bims-tumhet 2026-11-01 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–11–01
eleven papers selected by
Sergio Marchini, Humanitas Research

Sacituzumab tirumotecan versus treatment of physician's choice in previously treated endometrial cancer (TroFuse-005/ENGOT-en23/GOG-3095): a randomised, open-label, phase 3 trial.
Sacituzumab Tirumotecan plus Pembrolizumab in PD-L1-Negative Advanced NSCLC.
PARP Inhibitors in the Management of Ovarian Cancer: ASCO Living Guideline, Version 2026.1.0.
Liquid Biopsy: Past, Present, and Future.
DNA Methylation Patterns Between Serous Uterine and Ovarian Carcinomas Indicate Shared Markers with Fallopian Tube Epithelium and Distinctions Consistent with Histopathology.
Circulating tumor DNA in breast cancer in 2027: advancing liquid biopsy and molecular monitoring.
Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy.
First-line pembrolizumab versus carboplatin plus paclitaxel in participants with mismatch repair-deficient advanced or recurrent endometrial cancer (KEYNOTE-C93/GOG-3064/ENGOT-en15): interim analysis of a multicentre, open-label, randomised, active-comparator controlled, phase 3 trial.
Circulating Tumor DNA (ctDNA) for Minimal Residual Disease (MRD) Detection in Colorectal Cancer (CRC): Current Evidence, Clinical Applications, and Future Directions.
Divarasib as Compared with Sotorasib or Adagrasib in KRAS G12C-Mutated NSCLC.
Comparative prognostic performance of the FIGO 2023 and FIGO 2009 staging systems integrated with molecular classification in endometrial cancer: a retrospective single-centre cohort study.

Lancet. 2026 Oct 26. pii: S0140-6736(26)02099-4. [Epub ahead of print]

Sacituzumab tirumotecan versus treatment of physician's choice in previously treated endometrial cancer (TroFuse-005/ENGOT-en23/GOG-3095): a randomised, open-label, phase 3 trial.

TroFuse-005/ENGOT-en23/GOG-3095 Investigators

BACKGROUND: Therapeutic options for patients with endometrial cancer who progress after platinum-based chemotherapy and immunotherapy are scarce, and prognosis is poor. Sacituzumab tirumotecan (sac-TMT) is a trophoblast cell-surface antigen 2-directed antibody-drug conjugate with a unique, bifunctional linker that maximises delivery of a belotecan-derived topoisomerase I inhibitor payload to tumour cells. This study aimed to compare sac-TMT with the treatment of physician's choice (TPC) in patients with endometrial cancer who had been previously treated with platinum-based chemotherapy and immunotherapy.
METHODS: In this randomised, open-label, phase 3 trial, patients were recruited from 242 gynaecological oncology centres across 31 countries and regions. Participating centres were selected based on established expertise in gynaecological oncology and an adequate volume of potentially eligible patients. Eligible patients were female and aged 18 years or older with histologically confirmed advanced or recurrent endometrial carcinoma or carcinosarcoma, who had received up to three previous lines of therapy, including systemic platinum-based chemotherapy and anti-programmed death 1 or anti-programmed death ligand 1 therapy. Patients were randomly assigned (1:1) via central interactive response technology to receive intravenous sac-TMT (4 mg/kg on days 1 and 15 of each 28-day cycle) or TPC (intravenous doxorubicin 60 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle). Investigators and patients were not masked to treatment; radiologists performing blinded independent central review were fully masked. Randomisation was stratified by mismatch repair status (deficient vs proficient), trophoblast cell-surface antigen 2 expression by immunohistochemistry (TROP2 EPR20043 Formulation Locked Assay [Roche Tissue Diagnostics, Tucson, AZ, USA]; low [0% to <50% of tumour cells with moderate (2+) or strong (3+) membrane staining intensity] vs medium-high [≥50% tumour cells with moderate (2+) or strong (3+) membrane staining intensity]), number of previous lines of systemic therapy (≤2 vs 3), and baseline disease status per Response Evaluation Criteria in Solid Tumors (version 1.1) by blinded independent central review (measurable vs non-measurable). Dual primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumors (version 1.1) assessed by blinded independent central review and overall survival, analysed in the intention-to-treat population. The data cutoff date was March 23, 2026. Progression-free survival and overall survival were evaluated as dual primary endpoints using a graphical multiple-testing approach with prespecified alpha allocation. Progression-free survival was assessed every 8 weeks through to week 56, then every 12 weeks thereafter; overall survival was assessed continuously. The safety analysis included all randomly assigned patients who received at least one dose of study treatment. For progression-free survival, missing radiographic assessments were handled using prespecified censoring rules; no imputation was performed for missing overall survival or safety data. The trial was registered on ClinicalTrials.gov (NCT06132958) and is ongoing.
FINDINGS: Between Jan 5, 2024, and Sept 17, 2025, 776 patients were randomly assigned to sac-TMT (n=386) or TPC (n=390). 384 (99%) of 386 patients in the sac-TMT group and 367 (94%) of 390 in the TPC group received at least one dose of study treatment. At data cutoff, median follow-up was 14·0 months (IQR 11·0-16·9). Median progression-free survival was 7·2 months (95% CI 5·6-7·6) in the sac-TMT group and 3·9 months (3·7-5·3) in the TPC group (hazard ratio 0·59 [95% CI 0·50-0·70]; p<0·0001) and median overall survival was 19·0 months (16·1-not reached) in the sac-TMT group and 12·1 months (11·0-15·2) in the TPC group (0·68 [0·55-0·84]; p=0·0001). 265 (69%) of 384 patients in the sac-TMT group and 210 (57%) of 367 in the TPC group had a grade 3 or higher adverse event. Serious adverse events were reported in 133 (35%) patients in the sac-TMT group and 117 (32%) patients in the TPC group. Treatment-related adverse events led to death in three (<1%) patients in the sac-TMT group and three (<1%) in the TPC group.
INTERPRETATION: Sac-TMT significantly improved progression-free survival and overall survival versus TPC in patients with advanced or recurrent endometrial cancer previously treated with platinum-based chemotherapy and immunotherapy. These findings support sac-TMT as a new standard of care for patients with endometrial cancer who have received chemotherapy and immunotherapy and have few effective treatment options.
FUNDING: Merck Sharp & Dohme.

DOI: https://doi.org/10.1016/S0140-6736(26)02099-4
N Engl J Med. 2026 Oct 25.

Sacituzumab Tirumotecan plus Pembrolizumab in PD-L1-Negative Advanced NSCLC.

Fei Zhou, Xiangjiao Meng, Qingqing Ding, Peng Zhang, Wenhua Liang, Sanxing Guo, Yan Yu, Wenxiu Yao, Yun Fan, Xingxiang Pu, Chunling Liu, Jiuwei Cui, Peng Chen, Hua Zhong, Yongsheng Wang, Zhangzhou Huang, Zhi Xu, Xiaorong Dong, Tienan Yi, Ying Hu, Qiming Wang, Bolin Chen, Hui Wang, Longhua Sun, Lang He, Wei Zheng, Yina Wang, Xiaochen Zhang, Yu Yao, Yongsheng Li, Zhe Yang, Feng Ye, Xia Song, Ming Zhou, Li Yin, Yan Qing, Xiaoping Jin, Junyou Ge, Caicun Zhou.

BACKGROUND: Pembrolizumab plus chemotherapy with a platinum-based agent and pemetrexed is a widely used standard first-line treatment option for patients with programmed death ligand 1 (PD-L1)-negative advanced nonsquamous non-small-cell lung cancer (NSCLC) without targetable genomic alterations, but outcomes remain suboptimal.
METHODS: In this phase 3, open-label, randomized trial, we evaluated sacituzumab tirumotecan plus pembrolizumab in patients with previously untreated locally advanced or metastatic nonsquamous NSCLC without targetable genomic alterations and a PD-L1 tumor proportion score of less than 1%. Patients were randomly assigned in a 1:1 ratio to receive sacituzumab tirumotecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Overall survival was a secondary end point. This report presents the results of the prespecified interim analysis.
RESULTS: A total of 455 patients were randomly assigned to receive sacituzumab tirumotecan plus pembrolizumab (229 patients) or chemotherapy plus pembrolizumab (226 patients). After a median follow-up of 9.7 months, the median progression-free survival was significantly longer with sacituzumab tirumotecan plus pembrolizumab than with chemotherapy plus pembrolizumab (15.0 months vs. 5.7 months; hazard ratio for disease progression or death, 0.49; 95% confidence interval [CI], 0.36 to 0.65; P<0.001). An objective response occurred in 50.2% and 47.3% of the patients, respectively, and the median duration of response was 13.6 months and 6.8 months. Overall survival data were immature; the hazard ratio for death was 0.58 (95% CI, 0.38 to 0.88). Adverse events of grade 3 or higher that occurred after the start of treatment were reported in 47.6% of the patients assigned to receive sacituzumab tirumotecan plus pembrolizumab and in 60.6% of those assigned to receive chemotherapy plus pembrolizumab. Stomatitis was common with sacituzumab tirumotecan plus pembrolizumab, but the events were predominantly grade 1 or 2.
CONCLUSIONS: Among patients with PD-L1-negative advanced nonsquamous NSCLC without targetable genomic alterations, first-line treatment with sacituzumab tirumotecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab. (Funded by Sichuan Kelun-Biotech Biopharmaceutical; OptiTROP-Lung06 ClinicalTrials.gov number, NCT06711900.).

DOI: https://doi.org/10.1056/NEJMoa2611280
J Clin Oncol. 2026 Oct 27. 101200JCO2602412

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Living Guideline, Version 2026.1.0.

William P Tew, Christina Lacchetti, Tracey Sheridan Adams, Susana Banerjee, Elizabeth V Connor, Katherine Fuh, Monica B Jones, Stéphanie Lheureux, Ying L Liu, Kathleen Maxian, Kathleen Moore, Carolyn Y Muller, Navya Nair, Clare L Scott, Anil K Sood, Kristin Taylor, Oladapo Yeku, Elise C Kohn.

PURPOSE: This living guideline provides recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) in the management of epithelial ovarian cancer (EOC).
METHODS: An Expert Panel developed recommendations based on a systematic review of randomized controlled trials, and cohort studies evaluating homologous recombination deficiency (HRD) testing and PARPi efficacy and safety.
RESULTS: The updated evidence base comprises 79 publications, including 18 studies evaluating 13 homologous recombination deficiency (HRD) assays and 31 pivotal trials assessing PARPi efficacy and safety. Frontline trials demonstrated progression-free survival benefits. However, later-line treatment and recurrent maintenance trials reported potential overall survival disadvantages.
RECOMMENDATIONS: All patients with newly diagnosed advanced EOC should undergo genetic testing, and HRD tumor testing if BRCA-negative, using FDA-approved or prospectively validated companion diagnostic assays. In advanced EOC, PARPi maintenance should be prioritized for the first clinical remission. Frontline PARPi monotherapy maintenance should be offered after platinum-based chemotherapy response to patients with germline or somatic BRCA1/2 mutations or HRD-positive disease. Olaparib plus bevacizumab maintenance may be offered to patients responding to first-line platinum-based chemotherapy plus bevacizumab who have BRCA1/2 mutations or HRD-positive disease. PARPi maintenance therapy is not recommended for patients with non-BRCAmut HRD-negative tumors or early-stage EOC. In the recurrent setting, PARPi maintenance should be restricted primarily to PARPi-naïve patients with BRCA1/2 mutations responding to second-line or greater platinum-based chemotherapy. Monotherapy PARPi should not be offered for the treatment of recurrent EOC outside clinical trials. Furthermore, PARPi are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents outside a clinical trial. Clinicians should monitor for serious adverse events, including myelodysplastic syndrome, acute myeloid leukemia, and pulmonary complications.

DOI: https://doi.org/10.1200/JCO-26-02412
MedComm (2020). 2026 Nov;7(11): e71085

Liquid Biopsy: Past, Present, and Future.

Jiachen Liu, Dianjie Zeng, Keran Zhao, Yuxi Wang, Huijie Hu, Fei Deng, Yinhuai Wang, Liya Sun, Liangmin Fu.

  Liquid biopsy has evolved over two decades from an extension of tissue genotyping into a minimally invasive approach for repeat and longitudinal molecular assessment across the cancer continuum. Advances in sequencing, digital PCR, error suppression, and computational analytics have expanded analytes beyond circulating tumor DNA and circulating tumor cells to extracellular vesicles, circulating RNAs, and tumor-educated platelets, while broadening readouts from mutations to methylation, fragmentomics, transcriptomics, proteomics, and multiomic integration. This review traces the field from its technological foundations to current applications in early detection and multicancer early detection, therapy selection and resistance monitoring, minimal residual disease, recurrence-risk stratification, and longitudinal response assessment across major cancers and selected nononcologic settings. We distinguish clinically established applications from emerging and exploratory strategies and emphasize that high analytical performance does not by itself establish clinical utility. We further discuss preanalytical handling, standardization, biological confounders, and evidence required for implementation. Future progress will depend on use-case-driven development, prospective utility studies, longitudinal and multimodal interpretation, and integration with established diagnostic pathways. Together, these priorities define a transition from molecular detectability toward reproducible, actionable, and clinically meaningful liquid biopsy.

Keywords:  circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); extracellular vesicles (EVs); liquid biopsy; minimal residual disease (MRD); multicancer early detection (MCED)

DOI:  https://doi.org/10.1002/mco2.71085
Genes (Basel). 2026 Sep 22. pii: 1160. [Epub ahead of print]17(10):

DNA Methylation Patterns Between Serous Uterine and Ovarian Carcinomas Indicate Shared Markers with Fallopian Tube Epithelium and Distinctions Consistent with Histopathology.

Emily Kistner-Griffin, Mirna Mina-Abouda, Lulu Serang, Rachel Choe, Wendy Y Zhang, David P Mysona, Joe R Delaney.

   BACKGROUND/OBJECTIVES: Uterine serous carcinoma (USC) is a deadly form of Type II endometrial cancer of rising incidence in the USA. It is currently thought to originate in the uterus, but emerging evidence suggests USC etiology is more complex and may involve the fallopian tube. DNA methylation is an inheritable suppressive epigenetic marker that can differentiate cellular origins, so we opted to perform a study comparing DNA methylation of USC to the fallopian tube and uterus.
METHODS: DNA methylation profiles were compared between USC, fallopian tube epithelium (FTE), normal uterus, and a cancer known to primarily originate from FTE: high-grade serous ovarian cancer (HGSC). Hierarchical clustering of DNA methylation was performed. Variably DNA-methylated genes were defined for tumors and the FTE relative to normal uterus.
RESULTS: Hierarchical clustering of USC separated USC from normal uterus but showed similarity with some FTE profiles, such as HGSC. Differentially methylated genes in USC correspond to both known and novel genes related to USC biology. Known biomarkers included hypomethylation of PAX8 in both HGSC and USC, which is often used in histopathology. Another known histopathological marker is WT1, which is more often expressed in HGSC than USC. By DNA methylation, hypomethylation was observed with WT1 in HGSC, whereas in USC WT1 hypermethylation was observed. Other novel markers of interest are discussed within.
CONCLUSIONS: There is substantial overlap in DNA methylation biomarkers between the fallopian tube epithelium and USC tumors, just like the known FTE-originating carcinoma: HGSC. These results are supportive of the possibility of certain USCs arising first from the FTE (thereby retaining inheritable DNA methylation markers from the FTE) and then metastasizing to the uterus.

Keywords:  DNA methylation; cell-of-origin; epigenetics; high-grade serous ovarian cancer; uterine serous carcinoma

DOI:  https://doi.org/10.3390/genes17101160
Curr Opin Obstet Gynecol. 2026 Oct 27.

Circulating tumor DNA in breast cancer in 2027: advancing liquid biopsy and molecular monitoring.

Gaia Rachele Oliva, Massimo Cristofanilli, Carolina Reduzzi, Nicola Normanno, Eleonora Nicolò, Letizia Pontolillo.

   PURPOSE OF REVIEW: Circulating tumor DNA (ctDNA) is increasingly used for molecular profiling in breast cancer, and its role as a longitudinal biomarker is expanding. This review examines recent evidence on serial ctDNA assessment, focusing on minimal residual disease (MRD) and molecular relapse in early breast cancer (EBC) and on molecular response and emerging resistance in metastatic breast cancer (MBC).
RECENT FINDINGS: In EBC, ctDNA dynamics and MRD detection carry prognostic value, and serial surveillance can identify molecular relapse before overt recurrence. However, molecular lead time is not necessarily a therapeutic interception window, and the benefit of treating molecular relapse remains unproven. In MBC, serial ctDNA analysis can capture tumor dynamics, clonal evolution, and emerging resistance. Emerging cell-free DNA methylation-based approaches may enable molecular breast cancer subtyping, complementing genomic profiling. Definitions of molecular response and progression lack standardization across assays, metrics, thresholds, and sampling schedules. Nevertheless, randomized evidence shows that adapting treatment to selected actionable resistance alterations detected before radiological progression can improve clinical outcomes.
SUMMARY: ctDNA monitoring is shifting liquid biopsy from a static molecular characterization toward the longitudinal assessment of disease evolution. Its future clinical value will depend on identifying molecular changes reliable and actionable enough to translate earlier detection into patient benefit.

Keywords:  breast cancer; circulating tumor DNA; liquid biopsy; minimal residual disease; molecular monitoring

DOI:  https://doi.org/10.1097/GCO.0000000000001160
N Engl J Med. 2026 Oct 25.

Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy.

SAFFRON Investigators

BACKGROUND: Savolitinib is an oral, potent, highly selective MET-tyrosine kinase inhibitor (TKI). Combination therapy with savolitinib and osimertinib, an epidermal growth factor receptor (EGFR)-TKI, has shown activity in patients with EGFR-mutated, advanced non-small-cell lung cancer (NSCLC) with MET overexpression, MET amplification, or both, after progression during EGFR-TKI therapy.
METHODS: In this international, phase 3, open-label trial, we randomly assigned, in a 1:1 ratio, patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression (staining intensity of 3+ for MET in ≥90% of tumor cells on immunohistochemical analysis), MET amplification (≥10 gene copies on fluorescence in situ hybridization), or both whose disease had progressed during osimertinib therapy to receive osimertinib (at a dose of 80 mg once daily) plus savolitinib (300 mg twice daily) or intravenous platinum-pemetrexed. The primary end point was progression-free survival, as assessed by blinded independent central review. Secondary end points included overall survival and safety.
RESULTS: Of the 1746 patients screened, 338 were randomly assigned to receive osimertinib-savolitinib (171 patients) or platinum-pemetrexed (167 patients). Osimertinib-savolitinib led to significantly longer progression-free survival than platinum-pemetrexed (hazard ratio for disease progression or death, 0.55; 95% confidence interval [CI], 0.42 to 0.72; P<0.001), as well as significantly longer overall survival (hazard ratio for death, 0.68; 95% CI, 0.50 to 0.91; P = 0.01; final analysis). The Kaplan-Meier estimate of 12-month progression-free survival was 36% in the osimertinib-savolitinib group and 10% in the platinum-pemetrexed group, and the estimate of 12-month overall survival was 70% and 53%, respectively. The most frequently reported adverse events that occurred during treatment in the osimertinib-savolitinib group were peripheral edema (in 49% of the patients), anemia (in 26%), and diarrhea (in 26%). Grade 3 or higher adverse events during treatment were reported in 64% of the patients in the osimertinib-savolitinib group and in 63% of those in the platinum-pemetrexed group.
CONCLUSIONS: Osimertinib-savolitinib led to significantly longer progression-free and overall survival than platinum-pemetrexed among patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression, MET amplification, or both that had progressed during osimertinib therapy (Funded by AstraZeneca; SAFFRON ClinicalTrials.gov number, NCT05261399.).

DOI: https://doi.org/10.1056/NEJMoa2611335
Lancet. 2026 Oct 26. pii: S0140-6736(26)02095-7. [Epub ahead of print]

First-line pembrolizumab versus carboplatin plus paclitaxel in participants with mismatch repair-deficient advanced or recurrent endometrial cancer (KEYNOTE-C93/GOG-3064/ENGOT-en15): interim analysis of a multicentre, open-label, randomised, active-comparator controlled, phase 3 trial.

Brian M Slomovitz, Jianqing Zhu, Rutie Yin, Floor Backes, Mariusz Bidziński, Lucy Gilbert, Lyndsay J Willmott, Kosei Hasegawa, Jae-Weon Kim, Judith R Kroep, Ignacio Romero, Murat Gultekin, Peng-Hui Wang, Sally Baron-Hay, Jaroslav Klát, Ora Rosengarten, Maggie Polignano, Marcela Berrios, Karen Cadoo, Heini Lassus, Beata Maćkowiak-Matejczyk, Domenica Lorusso, Anna K L Reyners, Elizabeth R Burton, Vicky Makker, Lili Yao, Robin Meng, Robert Orlowski, Sandro Pignata.

BACKGROUND: A need exists for first-line chemotherapy-free options in advanced or recurrent endometrial cancer. We therefore assessed the efficacy, quality of life, and safety of first-line pembrolizumab versus carboplatin plus paclitaxel in mismatch repair-deficient (dMMR) advanced or recurrent endometrial cancer.
METHODS: The KEYNOTE-C93/GOG-3064/ENGOT-en15 multicentre, open-label, randomised, active-comparator controlled, phase 3 trial was conducted at 122 centres in 24 countries in the Americas, Asia, Europe, and Oceania. Adult participants (≥18 years) with inoperable, stage III or IV, persistent, advanced, or recurrent dMMR endometrial cancer were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles or intravenous carboplatin area under the curve 5 mg/mL or 6 mg/mL per min plus paclitaxel 175 mg/m2 on day 1 of each 3-week cycle for six cycles. Randomisation was stratified by disease status, histology, and previous receipt of (neo)adjuvant chemotherapy. Primary endpoints were progression-free survival per RECIST version 1.1, by blinded independent central review, and overall survival. This trial is registered at ClinicalTrials.gov, NCT05173987, and is ongoing.
FINDINGS: Between Feb 22, 2022, and Dec 12, 2023, 299 participants were assigned to pembrolizumab (n=149) or carboplatin plus paclitaxel (n=150). At the cutoff for the prespecified interim analysis in the intention-to-treat population (April 24, 2026), median progression-free survival was 38·2 months (95% CI 17·9 months-not reached) in the pembrolizumab group versus 8·4 months (6·8-10·4) in the carboplatin plus paclitaxel group (hazard ratio [HR] 0·57, 95% CI 0·42-0·79; p=0·0002). Estimated progression-free survival was 75% (95% CI 67-81) versus 76% (68-82) at 6 months, 67% (59-74) versus 40% (32-48) at 12 months, and 53% (44-61) versus 30% (22-38) at 36 months. The prespecified statistical significance criterion for overall survival was not met at the interim analysis (medians not reached; HR 0·77, 95% CI 0·52-1·15; p=0·10). Grade 3 or higher treatment-related adverse events occurred in 27 (18%) of 149 participants in the pembrolizumab group and 73 (51%) of 144 in the carboplatin plus paclitaxel group. Treatment-related adverse events of any grade that occurred in at least 25% of participants in either group included alopecia (three [2%] of 149 in the pembrolizumab group, 72 [50%] of 144 in the carboplatin plus paclitaxel group), anaemia (seven [5%], 71 [49%]), nausea (seven [5%], 41 [28%]), decreased neutrophil count (five [3%], 40 [28%]), peripheral neuropathy (none, 38 [26%]), and fatigue (20 [13%], 37 [26%]). Treatment-related adverse events led to treatment discontinuation in 14 (9%) of 149 participants in the pembrolizumab group and 21 (15%) of 144 participants in the carboplatin plus paclitaxel group; they resulted in death in two participants in the pembrolizumab group (hepatic failure and bacterial meningitis [n=1 each]) and one participant in the carboplatin plus paclitaxel group (pulmonary embolism).
INTERPRETATION: First-line pembrolizumab showed a statistically significant and clinically meaningful improvement in progression-free survival, with lower frequency of overall and grade 3 or above treatment-related adverse events. The study did not compare pembrolizumab monotherapy with the current standard of care (immunotherapy plus chemotherapy).
FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

DOI: https://doi.org/10.1016/S0140-6736(26)02095-7
Curr Oncol. 2026 Oct 09. pii: 606. [Epub ahead of print]33(10):

Circulating Tumor DNA (ctDNA) for Minimal Residual Disease (MRD) Detection in Colorectal Cancer (CRC): Current Evidence, Clinical Applications, and Future Directions.

Hannah Hyde, Emma Mageau, Chelsea M Leduc, Mitul J Madhu, Noah Dickinson, Tafheem-Un Nisa, Karolina M Czajka, Stacey A Santi, Prashant Jani, Grace W Ma, Sujeenthar Tharmalingam.

  Minimal residual disease (MRD) is a major contributor to colorectal cancer (CRC) recurrence following curative-intent treatment, yet conventional surveillance methods may fail to detect residual disease at its earliest stages. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for MRD detection and postoperative monitoring. We conducted a structured PubMed-based literature review and included 94 publications evaluating ctDNA in CRC. Across the literature, postoperative ctDNA positivity was consistently associated with increased recurrence risk and poorer disease-free and overall survival, while serial monitoring improved detection sensitivity and enabled assessment of treatment response. ctDNA frequently identified molecular recurrence approximately 2.5-11.5 months before conventional surveillance. Both tumor-informed and tumor-naive strategies were represented, using PCR/ddPCR, targeted next-generation sequencing, whole-exome or whole-genome sequencing, methylation-based assays, and emerging multiomic approaches. Although ctDNA demonstrates strong prognostic value, evidence supporting treatment modification based solely on ctDNA status remains limited. Further prospective randomized trials, assay standardization, and consensus clinical guidelines are required before routine implementation. Overall, ctDNA is a promising tool for recurrence prediction, surveillance, and precision management of CRC.

Keywords:  circulating tumor DNA (ctDNA); colon cancer; colorectal cancer (CRC); disease surveillance; liquid biopsy; minimal residual disease (MRD); precision oncology; rectal cancer; recurrence prediction; tumor-informed assays

DOI:  https://doi.org/10.3390/curroncol33100606
N Engl J Med. 2026 Oct 25.

Divarasib as Compared with Sotorasib or Adagrasib in KRAS G12C-Mutated NSCLC.

Ferdinandos Skoulidis, Myung-Ju Ahn, Shirish Gadgeel, Sanjay Popat, Niels Reinmuth, Bianca van Veggel, Farastuk Bozorgmehr, Victoria J Bray, Michael Duruisseaux, Wade T Iams, Julien Mazieres, Laura Bonanno, Lore Decoster, Jiaxin Niu, Marcos Pantarotto, Carlos Henrique Andrade Teixeira, Sevim Uzun, Bo Wang, Bryan A Chan, Enriqueta Felip, Molly S C Li, Hiroaki Akamatsu, Kristof Cuppens, Tae Min Kim, Martin Reck, Youyou Hu, Sarah M Shagan, Mark T Lin, Uyi Osaghae, Tien Hoang, Felice Wu, Raymond Meng, Michael S Mathisen, Benjamin J Solomon.

BACKGROUND: Divarasib, a next-generation, oral KRAS G12C inhibitor, is more potent and selective in vitro than the first-generation KRAS G12C inhibitors sotorasib and adagrasib.
METHODS: In this phase 3, international, open-label trial, patients with previously treated KRAS G12C-mutated advanced or metastatic non-small-cell lung cancer (NSCLC) were randomly assigned to receive divarasib orally at a dose of 400 mg once daily or control treatment (sotorasib orally at a dose of 960 mg once daily or adagrasib orally at a dose of 600 mg twice daily) until the occurrence of disease progression, unacceptable adverse events, loss of clinical benefit, withdrawal of consent, death, or trial termination. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, confirmed overall response, duration of response, patient-reported outcomes, and safety.
RESULTS: A total of 338 patients received divarasib (167 patients) or control treatment (171 patients; 156 received sotorasib and 15 received adagrasib). The median follow-up was 14.3 months. The median progression-free survival was 9.8 months with divarasib and 5.7 months with control treatment (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.44 to 0.76; P<0.001). The median overall survival was 17.7 months with divarasib and 12.0 months with control treatment (hazard ratio for death, 0.56; 95% CI, 0.41 to 0.78; P<0.001). Of the 328 patients who could be evaluated for response, a confirmed response occurred in 58.4% in the divarasib group and in 32.3% in the control group. The median duration of response was 11.9 months with divarasib and 6.9 months with control treatment. Fewer grade 3 or 4 treatment-related adverse events were noted with divarasib (24.6%) than with control treatment (34.5%).
CONCLUSIONS: Among patients with previously treated KRAS G12C-mutated advanced or metastatic NSCLC, divarasib led to significantly longer progression-free and overall survival than control treatment. (Supported by F. Hoffmann-La Roche; Krascendo 1 ClinicalTrials.gov number, NCT06497556.).

DOI: https://doi.org/10.1056/NEJMoa2605703
Eur J Obstet Gynecol Reprod Biol. 2026 Oct 15. pii: S0301-2115(26)00570-1. [Epub ahead of print]327 115502

Comparative prognostic performance of the FIGO 2023 and FIGO 2009 staging systems integrated with molecular classification in endometrial cancer: a retrospective single-centre cohort study.

Wei Xia, Bingjie Liu, Rui Kong, Yue Li, Chao Zhang, Huimin Liu.

   BACKGROUND: The 2023 revision of the International Federation of Gynecology and Obstetrics (FIGO) staging system incorporates molecular classification, aggressive histology, and substantial lymphovascular space invasion (LVSI) as key determinants. Its prognostic performance compared with FIGO 2009 requires validation in real-world cohorts.
METHODS: A retrospective review was undertaken of 712 consecutive patients with endometrial carcinoma treated between January 2019 and April 2025. Cases were restaged according to FIGO 2009 and FIGO 2023 integrated with molecular classification (FIGO 2023 m). Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier methods. Prognostic discrimination was assessed using Harrell's concordance index (C-index), time-dependent area under the curve, information criteria, and continuous net reclassification index (NRI).
RESULTS: Stage migration occurred in 26.4% of patients, predominantly due to upstaging driven by p53 abnormality, aggressive histology, and substantial LVSI. Molecular subtypes included. POLE-ultramutated (7.2%), microsatellite instability hypermutated (25.8%), no specific molecular profile (copy-number low) (51.3%), and p53 abnormal (copy-number high) (15.7%). Five-year PFS varied substantially across molecular groups. The C-index improved from 0.712 to 0.785 for PFS, and from 0.725 to 0.811 for OS. The continuous NRI for PFS was 0.241.
CONCLUSIONS: FIGO 2023 m demonstrated superior prognostic discrimination compared with FIGO 2009, supporting incorporation of molecular subtypes into routine endometrial cancer staging and risk assessment. Clinically, this integrated framework may help identify patients at risk of under- or over-treatment, particularly in those with disease previously considered as early stage, although prospective studies are needed before treatment algorithms can be changed definitively.

Keywords:  Endometrial cancer; FIGO 2009 staging; FIGO 2023 staging; Mismatch repair deficiency; Molecular classification; P53; POLE; Retrospective cohort; Survival analysis

DOI:  https://doi.org/10.1016/j.ejogrb.2026.115502