See related commentary by Hassel and Luke, p. 3914
Data from Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability–High Locally Advanced Rectal Cancer
Authors: Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Togashi Yosuke , Koyama Shohei , Kotani Daisuke , Fukuoka Shota , Yuki Satoshi , Komatsu Yoshito , Homma Shigenori , Taketomi Akinobu , Uemura Mamoru , Kato Takeshi , Fukui Makoto , Wakabayashi Masashi , Nakamura Naoki , Kojima Motohiro , Kawachi Hiroshi , Kirsch Richard , Yoshida Tsutomu , Suzuki Yutaka , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki
Published: April 2023

AbstractPurpose:
Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC.
Patients and Methods:
In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated.
Results:
Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%–44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and <1%, respectively; IHC staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15; P = 0.003, Fisher exact test) were observed for CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and <2.5, respectively, in tumor-infiltrating lymphocytes.
Conclusions:
CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.
Data from Neoantigen Identification and Response to Adoptive Cell Transfer in Anti–PD-1 Naïve and Experienced Patients with Metastatic Melanoma
Authors: Levi Shoshana T. , Copeland Amy R. , Nah Shirley , Crystal Jessica S. , Ivey Gabriel D. , Lalani Almin , Jafferji Mohammad , White Bradley S. , Parikh Neilesh B. , Leko Vid , Krishna Sri , Lowery Frank , Prickett Todd D. , Gartner Jared J. , Jia Li , Li Yong F. , Sachs Abraham , Sindiri Sivasish , Robinson Welles , Gasmi Billel , Yang James C. , Goff Stephanie L. , Rosenberg Steven A. , Robbins Paul F.
Published: April 2023

AbstractPurpose:
Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the NCI demonstrated decreased responses in patients previously treated with anti–PD-1 agents. We aimed to find a basis for the difference in response rates between anti–PD-1 naïve and experienced patients.
Patients and Methods:
We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti–PD-1 naïve and 69 anti–PD-1 experienced patients.
Results:
Anti–PD-1 naïve patients were found to possess tumors with higher TMBs (352.0 vs. 213.5, P = 0.005) and received TIL reactive with more neoantigens (2 vs. 1, P = 0.003) compared with anti–PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT nonresponders in both anti–PD-1 naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, treatment products administered to anti–PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti–PD-1 experienced patients (2.5 vs. 1, P = 0.02).
Conclusions:
These results indicate that decreases in TMB and targeted neoantigens partially account for the difference in response to ACT and that additional factors likely influence responses in these patients.

See related commentary by Blass and Ott, p. 2980
Data from HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non–Small Cell Lung Cancer
Authors: Yonesaka Kimio , Tanizaki Junko , Maenishi Osamu , Haratani Koji , Kawakami Hisato , Tanaka Kaoru , Hayashi Hidetoshi , Sakai Kazuko , Chiba Yasutaka , Tsuya Asuka , Goto Hiroki , Otsuka Eri , Okida Hiroaki , Kobayashi Maki , Yoshimoto Ryoto , Funabashi Masanori , Hashimoto Yuuri , Hirotani Kenji , Kagari Takashi , Nishio Kazuto , Nakagawa Kazuhiko
Published: April 2023

AbstractPurpose:
EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non–small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC.
Experimental Design:
Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells.
Results:
We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd.
Conclusions:
Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.
Data from Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results
Authors: Bundred Nigel , Porta Nuria , Brunt Adrian Murray , Cramer Angela , Hanby Andrew , Shaaban Abeer M. , Rakha Emad A. , Armstrong Anne , Cutress Ramsey I. , Dodwell David , Emson Marie A. , Evans Abigail , Hartup Sue M. , Horgan Kieran , Miller Sarah E. , McIntosh Stuart A. , Morden James P. , Naik Jay , Narayanan Sankaran , Ooi Jane , Skene Anthony I. , Cameron David A. , Bliss Judith M.
Published: April 2023

AbstractPurpose:
EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer.
Patients and Methods:
This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects.
Results:
Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002).
Conclusions:
Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.
Data from Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication
Authors: Inaba Hiroto , van Oosterwijk Jolieke G. , Panetta John C. , Li Lie , Buelow Daelynn R. , Blachly James S. , Shurtleff Sheila , Pui Ching-Hon , Ribeiro Raul C. , Rubnitz Jeffrey E. , Pounds Stanley , Baker Sharyn D.
Published: April 2023

AbstractPurpose:
To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD).
Patients and Methods:
After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1–28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8–28) in 9 pediatric patients with refractory/relapsed FLT3-ITD–positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies.
Results:
The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P < 0.005) and survival (P < 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P < 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug–drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L).
Conclusions:
The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
Data from VCAM-1–targeted MRI Improves Detection of the Tumor-brain Interface
Authors: Cheng Vinton W.T. , de Pennington Nicholas , Zakaria Rasheed , Larkin James R. , Serres Sébastien , Sarkar Manjima , Kirkman Matthew A. , Bristow Claire , Croal Paula , Plaha Puneet , Campo Leticia , Chappell Michael A. , Lord Simon , Jenkinson Michael D. , Middleton Mark R. , Sibson Nicola R.
Published: April 2023

AbstractPurpose:
Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI.
Experimental Design:
Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression.
Results:
The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA–enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI.
Conclusions:
This work illustrates the potential of VCAM-1–targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.
Data from Efficacy and Safety of the Anti–PD-L1 mAb Socazolimab for Recurrent or Metastatic Cervical Cancer: a Phase I Dose-Escalation and Expansion Study
Authors: An Jusheng , Tang Jie , Li Benjamin X. , Xiong Huihua , Qiu Hui , Luo Lin , Wang Li , Wang Danbo , Zhou Qi , Xu Qin , Song Honglin , Zhang Yunyan , Zhang Hongping , Li Yujie , Yu Xiaohui , Zhang Jing , Ng Rachel , Zhao Wayne , Wong Michael , Dai Xiangrong , Li Guiling , Wu Lingying
Published: April 2023

AbstractPurpose:
This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti–programmed death ligand 1 (PD-L1) mAb socazolimab in patients diagnosed with recurrent or metastatic cervical cancer.
Patients and Methods:
Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5 mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Results:
104 patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1–positive tumor expression (combined positive score ≥1). ORR was 15.4% [95% confidence interval (CI), 8.7%–24.5%]. Median PFS was 4.44 months (95% CI, 2.37–5.75 months), and the median OS was 14.72 months (95% CI, 9.59–NE months). ORR of PD-L1–positive patients was 16.7%, and the ORR of PD-L1–negative patients was 17.9%. No treatment-related deaths occurred.
Conclusions:
Our study demonstrates that socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 mAbs.
Data from Preclinical and Clinical Trial Results Using Talazoparib and Low-Dose Chemotherapy
Authors: Wainberg Zev A. , Singh Arun S. , Konecny Gottfried E. , McCann Kelly E. , Hecht J. Randolph , Goldman Jonathan , Chmielowski Bartosz , Finn Richard S. , O'Brien Neil , Von Euw Erika , Price Megan M. , Martinez Diego , Yonemoto Lisa , Brennan Meghan , Glaspy John A. , Slamon Dennis J.
Published: April 2023

AbstractPurpose:
On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability.
Patients and Methods:
In this phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib/temozolomide or talazoparib/irinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomide/irinotecan. The starting dose of temozolomide was 25 mg/m2/day orally on days 1 to 5 and irinotecan was 25 mg/m2/day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD).
Results:
Of 40 patients enrolled, 18 (mean: 7 prior therapies) were enrolled in talazoparib + temozolomide and 22 in talazoparib + irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption and/or dose reductions of talazoparib. The MTDs were talazoparib 1 mg + temozolomide 37.5 mg/m2 and talazoparib 1 mg + irinotecan 37.5 mg/m2. There were four partial responses in the talazoparib + temozolomide arm and five in the talazoparib + irinotecan arm for a response rate of 23% (9/40). The pharmacokinetic profiles of talazoparib + temozolomide/irinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score.
Conclusions:
These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.
Data from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)
Authors: Wang Feng , He Ming-Ming , Xiao Jian , Zhang Yan-Qiao , Yuan Xiang-Lin , Fang Wei-Jia , Zhang Yan , Wang Wei , Hu Xiao-Hua , Ma Zhi-Gang , Yao Yi-Chen , Zhuang Zhi-Xiang , Zhou Fu-Xiang , Ying Jie-Er , Yuan Ying , Zou Qing-Feng , Guo Zeng-Qing , Wu Xiang-Yuan , Jin Ying , Mai Zong-Jiong , Wang Zhi-Qiang , Qiu Hong , Guo Ying , Shi Si-Mei , Chen Shuang-Zhen , Luo Hui-Yan , Zhang Dong-Sheng , Wang Feng-Hua , Li Yu-Hong , Xu Rui-Hua
Published: April 2023

AbstractPurpose:
To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC).
Patients and Methods:
Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription.
Results:
The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70–1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50–0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only.
Conclusions:
High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.
Data from Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice
Authors: Park Wungki , O'Connor Catherine A. , Bandlamudi Chaitanya , Forman Daniella , Chou Joanne F. , Umeda Shigeaki , Reyngold Marsha , Varghese Anna M. , Keane Fergus , Balogun Fiyinfolu , Yu Kenneth H. , Kelsen David P. , Crane Christopher , Capanu Marinela , Iacobuzio-Donahue Christine , O'Reilly Eileen M.
Published: April 2023

AbstractPurpose:
Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC).
Experimental Design:
Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated.
Results:
Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (<a href="#bib18 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib10 bib11 bib12 bib13 bib14 bib15 bib16 bib17 bib18 bib19 bib20 bib21 bib22 bib23 bib24 bib25 bib26 bib27 bib28 bib29 bib30 bib31 bib32 bib33 bib34 bib35 bib36 bib37 bib38 bib39 bib40 bib41 bib42 bib43 bib44 bib45 bib46 bib47 bib48 bib49 bib50 bib51 bib52 bib53 bib54 bib55" target="_blank">18, 3–55) or ovarian (<a href="#bib25 bib3 bib4 bib5 bib6 bib7 bib8 bib9 bib10 bib11 bib12 bib13 bib14 bib15 bib16 bib17 bib18 bib19 bib20 bib21 bib22 bib23 bib24 bib25 bib26 bib27 bib28 bib29 bib30 bib31 bib32 bib33 bib34 bib35 bib36 bib37 bib38 bib39 bib40 bib41 bib42 bib43 bib44 bib45 bib46 bib47 bib48 bib49 bib50 bib51 bib52 bib53 bib54 bib55 bib56" target="_blank">25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC.
Conclusions:
ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.
Data from Anlotinib plus Epirubicin Followed by Anlotinib Maintenance as First-line Treatment for Advanced Soft-tissue Sarcoma: An Open-label, Single-arm, Phase II Trial
Authors: Wang Zhi-ming , Zhuang Rong-yuan , Guo Xi , Zhang Chen-lu , You Yang , Chen Li-sha , Liu Wen-shuai , Zhang Yong , Luo Rong-kui , Hou Ying-yong , Lu Wei-qi , Zhou Yu-hong
Published: April 2023

AbstractPurpose:
The treatment outcome for locally advanced or metastatic soft-tissue sarcoma (STS) remains unsatisfactory. Anlotinib had demonstrated impressive activity in the subsequent-line treatment of STS. This study investigated the combination of anlotinib and epirubicin followed by anlotinib maintenance as first-line treatment for patients with advanced STS.
Patients and Methods:
This prospective, open-label, single-arm, phase II trial was conducted in Zhongshan Hospital, Fudan University. Eligible patients were ages 18 years or older and had previously untreated, pathologically confirmed, unresectable locally advanced or metastatic STS. All patients received up to six cycles of anlotinib plus epirubicin followed by anlotinib maintenance until disease progression, unacceptable toxicity, or death. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The study was registered on chictr.org (identifier ChiCTR1900024928).
Results:
From June 2019 to August 2020, 30 patients were enrolled. By December 2021, the median PFS was 11.5 months [95% confidence interval (CI): 8.6–14.4 months], while the median overall survival was not reached (95% CI: NE–NE). The objective response rate was 13.33% and the disease control rate was 80.0%. The most common adverse events (AE) included anemia (43.3%), nausea/vomiting (40.0%), fatigue (36.7%), leukopenia (30.0%), and proteinuria (10.0%), which were mainly of grade 1 or 2. The most frequent grade 3 or 4 AEs were anemia (10.0%), febrile neutropenia (33.3%), hypothyroidism (3.3%), and leukopenia (3.3%). No treatment-related death occurred.
Conclusions:
The combination of anlotinib and epirubicin followed by anlotinib maintenance demonstrated promising efficacy with a favorable safety profile.
Data from Inhibition of LSD1 with Bomedemstat Sensitizes Small Cell Lung Cancer to Immune Checkpoint Blockade and T-Cell Killing
Authors: Hiatt Joseph B. , Sandborg Holly , Garrison Sarah M. , Arnold Henry U. , Liao Sheng-You , Norton Justin P. , Friesen Travis J. , Wu Feinan , Sutherland Kate D. , Rienhoff Hugh Y. , Martins Renato , Houghton A. McGarry , Srivastava Shivani , MacPherson David
Published: April 2023

AbstractPurpose:
The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with (i) decreased neuroendocrine characteristics and (ii) activation of NOTCH signaling. We previously showed that inhibition of the lysine-specific demethylase 1a (LSD1) demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD-1 inhibition in SCLC.
Experimental Design:
We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD-1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models.
Results:
Bomedemstat potentiated responses to PD-1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T-cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by IFNγ and increased killing by tumor-specific T cells in cell culture.
Conclusions:
LSD1 inhibition increased MHC-I expression and enhanced responses to PD-1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard-of-care PD-1 axis inhibition in SCLC.