bims-tumhet 2026-09-13 papers

Issue of 2026–09–13
three papers selected by
Sergio Marchini, Humanitas Research

Lancet Oncol. 2026 Sep 07. pii: S1470-2045(26)00223-8. [Epub ahead of print]

Chemotherapy with or without pembrolizumab followed by maintenance pembrolizumab with or without olaparib as first-line treatment of patients with advanced BRCA non-mutated epithelial ovarian cancer (ENGOT-OV43/GOG-3036/KEYLYNK-001): a randomised, double-blind, placebo-controlled, phase 3 trial.

ENGOT-OV43/GOG-3036/KEYLYNK-001 investigators

BACKGROUND: The PARP inhibitor olaparib is used for first-line maintenance of patients with BRCA-mutated advanced ovarian cancer. We aimed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance with or without bevacizumab as first-line treatment for patients with advanced BRCA1/2 non-mutated epithelial ovarian cancer.
METHODS: This randomised, double-blind, active-controlled, placebo-controlled, phase 3 trial was conducted at 224 gynaecological oncology centres in 22 countries. Eligible participants were aged 18 years or older; had histologically confirmed stage III-IV epithelial ovarian, primary peritoneal, or fallopian tube cancer with no BRCA mutation; did not receive previous anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy or an agent directed at another stimulatory or coinhibitory T-cell receptor or a PARP inhibitor; had an Eastern Cooperative Oncology Group performance status score of 0 or 1; and evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST). After one lead-in chemotherapy cycle, participants were randomly assigned (1:1:1), using an integrated interactive voice and web response system, to receive pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance (pembrolizumab-olaparib group); pembrolizumab plus chemotherapy followed by pembrolizumab plus placebo maintenance (pembrolizumab group); or placebo plus chemotherapy followed by placebo maintenance (control group); and could receive bevacizumab at the investigators discretion. Treatment allocation was stratified by PD-L1 combined positive score (CPS <10 vs ≥10), planned bevacizumab use, and surgery status. Planned treatment was intravenous pembrolizumab 200 mg (or matching placebo) every 3 weeks for 35 cycles, carboplatin plus paclitaxel (or docetaxel) chemotherapy according to local standard of care for five cycles, and maintenance oral olaparib 300 mg (or matching placebo) twice per day until discontinuation or up to 2 years. The primary endpoint was progression-free survival, tested first in the CPS (≥10) population and then in the intention-to-treat (ITT) population using a hierarchical testing strategy. This study is registered with ClinicalTrials.gov, NCT03740165 and is complete.
FINDINGS: Between Jan 30, 2019, and Aug 6, 2021, 2547 patients were assessed for eligibility, and 1367 were randomly assigned (ITT population) to receive pembrolizumab-olaparib (n=455), pembrolizumab (n=458), or the control (n=454). All participants were female and the median age was 61 years (IQR 52-68). 1084 (79%) of 1364 participants were White, 233 (17%) were Asian, 27 (2%) were of multiple race, 15 (1%) were Black or African American, and 5 (<1%) were American Indian or Alaska Native. At the first interim analysis (Jan 9, 2023; median follow-up 30·1 months [IQR 23·9-37·0]), pembrolizumab-olaparib significantly improved progression-free survival versus the control in the CPS (≥10; HR 0·63 [95% CI 0·49-0·80]; p<0·0001) and ITT populations (HR 0·68 [0·58-0·81]; p<0·0001). At the final analysis (Aug 26, 2024; median follow-up 49·6 months [IQR 43·4-56·5]), progression-free survival with pembrolizumab-olaparib was maintained (HR 0·66 [95% CI 0·53-0·83] in the CPS [≥10] population and 0·71 [0·61-0·84] in the ITT population). Pembrolizumab alone compared with the control group remained non-significant in the CPS (≥10) population (HR 0·95 [0·77-1·19]; p=0·33); therefore, there was no formal testing of progression-free survival in the ITT population. 297 (66%) of 452 participants in the pembrolizumab-olaparib group, 255 (56%) of 456 in the pembrolizumab group, and 232 (51%) of 454 in the control group had a grade 3 or higher treatment-related adverse event; the most common being neutropenia (102 [23%], 78 [17%], and 89 [20%]), anaemia (100 [22%], 59 [13%], and 48 [11%]), and neutrophil count decreased (66 [15%], 66 [15%], 68 [15%]). Serious treatment-related adverse events were reported in 110 (24%) participants in the pembrolizumab-olaparib group, 96 (21%) in the pembrolizumab group, and 39 (9%) in the control group, with the most common being febrile neutropenia (19 [4%], 16 [4%], and nine [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab-olaparib group (cerebral haemorrhage, cholangitis sclerosing, haemophagocytic lymphohistiocytosis, and colitis), and one (<1%) in the pembrolizumab group (gastrointestinal haemorrhage).
INTERPRETATION: Pembrolizumab plus chemotherapy followed by maintenance with pembrolizumab-olaparib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy, suggesting that this regimen might have potential for patients with newly diagnosed BRCA non-mutated stage III-IV epithelial ovarian cancer.
FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

DOI: https://doi.org/10.1016/S1470-2045(26)00223-8

Front Oncol. 2026 ;16 1919279

Epigenetic profiling of circulating cell-free DNA for early detection and minimal residual disease assessment in lung cancer: a focus on DNA methylation.

Tancredi Didier Bazan Russo, Valerio Gristina, Marco Donatello Delcuratolo, Leonardo Tamburi, Francesco Delli Muti, Filomena Mangiacotti, Clarissa Mujacic, Daniele Fanale, Antonio Galvano, Stefania Gori, Lorena Incorvaia, Antonio Giordano, Francesco Pepe, Umberto Malapelle, Antonio Russo, Lucia Anna Muscarella, Federico Pio Fabrizio.

Lung Cancer (LC) continues to be the biggest cause of cancer-related deaths around the world, mostly because of delayed diagnosis. Even if tissue biopsies and circulating tumor DNA (ctDNA) tests have revolutionized clinical management of LC patients, their effectiveness is restricted in settings with lower tumor burden, molecular heterogeneity, and bias in sampling approaches. In this scenario, the epigenetic profiling of cell-free DNA (cfDNA) stands out as a promising, less invasive approach, accurately detect cancer traces. Evidence from stage I-II disease and CT-detected pulmonary nodules supports the diagnostic potential of cfDNA methylation, although further validation in prospective screening cohorts remains necessary. Beyond genomic alterations, cfDNA epigenetic changes, including DNA methylation, chromatin organization, nucleosome positioning, and fragmentation patterns, reflect multi-dimensional complexity of tumor biology. These properties convey both the functional status and the origin of the circulating DNA fragments, accelerating for tumor integrating genomic analysis. Within this group, DNA methylation is the biologically robust and clinically well-established epigenetic marker, as alterations in methylation linked to cancer often occur in the early stages of tumorigenesis and are commonly found across different cancer cell types. Here, we explored the biological and clinical relevance of the epigenetic landscape of cfDNA in LC patients, particularly focusing on DNA methylation-based biomarkers and their evolving applications towards early diagnosis and post-surgical monitoring of minimal residual disease (MRD). We aimed to comprehensively overview analytical approaches for cfDNA methylation analysis, including targeted and genome-wide profiling strategies, and discuss their integration with machine learning (ML) and multi-omics frameworks in order to improve diagnostic performance and clinical applicability in LC management.

Keywords: DNA methylation; cell-free DNA; early detection; epigenetics; liquid biopsy; lung cancer; machine learning; minimal residual disease

DOI: https://doi.org/10.3389/fonc.2026.1919279

Cancer. 2026 Sep 15. 132(18): e70581

The evolving role of immunotherapy in ovarian cancer.

Ana Carolina Veneziani, Laura Venegas, Amit M Oza.

Ovarian cancer remains a major cause of gynecologic cancer mortality; and, although immune checkpoint inhibitors have transformed treatment in other solid tumors, their activity in ovarian cancer has been limited by tumor heterogeneity, an immunosuppressive tumor microenvironment, and the lack of robust predictive biomarkers. Recent research therefore has shifted toward combination and precision-based strategies, including dual-checkpoint blockade, integration with chemotherapy, antiangiogenic therapy, and poly(adenosine diphosphate-ribose) polymerase inhibitors, as well as adoptive cell therapies, vaccines, and oncolytic viruses. To date, added benefit from checkpoint inhibition has been clearest in chemotherapy-based combinations for programmed death-ligand-positive, platinum-resistant disease, whereas its contribution to maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors and/or bevacizumab in first-line or platinum-sensitive relapse appears limited. Emerging evidence also supports the role of antibody-drug conjugates as both direct cytotoxic agents and immune modulators. In parallel, biomarkers such as programmed death-ligand 1, tumor mutational burden, microsatellite instability high, and immune-cell infiltrates are being evaluated to improve patient selection, while artificial intelligence and machine learning are increasingly being explored to integrate clinical, pathologic, radiomic, and molecular data for response prediction. Research directions to make ovarian cancer more susceptible to immunotherapy are moving from empiric treatment to more biologically informed, multimodal approaches aimed at overcoming immune suppression, enhancing antitumor immunity, and personalizing treatment for patients with ovarian cancer.

Keywords: adoptive; biomarkers; cancer vaccines; carcinoma; immunotherapy; ovarian epithelial; ovarian neoplasms; tumor; tumor microenvironment

DOI: https://doi.org/10.1002/cncr.70581