bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S14 from Multiomic mapping of acquired chromosome 1 copy number and structural variants to identify therapeutic vulnerabilities in multiple myeloma.
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: September 2024

Genes with increased dependency in cell lines with gain(1q).
Supplementary Table S4 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: September 2024

GENIE ID and PANID reference IDs for access to KRAS WT PDAC dataset
Study Representativeness Table1 from Randomized Trial of a Personalized Dendritic Cell Vaccine after Autologous Stem Cell Transplant for Multiple Myeloma
Authors: Chung David J. , Shah Nina , Wu Juan , Logan Brent , Bisharat Lina , Callander Natalie , Cheloni Giulia , Anderson Kenneth , Chodon Thinle , Dhakal Binod , Devine Steven , Somaiya Dutt Poorvi , Efebera Yvonne , Geller Nancy , Ghiasuddin Haider , Hematti Peiman , Holmberg Leona , Howard Alan , Johnson Bryon , Karagkouni Dimitra , Lazarus Hillard M. , Malek Ehsan , McCarthy Philip , McKenna David , Mendizabal Adam , Nooka Ajay , Munshi Nikhil , O'Donnell Lynn , Rapoport Aaron P. , Reese Jane , Rosenblatt Jacalyn , Soiffer Robert , Stroopinsky Dina , Uhl Lynne , Vlachos Ioannis S. , Waller Edmund K. , Young James W. , Pasquini Marcelo C. , Avigan David
Published: September 2024

Study representation of underserved communities
Supplementary table 2 from Unique spectrum of activating BRAF alterations in prostate cancer
Authors: Chehrazi-Raffle Alex , Tukachinsky Hanna , Toye Eamon , Sivakumar Smruthy , Schrock Alexa B. , Bergom Hannah E. , Ebrahimi Hedyeh , Pal Sumanta , Dorff Tanya , Agarwal Neeraj , Mahal Brandon A. , Oxnard Geoffrey R. , Hwang Justin , Antonarakis Emmanuel S.
Published: September 2024

Supplementary table 2
Supplementary Table S2 from The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 After Progression on Rucaparib
Authors: Brown Timothy J. , Yablonovitch Arielle , Till Jacob E. , Yen Jennifer , Kiedrowski Lesli A. , Hood Ryan , O'Hara Mark H. , Teitelbaum Ursina , Karasic Thomas B. , Schneider Charles , Carpenter Erica L. , Nathanson Katherine , Domchek Susan M. , Reiss Kim A.
Published: September 2024

Patient-level data
Supplementary Figure S4 from Baseline mutations and ctDNA dynamics as prognostic and predictive factors in ER-positive/HER2-negative metastatic breast cancer patients
Authors: Pascual Javier , Gil-Gil Miguel , Proszek Paula , Zielinski Christoph , Reay Alistair , Ruiz-Borrego Manuel , Cutts Rosalind , Ciruelos Gil Eva M. , Feber Andrew , Muñoz-Mateu Montserrat , Swift Claire , Bermejo Begoña , Herranz Jesus , Margeli Vila Mireia , Antón Antonio , Kahan Zsuzsanna , Csöszi Tibor , Liu Yuan , Fernandez Garcia Daniel , Garcia-Murillas Isaac , Hubank Michael , Turner Nicholas C. , Martín Miguel
Published: September 2024

Supplementary Figure 4. OS analysis in baseline population (C1D1) on ESR1 and PIK3CA mutations, within the population with any detectable mutation (N=146).
Supplementary Figure S6 from Prognostic markers of DNA methylation and NGS sequencing in progressive glioblastoma from the EORTC-26101 trial
Authors: Kessler Tobias , Schrimpf Daniel , Doerner Laura , Hai Ling , Kaulen Leon D. , Ito Jakob , van den Bent Martin , Taphoorn Martin , Brandes Alba A. , Idbaih Ahmed , Dômont Julien , Clement Paul M. , Campone Mario , Bendszus Martin , von Deimling Andreas , Sahm Felix , Platten Michael , Wick Wolfgang , Wick Antje
Published: September 2024

Supplementary Figure 6: Overall Survival according to PTEN mutation status in the group of IDH-wildtype glioblastomas (n = 362).
Supplementary Figure S5 from Integrated genomic and transcriptomic analysis improves disease classification and risk stratification of MDS with ring sideroblasts.
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis. , Tesi Bianca , Mortera Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana. , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svanhildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten-Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: September 2024

Cumulative proportion of principal components derived from principal component analysis. The first 14 explain 2/3 of the total variability.
Supplementary Figure S21 from Integrated genomic and transcriptomic analysis improves disease classification and risk stratification of MDS with ring sideroblasts.
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis. , Tesi Bianca , Mortera Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana. , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svanhildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten-Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: September 2024

MDSRS+ event free survival (EFS, A) and overall survival (OS, B) stratified by estimated MEP percentage and IPSS-mol risk category.
Supplementary Figure S13 from Integrated genomic and transcriptomic analysis improves disease classification and risk stratification of MDS with ring sideroblasts.
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis. , Tesi Bianca , Mortera Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana. , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svanhildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten-Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: September 2024

Digital sorting analysis on bulk CD34+ MNC transcriptome from MDSRS+ cases. Plots refer to unfiltered data, i.e. including hematopoietic stem/progenitor and mature hematopoietic cells. CMP, common myeloid progenitors; EryP, erythroid precursors; GMP, granulocyte–monocyte progenitors; Gran, granulocytes; HSC, hematopoietic stem cells; Lymph, lymphocytes; MK, megakaryocytes; MLP, multi-lymphoid progenitors; MPP, multipotent progenitors; MEP, megakaryocyte-erythroid progenitors). Cases (x-axis) are sorted by decreasing estimated MEP abundance, showing enriched IMP signature in cases with MEP depletion on right-side of the plots.
Supplementary Table S17 from Comprehensive analysis of tumor microenvironment reveals prognostic ceRNA network related to immune infiltration in sarcoma
Authors: Leng Dongliang , Yang Ziyi , Sun Heng , Song Chengcheng , Huang Chen , Ip Ka U. , Chen Guokai , Deng Chu-Xia , Zhang Xiaohua Douglas. , Zhao Qi
Published: September 2024

Supplementary Table S17. CD4+/CD8+ T cells infiltration levels in tumor tissues of mice bearing with S180.
Supplementary Methods 1 from Analysis of tumor microenvironment changes after neoadjuvant chemotherapy with or without bevacizumab in advanced ovarian cancer (GEICO-89T/MINOVA study).
Authors: Tavira Beatriz , Iscar Teresa , Manso Luis , Santaballa Ana , Gil-Martin Marta , García García Yolanda , Romeo Margarita , Iglesias Maria , de Juan Ferré Ana , Barretina-Ginesta Maria Pilar , Manzano Aránzazu , Gaba Lydia , Rubio María Jesús , de Andrea Carlos E. , González-Martín Antonio
Published: September 2024

Supplementary Methods. Detailed description of methodology.
Figure S2 from Analysis of tumor microenvironment changes after neoadjuvant chemotherapy with or without bevacizumab in advanced ovarian cancer (GEICO-89T/MINOVA study).
Authors: Tavira Beatriz , Iscar Teresa , Manso Luis , Santaballa Ana , Gil-Martin Marta , García García Yolanda , Romeo Margarita , Iglesias Maria , de Juan Ferré Ana , Barretina-Ginesta Maria Pilar , Manzano Aránzazu , Gaba Lydia , Rubio María Jesús , de Andrea Carlos E. , González-Martín Antonio
Published: September 2024

Supplementary Figure 2. Association between progression free survival (PFS) and immune populations presence.
Supplementary Data MS2 from Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men
Authors: Gosens Karien C.M. , van der Burg Sjoerd H. , Welters Marij J.P. , Boekestijn Sanne , Loof Nikki M. , Quint Wim G.V. , van Noesel Carel J.M. , van der Wal Allard C. , Richel Olivier , Krebber Wilhelmus J.T.A. , Melief Cornelis J.M. , de Vries Henry J.C. , Prins Jan M.
Published: September 2024

Supplementary material 2: HPV-Typing of AIN lesions.
Supplementary Table S9 from Single-cell RNA analysis reveals cell-intrinsic functions of CAR-T cells correlating with response in a phase II study of lymphoma patients
Authors: Sarén Tina , Ramachandran Mohanraj , Gammelgård Gustav , Lövgren Tanja , Mirabello Claudio , Björklund Åsa K. , Wikström Kristina , Hashemi Jamileh , Freyhult Eva , Ahlström Håkan , Amini Rose-Marie , Hagberg Hans , Loskog Angelica , Enblad Gunilla , Essand Magnus
Published: September 2024

Proteomics analysis of plasma three week post CAR-T infusion in relation to CRS
Supplementary Figure S11 from Single-cell RNA analysis reveals cell-intrinsic functions of CAR-T cells correlating with response in a phase II study of lymphoma patients
Authors: Sarén Tina , Ramachandran Mohanraj , Gammelgård Gustav , Lövgren Tanja , Mirabello Claudio , Björklund Åsa K. , Wikström Kristina , Hashemi Jamileh , Freyhult Eva , Ahlström Håkan , Amini Rose-Marie , Hagberg Hans , Loskog Angelica , Enblad Gunilla , Essand Magnus
Published: September 2024

Supplementary Figure S11. Expression of genes included in the single-cell polyfunctionality
strength index analysis in individual patients
Supplementary Figure S6 from Neoantigen targetability in progressive advanced melanoma
Authors: van den Bulk Jitske , Verdegaal Els M.E. , van der Ploeg Manon , Visser Marten , Nunes Joana B. , de Ru Arnoud H. , Tjokrodirijo Rayman T.N. , Ijsselsteijn Marieke E. , Janssen Natasja I. , van der Breggen Ruud , de Bruin Linda , de Kok Pita , Janssen George M.C. , Ruano Dina , Kapiteijn Ellen H.W. , van veelen Peter A. , de Miranda Noel F.C.C. , van der Burg Sjoerd H.
Published: September 2024

Expression of tumor associated antigens in early and later metastatic lesions.
Supplementary Table S1 from Memory-like differentiation, tumor targeting monoclonal antibodies, and chimeric antigen receptors enhance natural killer cell responses to head and neck cancer
Authors: Jacobs Miriam T. , Wong Pamela , Zhou Alice Y. , Becker-Hapak Michelle , Marin Nancy D. , Marsala Lynne , Foster Mark , Foltz Jennifer A. , Cubitt Celia C. , Tran Jennifer , Russler-Germain David A. , Neal Carly , Kersting-Schadek Samantha , Chang Lily , Schappe Timothy , Pence Patrick , McClain Ethan , Zevallos Jose P. , Rich Jason T. , Paniello Randal C. , Jackson Ryan S. , Pipkorn Patrik , Adkins Douglas R. , DeSelm Carl J. , Berrien-Elliott Melissa M. , Puram Sidharth V. , Fehniger Todd A.
Published: September 2024

Supplementary Table S1. Demographic and clinical data of advanced head and neck squamous cell carcinoma patients. 
Supplementary Table S12 from SPOP mutations target STING1 signaling in prostate cancer and create therapeutic vulnerabilities to PARP inhibitor–induced growth suppression
Authors: Geng Chuandong , Zhang Man-Chao , Manyam Ganiraju C. , Vykoukal Jody V. , Fahrmann Johannes F. , Peng Shan , Wu Cheng , Park Sanghee , Kondraganti Shakuntala , Wang Daoqi , Robinson Brian D. , Loda Massimo , Barbieri Christopher E. , Yap Timothy A. , Corn Paul G. , Hanash Samir , Broom Bradley M. , Pilie Patrick G. , Thompson Timothy C.
Published: September 2024

Supplemental Table S12. Quantification of each protein-specific band normalized to vinculin (RM-1-BM–derived models, Fig 4E).
Supplementary Table S10 from SPOP mutations target STING1 signaling in prostate cancer and create therapeutic vulnerabilities to PARP inhibitor–induced growth suppression
Authors: Geng Chuandong , Zhang Man-Chao , Manyam Ganiraju C. , Vykoukal Jody V. , Fahrmann Johannes F. , Peng Shan , Wu Cheng , Park Sanghee , Kondraganti Shakuntala , Wang Daoqi , Robinson Brian D. , Loda Massimo , Barbieri Christopher E. , Yap Timothy A. , Corn Paul G. , Hanash Samir , Broom Bradley M. , Pilie Patrick G. , Thompson Timothy C.
Published: September 2024

Supplementary Table S10. Quantification of each protein-specific band normalized to vinculin (Dox-inducible RM-1-BM–derived models, Fig. 4D, lower panel).
Supplementary Figure S9 from SPOP mutations target STING1 signaling in prostate cancer and create therapeutic vulnerabilities to PARP inhibitor–induced growth suppression
Authors: Geng Chuandong , Zhang Man-Chao , Manyam Ganiraju C. , Vykoukal Jody V. , Fahrmann Johannes F. , Peng Shan , Wu Cheng , Park Sanghee , Kondraganti Shakuntala , Wang Daoqi , Robinson Brian D. , Loda Massimo , Barbieri Christopher E. , Yap Timothy A. , Corn Paul G. , Hanash Samir , Broom Bradley M. , Pilie Patrick G. , Thompson Timothy C.
Published: September 2024

Supplementary Fig. S9. MALDI-TOF mass spectrometry analysis of ubiquitinated STING1 protein at K347 from in vivo ubiquitination sample co-transfected with SPOPwt shown in Fig. 3D.
Data from Targeting the Inducible T-cell Costimulator (ICOS) in patients with Relapsed/Refractory T-Follicular Helper Phenotype Peripheral T-Cell and Angioimmunoblastic T-Cell Lymphoma
Authors: Chavez Julio C. , Foss Francine M. , William Basem M. , Brammer Jonathan E. , Smith Sonali M. , Prica Anca , Zain Jasmine M. , Tuscano Joseph M. , Shah Harsh , Mehta-Shah Neha , Ramakrishnan Geethakumari Praveen Ramakrishnan. , Wang Ben X. , Zantinge Stephanie , Wang Lisa , Zhang Ling , Boutrin Anmarie , Zhao Weiguang , Cheng Lily , Standifer Nathan , Hewitt Lisa , Enowtambong Enowmpey , Shao Weiping , Sharma Shringi , Carlesso Gianluca , Moscow Jeffrey A. , Siu Lillian L.
Published: September 2024

Abstract
Purpose: Proliferation of T-follicular helper (TFH) CD4+ T-cells is a postulated pathogenic mechanism for T-cell non-Hodgkin’s lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models. Patients and Methods: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT) and recommended phase 2 dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791). Results: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01 mg/kg to 3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29 - 86) and the median prior lines of therapies was 3 (1 - 16). Most common grade 3 or 4 adverse events were decreased CD4+ T-cells (57%), lymphopenia (22%), anemia (13%), and infusion related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%. Conclusions: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.
Data from Early on-treatment changes in circulating tumor DNA fraction and response to enzalutamide or abiraterone in metastatic castration-resistant prostate cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah , Annala Matti , Donnellan Grainne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: September 2024

Abstract
Purpose: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. Experimental Design: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4-weeks of first-line ARPI treatment during two prospective multi-centre observational studies (NCT02426333;NCT02471469). CtDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy number profiles. Samples were classified into detected vs. undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Non-durable treatment response was defined as PFS ≤ 6 months. Results: CtDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. CtDNA fraction for samples with detected ctDNA was lower at 4-weeks vs. baseline (median 5.0% vs. 14.5%, P=0.017). PFS and OS was shortest for patients with persistent ctDNA at 4 weeks (univariate hazard ratio 4.79 (95%CI, 2.62-8.77) and 5.49 (95%CI, 2.76-10.91), respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4-weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. CtDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying non-durable responses. Conclusions: Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification.
Data from Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical implications
Authors: Gouda Mohamed A. , Nelson Blessie Elizabeth. , Buschhorn Lars , Wahida Adam , Subbiah Vivek
Published: September 2024

Abstract
Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAF V600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAF V600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples; respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
Data from Clinical relevance of BRCA1 promoter methylation testing in ovarian cancer patients.
Authors: Blanc-Durand Félix , Tang Roseline , Pommier Margaux , Nashvi Marzieh , Cotteret Sophie , Genestie Catherine , Le Formal Audrey , Pautier Patricia , Michels Judith , Kfoury Maria , Hervé Robert , Mengue Sylvie , Wafo Estelle , Elies Antoine , Miailhe Gregoire , Uzan Jennifer , Rouleau Etienne , Leary Alexandra
Published: September 2024

Abstract
Purpose: Homologous-recombination deficiency (HRD) is closely related to PARPi benefit in ovarian cancer (OC). The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade OC to HRD status and clinical behavior to assess its clinical relevance. Design: This is a retrospective monocentric analysis of patients centrally tested for genomic-instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative ddPCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score≥42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA-wild-type OC had high BRCA1 methylation levels. All of the highly methylated tumors were classified HRD achieving a positive predictive value of 100%. We detected 14% (11/79) low methylated tumors (1-69%) and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth and 33.3 for BRCAwt unmethylated (P<0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: OC patients with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be relevant to other tumor types for HRD prediction.
Data from Inferred immune-cell activity is an independent predictor of HER2 negative breast cancer prognosis and response to paclitaxel-based therapy in the GeparSepto trial
Authors: Fasching Peter A. , Szeto Christopher , Denkert Carsten , Benz Stephen , Weber Karsten , Spilman Patricia , Budczies Jan , Schneeweiss Andreas , Stickeler Elmar , Schmatloch Sabine , Jackisch Christian , Karn Thomas , Sinn Hans-Peter , Warm Mathias , van Mackelenbergh Marion , Rabizadeh Shahrooz , Schem Christian , Heinmoeller Ernst , Mueller Volkmar , Marme Frederik , Soon-Shiong Patrick , Nekljudova Valentina , Untch Michael , Loibl Sibylle
Published: September 2024

Abstract
Purpose. Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in breast cancer (BC) patients. Here, immune-cell activity of BC tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426). Experimental Design. Pre-study biopsies from 279 HER2 negative BC patients in the G7 trial underwent RNAseq-based profiling of 104 immune-cell specfic genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA ‘hot’, ‘warm’ or ‘cold’ by comparison of iICA in the G7 cohort relative to that of 1467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed TILs, and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS) and overall survival (OS), were determined. Results. iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low. Conclusions. Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR and survival were observed for HR positive versus negative tumors, suggesting expanded study of the implication of these findings is warranted.
Data from Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial
Authors: Ailawadhi Sikander , Chen Zi , Huang Bo , Paulus Aneel , Collins Mary C. , Fu Lei (Tommy). , Li Mingyu , Ahmad Mohammad , Men Lichuang , Wang Hengbang , Davids Matthew S. , Liang Eric , Mekala Divya J. , He Zhicong , Lasica Masa , Yannakou Costas K. , Parrondo Ricardo , Glass Laura , Yang Dajun , Chanan-Khan Asher , Zhai Yifan
Published: September 2024

Abstract
Purpose: This global phase 1 trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective BCL-2 inhibitor, in patients with relapsed or refractory chronic or small lymphocytic leukemia (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase 2 dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%); fatigue (34.6%); nausea (30.8%); anemia and thrombocytopenia (28.8% each); neutropenia (26.9%); constipation (25.0%); vomiting (23.1%); headache (21.2%); peripheral edema and hypokalemia (17.3% each); and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%); thrombocytopenia (13.5%); and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response of 63.6% and median time to response of 2 (range, 2-8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.
Data from Genomic profiling of radiation-induced sarcomas reveals the immunological characteristics and its response to immune checkpoint blockade
Authors: Hong Dong-Chun , Yang Jing , Sun Cong , Liu Yuan-Tao , Shen Lu-Jun , Xu Bu-Shu , Que Yi , Xia Xiaojun , Zhang Xing
Published: September 2024

Abstract
Purpose: Radiation-induced sarcomas (RISs) have poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration. Experimental Design: Here, we perform whole exome (WES) and mRNA sequencing (mRNA-seq) on patient with RISs and primary sarcomas (WES samples 46 vs 48, mRNA-seq samples 16 vs 8, mainly in head and neck), investigate the anti-tumor effect of PD-1 blockade in RIS-PDX models, and analyze clinical data of RIS patients treated with chemotherapy alone or combined with an anti-PD-1 antibody. Results: Compared to primary sarcomas, RISs manifested different pattern of copy number variations, significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher overall response rate (ORR) (36.67% vs 8.00%, p = 0.003), longer overall survival (31.9 months vs 14.8 months, p = 0.014) and longer progression free survival (4.7 months vs 9.5 months, p = 0.032) in RIS patients compared to single chemotherapy. Conclusion: Elevated genomic instability and higher immune cell infiltrations was found in RISs than primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiment and clinical practice. These evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RISs.
Data from Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Authors: DiPeri Timothy P. , Evans Kurt W. , Raso Maria Gabriela , Zhao Ming , Rizvi Yasmeen Q. , Zheng Xiaofeng , Wang Bailiang , Kirby Bryce P. , Kong Kathleen , Kahle Michael , Yap Timothy A. , Ileana Dumbrava Ecaterina E. , Ajani Jaffer A. , Fu Siqing , Keyomarsi Khandan , Meric-Bernstam Funda
Published: September 2024

Abstract
Purpose: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. Experimental Design: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and immunohistochemistry. In vitro CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by immunohistochemistry and reverse phase protein array. Results: Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43% and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2 overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2 expressing tumor types, including a T-DXd-treated colon cancer model. Conclusions: We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications.
Data from Anti-tumor efficacy of the novel KIT inhibitor IDRX-42 (formerly M4205) in patient- and cell line-derived xenograft models of gastrointestinal stromal tumor (GIST)
Authors: De Sutter Luna , Wozniak Agnieszka , Verreet Jasper , Vanleeuw Ulla , De Cock Lore , Linde Nina , Drechsler Christine , Esdar Christina , Sciot Raf , Schöffski Patrick
Published: September 2024

Abstract
Background: The majority of GIST are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity towards the most relevant KIT mutations, in 4 GIST xenograft models. Methods: NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E) and the cell-line derived model GIST882 (KIT:p.K642E). Mice were treated daily with vehicle (control), imatinib (100mg/kg), sunitinib (20mg/kg), avapritinib (5mg/kg), or IDRX-42 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histological response and immunohistochemistry. The Kruskal-Wallis and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant. Results: IDRX-42 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882 and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3% and 35.1% on the last day as compared to baseline, and tumor growth delay (160.9%) compared to control in UZLX-GIST9. Compared to controls, IDRX-42 (25mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all IDRX-42 (25mg/kg)-treated tumors. Conclusion: IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.
Data from The Immunogenomic Landscape of Neuroendocrine Prostate Cancer
Authors: Bhinder Bhavneet , Ferguson Alison , Sigouros Michael , Uppal Manik , Elsaeed Ahmed G. , Bareja Rohan , Alnajar Hussein , Eng Kenneth Wha. , Conteduca Vincenza , Sboner Andrea , Mosquera Juan Miguel , Elemento Olivier , Beltran Himisha
Published: September 2024

Abstract
Purpose: Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared to other prostate cancer types and SCLC. Experimental Design: In this retrospective study, a cohort of 170 patients with 230 RNA sequencing and 104 matched whole exome sequencing data were analyzed. Differences in immune and stromal constituents, frequency of genomic alterations, and associations with outcomes were evaluated. Results: In our cohort, 36% of the prostate tumors were identified as CD8+ T-cell inflamed, while the remaining 64% were T-cell depleted. T-cell inflamed tumors were enriched in anti-inflammatory M2 macrophages and exhausted T-cells and associated with shorter overall survival relative to T-cell depleted tumors (HR=2.62, p<0.05). Among all prostate cancer types in the cohort, NEPC was identified to be the most immune depleted, wherein only 9 out of the 36 total NEPC tumors were classified as T-cell inflamed. These inflamed NEPC cases were enriched in interferon gamma signaling and PD-1 signaling compared to other NEPC tumors. Comparison of NEPC with SCLC revealed that NEPC had poor immune content and less mutations compared with SCLC, but expression of checkpoint genes PD-L1 and CTLA-4 was comparable between NEPC and SCLC. Conclusions: NEPC is characterized by a relatively immune-depleted tumor immune microenvironment compared with other primary and metastatic prostate adenocarcinoma except in a minority of cases. These findings may inform development of immunotherapy strategies for patients with advanced prostate cancer.
Data from Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer
Authors: Anobile Dario P. , Salaroglio Iris C. , Tabbò Fabrizio , La Vecchia Sofia , Akman Muhlis , Napoli Francesca , Bungaro Maristella , Benso Federica , Aldieri Elisabetta , Bironzo Paolo , Kopecka Joanna , Passiglia Francesco , Righi Luisella , Novello Silvia , Scagliotti Giorgio V. , Riganti Chiara
Published: September 2024

AbstractPurpose:
The response to immune checkpoint inhibitors (ICI) often differs between genders in non–small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti–PD-1/anti–PD-L1 agents in NSCLC.
Experimental Design:
We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients’ phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system (“immune-PDXs”).
Results:
In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα highfemale immune-xenografts.
Conclusions:
Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC.

See related commentary by Valencia et al., p. 3832
Data from Clinical Activity of Combined Telomerase Vaccination and Pembrolizumab in Advanced Melanoma: Results from a Phase I Trial
Authors: Ellingsen Espen B. , O'Day Steven , Mezheyeuski Artur , Gromadka Agnieszka , Clancy Trevor , Kristedja Timothy S. , Milhem Mohammed , Zakharia Yousef
Published: September 2024

Abstract
Purpose: Cancer vaccines represent a novel treatment modality with a complementary mode of action addressing a crucial bottleneck for checkpoint inhibitor (CPI) efficacy. CPIs are expected to release brakes in T-cell responses elicited by vaccination, leading to more robust immune responses. Increased anti-tumor T-cell responses may confer increased anti-tumor activity in patients with less immunogenic tumors, a subgroup expected to achieve reduced benefit from CPIs alone. In this trial, a telomerase-based vaccine was combined with pembrolizumab to assess the safety and clinical activity in patients with melanoma. Patients and Methods: Thirty treatment-naïve patients with advanced melanoma were enrolled. Patients received intradermal injections of UV1 with adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) at two dose levels, and pembrolizumab according to the label. Blood samples were assessed for vaccine-induced T-cell responses, and tumor tissues were collected for translational analyses. The primary endpoint was safety, with secondary objectives including progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: The combination was considered safe and well-tolerated. Grade 3 adverse events were observed in 20% of patients, with no grade 4 or 5 adverse events reported. Vaccination-related adverse events were mostly mild injection site reactions. The median PFS was 18.9 months, and the 1- and 2-year OS rates were 86.7% and 73.3%, respectively. The ORR was 56.7%, with 33.3% achieving complete responses. Vaccine-induced immune responses were observed in evaluable patients, and inflammatory changes were detected in post-treatment biopsies. Conclusions: Encouraging safety and preliminary efficacy were observed. Randomized phase II trials are currently ongoing.
Data from Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies
Authors: Leclercq-Cohen Gabrielle , Steinhoff Nathalie , Albertí-Servera Llucia , Nassiri Sina , Danilin Sabrina , Piccione Emily , Yángüez Emilio , Hüsser Tamara , Herter Sylvia , Schmeing Stephan , Gerber Petra , Schwalie Petra , Sam Johannes , Briner Stefanie , Jenni Sylvia , Bianchi Roberta , Biehl Marlene , Cremasco Floriana , Apostolopoulou Katerina , Haegel Hélène , Klein Christian , Umana Pablo , Bacac Marina
Published: September 2024

Abstract
Purpose: Target-dependent TCB activity can result in strong and systemic release of cytokines that may develop into Cytokine Release Syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome. Experimental design: We explored the cellular and molecular players involved in TCB-mediated cytokine release by single cell RNA sequencing of whole blood treated with CD20-TCB together with bulk RNA sequencing of endothelial cells exposed to TCB-induced cytokine release. We used the in vitro whole blood assay and an in vivo DLBCL model in immunocompetent humanized mice to assess the effects of dexamethasone, anti-TNF-a, anti-IL-6R, anti-IL-1R and inflammasome inhibition, on TCB-mediated cytokine release and anti-tumor activity. Results: Activated T cells release TNF-α, IFN-γ, IL-2, IL-8 and MIP-1β, which rapidly activate monocytes, neutrophils, DCs and NKs along with surrounding T cells to amplify the cascade further, leading to TNF-α, IL-8, IL-6, IL-1β, MCP-1, MIP-1α, MIP-1β and IP-10 release. Endothelial cells contribute to IL-6 and IL-1β release and at the same time release several chemokines (MCP-1, IP-10, MIP-1α and MIP-1β). Dexamethasone and TNF-α blockade efficiently reduced CD20-TCB-mediated cytokine release while IL-6R blockade, inflammasome inhibition and IL1-R blockade induced a less pronounced effect. Dexamethasone, IL-6R blockade, IL-1R blockade and the inflammasome inhibitor did not interfere with CD20-TCB activity, in contrast to TNF-α blockade, which partially inhibited anti-tumor activity. Conclusion: Our work sheds a new light on the cellular and molecular players involved in cytokine release driven by TCBs and provides rationale for the prevention of CRS in patients treated with TCBs.
Data from Genomic profiling of metastatic castration-resistant prostate cancer samples resistant to androgen-receptor pathway inhibitors
Authors: Menssouri Naoual , Poiraudeau Loic , Helissey Carole , Bigot Ludovic , Sabio Jonathan , Ibrahim Tony , Pobel Cedric , Nicotra Claudio , Ngo-Camus Maud , Lacroix Ludovic , Rouleau Etienne , Tselikas Lambros , CHAUCHEREAU Anne , Blanc-Durand Félix , Bernard-Tessier Alice , Patrikidou Anna , Naoun Natacha , Flippot Ronan , Colomba Emeline , Fuerea Alina , Albiges Laurence , Lavaud Pernelle , van de Wiel Paul , den Biezen-Timmermans Eveline , Wesseling-Rozendaal Yvonne , Ponce-Aix Santiago , Michiels Stefan , Massard Christophe , Gautheret Daniel , Barlesi Fabrice , Andre Fabrice , Besse Benjamin , Scoazec Jean-Yves , Friboulet Luc , Fizazi Karim , Loriot Yohann
Published: September 2024

Abstract
Purpose: The androgen receptor axis inhibitors (ARPI) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown Experimental Design: In a prospective trial MATCH-R (NCT02517892), 59 mCRPC patients underwent whole exome sequencing (WES) and/or RNA-sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 mCRPC patients underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher's exact tests. Results: WES analysis indicated that no single-gene genomic alterations was strongly associated with primary resistance. RNA-seq analysis showed that AR gene alterations and expression levels were similar between responders and non-responders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. Conclusions:Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs’ resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation
Data from HLA-I evolutionary divergence confers response to PD-1 blockade plus chemotherapy in untreated advanced non-small-cell lung cancer
Authors: Jiang Tao , Jin Qiqi , Wang Jiahao , Wu Fengying , Chen Jian , Chen Gongyan , Huang Yunchao , Chen Jianhua , Cheng Ying , Wang QiMing , Pan Yueyin , Zhou Jianying , Shi Jianhua , Xu Xingxiang , Lin LiZhu , Zhang Wei , Zhang Yiping , Liu Yunpeng , Fang Yong , Feng Jifeng , Wang Zhehai , Hu Sheng , Fang Jian , Shu Yongqian , Cui Jiuwei , Hu Yi , Yao Wenxiu , Li Xingya , Lin Xiaoyan , Wang Rui , Wang Yongsheng , Shi Wei , Feng Gaohua , Ni Jun , Mao Beibei , Ren Dandan , Sun Huaibo , Zhang Henghui , Chen Luonan , Zhou Caicun , Ren Shengxiang
Published: September 2024

Abstract
Purpose: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small-cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. Patients and Methods: We integrated clinical, genomic and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase 3 trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). Results: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in those received PD-1 blockade plus chemotherapy (In the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio [HR], 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; In the CameL-sq trial, ORR: 89.2% vs 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002), but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS and OS in both two trials. Moreover, joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. Conclusion: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy.