N Nature Medicine · Nov 28, 2025 Targeting of HIF2-driven cachexia in kidney cancer Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show thatPTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increasedPTHLHexpression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma. Cancer metabolism Renal cancer Targeted therapies biology mouse experiments
N Nature Medicine · Nov 24, 2025 A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting children and young adults that is driven by a chimeric protein, DNAJ-PKAc. The development of molecular inhibitors of DNAJ-PKAc has been hampered by unacceptable on-target toxicity, but the chimera results in a tumor-specific antigen (neoantigen) that may be targeted immunologically. Here we conducted a phase 1 clinical trial of a therapeutic peptide vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC, who had not previously received immune checkpoint therapy. The primary objectives were safety and T cell responses after week 10 (priming phase). Of the 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. The median age was 24 years (range 12–47 years). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from which we identified multiple class-II-restricted T cell receptors with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in T cell receptor repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or human leukocyte antigen loss. Our findings demonstrate the potential for therapeutic vaccines targeting ‘undruggable’ oncogenic drivers and suggest a rubric for evaluating effective anti-neoantigen immunity. ClinicalTrials.gov identifier:NCT04248569. Cancer immunotherapy Immunology biology
N Nature Medicine · Oct 18, 2025 Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advancedHER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5–71.6%), median progression-free survival was 12.9 months (90% CI 9.8–14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1–77.1%) and 69% (90% CI 45.2–86.8%), median progression-free survival was 13.2 months (90% CI 11.3–15.2 months) and 14.5 months (90% CI 11.3 months–NE), and median overall survival was 26.7 months (90% CI 19.5 months–NE) and not reached (90% CI 17.4 months–NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier:NCT05329766. Cancer Cancer therapy Gastrointestinal cancer other
N Nature Medicine · Oct 18, 2025 Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial Perioperative treatment strategies for HER2-positive esophagogastric adenocarcinoma remain suboptimal. Here in the open-label, phase 2 IKF/AIO PHERFLOT trial, we evaluated the safety and efficacy of adding pembrolizumab and trastuzumab to FLOT chemotherapy in patients with localized HER2-positive esophagogastric adenocarcinoma. The primary endpoints are the pathological complete response rate and the 2-year disease-free survival rate. Secondary endpoints include the R0 resection rate, feasibility and safety. Exploratory endpoints include clinical efficacy in molecularly defined subgroups. In this prespecified interim analysis, given the limited median follow-up period of 14.8 months, only one of the primary endpoints, the pathological complete response rate, and selected secondary endpoints, including the R0 resection rate, feasibility and safety, are reported here. Among 31 enrolled patients, 30 proceeded to R0 resection, and one patient declined surgery without disease progression. The combination regimen resulted in grade ≥3 treatment-related serious adverse events in 48.4% of patients (15 out of 31) aligning with established toxicity profiles of the respective agents and no treatment-related deaths. After four cycles of therapy, the pathological complete response rate was 48.4% (95% confidence interval 30.2–66.9; 15 out of 31) in the intention-to-treat population, and the subtotal regression rate (TRG1b according to Becker classification) was 19.4% (95% confidence interval 7.5–37.5; 6 out of 31), resulting in a major pathological response rate of 67.7% (95% confidence interval 48.6–83.3; 21 out of 31). Responses tended to be enriched in tumors with strong HER2 expression (immunohistochemistry 3+), high PD-L1 combined positive scores and lower T stage, but were also observed in substantial fractions of HER2 immunohistochemistry 2+/ISH+, T3 or T4 and combined positive scores <10 tumors. These findings support the feasibility and antitumor activity of perioperative chemoimmunotherapy targeting HER2 and PD-1 and warrant further validation in randomized trials. ClinicalTrials.gov registration:NCT05504720. Cancer immunotherapy Chemotherapy Gastric cancer Oesophageal cancer Targeted therapies biology other
N Nature Medicine · Oct 16, 2025 Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P< 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels. Cancer biology mouse experiments
N Nature Medicine · Sep 29, 2025 Genomically matched therapy in advanced solid tumors: the randomized phase 2 ROME trial Despite recent advancements demonstrating the potential of tumor-agnostic biomarkers to guide effective therapies, randomized evidence supporting the clinical superiority of precision oncology approaches compared to standard therapies remains limited. The ROME trial was a multicenter, randomized, open-label phase 2 study comparing tailored treatment (TT) to standard of care (SoC) in patients with advanced solid tumors progressing after one or two lines of therapy. Comprehensive genomic profiling on tissue and blood was performed to identify actionable alterations. Overall response rate (ORR) was the primary endpoint, and progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), time to next treatment (TTNT) and safety were the secondary endpoints. Between November 2020 and August 2023, 1,794 patients were screened, 897 were evaluated by the molecular tumor board (MTB) and 400 were randomized to TT or SoC. TT achieved a significantly higher ORR (17.5% versus 10%;P= 0.0294) and improved median PFS (3.5 months versus 2.8 months; hazard ratio = 0.66 (0.53–0.82),P= 0.0002). TT also showed superior 12-month PFS rates (22.0% versus 8.3%). Median OS was similar, with a 52% crossover rate. Grade 3/4 adverse events were also similar (40% TT versus 52% SoC). These results highlight the potential of TT to improve outcomes for patients with diverse actionable genomic alterations. These results also provide relevant evidence supporting a tumor-agnostic precision oncology strategy and highlight the potential of TTs, guided by genomic profiling and MTB recommendations, to significantly improve outcomes for patients with diverse actionable genomic alterations. ClinicalTrials.gov identifier:NCT04591431. Cancer genomics Cancer immunotherapy Cancer models Drug development Targeted therapies Cancer Genomics Human Drug Development Clinical
N Nature Medicine · Sep 24, 2025 Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial Patients with stage III melanoma are at high risk of relapse. The NADINA trial evaluating neoadjuvant nivolumab plus ipilimumab and the SWOG-1801 trial evaluating neoadjuvant pembrolizumab have demonstrated superior clinical outcomes with neoadjuvant versus adjuvant checkpoint inhibition. Morpheus-Melanoma was a phase 1b/2, randomized umbrella trial evaluating tobemstomig (anti-PD-1/anti-LAG-3 bispecific antibody;n= 40), tobemstomig plus tiragolumab (anti-TIGIT monoclonal antibody;n= 20) and atezolizumab (PD-L1-targeting monoclonal antibody) plus tiragolumab (n= 20) versus nivolumab (anti-PD-1 monoclonal antibody) plus ipilimumab (anti-CTLA-4 monoclonal antibody;n= 22) in stage III melanoma. The primary endpoint was pathological response by independent pathological review. Additional endpoints included safety and exploratory biomarkers. Here tobemstomig showed a similar pathological response rate (pRR) versus nivolumab plus ipilimumab (80.0% (32/40) versus 77.3% (17/22)); major pathological responses were less frequent with tobemstomig versus nivolumab plus ipilimumab treatment (62.5% (25/40) versus 72.7% (16/22)). Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab showed a lower pRR versus nivolumab plus ipilimumab (60.0% (12/20) and 45.0% (9/20) versus 77.3% (17/22), respectively). Tobemstomig demonstrated improved safety versus nivolumab plus ipilimumab, with 2.5% (1/40) and 22.7% (5/22) of patients experiencing grade 3 or higher treatment-related adverse events (TRAEs), respectively, and 0% (0/40) and 13.6% (3/22) of patients discontinuing treatment due to TRAEs, respectively. Grade 3 or higher TRAEs were reported by 15% (3/20) of patients in the tobemstomig plus tiragolumab arm and by no patients in the atezolizumab plus tiragolumab arm. Baseline CD8+and CD3+tumor-infiltrating T cell density, IFNγ pathway and effector T cell gene expression, tumor mutational burden and pre-surgery circulating tumor DNA correlated with pathological response across treatments. In conclusion, in the Morpheus-Melanoma study, tobemstomig demonstrated a similar pathological response and improved safety profile versus nivolumab plus ipilimumab in patients with resectable stage III melanoma. ClinicalTrials.gov identifier:NCT05116202. Cancer immunotherapy Melanoma Translational research Tumour biomarkers Cancer Immunology Drug Development Clinical Human
N Nature Medicine · Sep 10, 2025 Critical evaluation of the ProfiLER-02 study design and outcomes arising fromOlivier Trédan et al.Nature Medicinehttps://doi.org/10.1038/s41591-025-03613-x(2025) Cancer genomics Diagnostic markers Predictive markers Tumour biomarkers Cancer Clinical Drug Development Human
N Nature Medicine · Sep 08, 2025 Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A,n= 16) or nivolumab 3 mg kg−1q2w for three cycles plus ipilimumab 1 mg kg−1on cycle 1 (Arm B,n= 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (CI): 2.5–27.7) and 19.3 months (95% CI: 14.9–34.7), respectively. In Arm B, median PFS and OS were 19.8 months (7.1–not reached) and 28.6 months (20.4–not reached), respectively. Persistent ctDNA was detected during neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher’s exact test,P= 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test,P= 0.027 andP= 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test,P= 1.8 × 10−6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier:NCT03918252. Cancer genomics Mesothelioma Tumour biomarkers Cancer Immunology Clinical Drug Development Human
N Nature Medicine · Aug 21, 2025 GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/phase 2 trial Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2–CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/phase 2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2–CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 × 106CAR+cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32—excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2–CART01 persisted ≥12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 × 106GD2–CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 78% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after ≥3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2–CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier:NCT03373097. Cancer immunotherapy Paediatric cancer Cancer Immunology Clinical Human Drug Development
N Nature Medicine · Aug 21, 2025 Perioperative IDH inhibition in treatment-naive IDH-mutant glioma: a pilot trial Mutant isocitrate dehydrogenase (mIDH) inhibition significantly improves progression-free survival in patients with mIDH WHO grade 2 glioma; however, a large proportion of patients will progress, and mechanisms of adaptation to mIDH inhibition remain poorly understood. Perioperative studies with evaluation of paired pre- and post-treatment samples enable detailed understanding of drug response, facilitating biomarker development, but are rare in glioma owing to safety and cost concerns. Here we conducted a single-arm, open-label feasibility perioperative trial in patients with mIDH1 low-grade glioma, treatment naive to radiation and chemotherapy, with safusidenib (AB-218/DS-1001b), an orally available small-molecule inhibitor of mIDH1. As of 8 November 2024, 10 patients were enrolled and have completed the perioperative component, with a median follow-up of 14 months. Patients continue postoperative safusidenib with ongoing follow-up for safety and efficacy. The primary endpoint showed the feasibility and acceptability of conducting a two-stage perioperative trial. One patient experienced a serious surgery-related adverse event, and ten reported safusidenib-related adverse events; most were grade 1, and one experienced grade 3 elevation of transaminases. Tumor 2-hydroxyglutarate quantification revealed on-target activity, associated with alterations in differentiation programs and neural excitability, functionally validated in post hoc analysis by patch-clamp electrophysiology. Taken together, these results provide a detailed investigation of observations associated with mIDH inhibition in glioma. The study shows the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, serving as proof of concept for advancing drug development in glioma. ClinicalTrials.gov registration:NCT05577416. Cancer metabolism CNS cancer Transcriptomics Translational research Cancer Drug Development Clinical Human
N Nature Medicine · Aug 19, 2025 First-line sacituzumab tirumotecan with tagitanlimab in advanced non-small-cell lung cancer: a phase 2 trial Sacituzumab tirumotecan (sac-TMT, also known as MK-2870 or SKB264) is an antibody–drug conjugate targeting trophoblast cell surface antigen 2. We report the initial findings from the ongoing phase 2 OptiTROP-Lung01 study, evaluating the combination of sac-TMT and tagitanlimab (KL-A167), an anti-PD-L1 antibody, as first-line therapy in patients with advanced or metastatic non-small-cell lung cancer who lack actionable genomic alterations (cohorts 1A and 1B). Cohort 1A received sac-TMT (5 mg kg−1, every 3 weeks) plus tagitanlimab (1,200 mg, every 3 weeks) in each 3-week cycle, whereas cohort 1B was treated with sac-TMT (5 mg kg−1, every 2 weeks) plus tagitanlimab (900 mg, every 2 weeks) in each 4-week cycle, in a nonrandomized manner until disease progression or unacceptable toxicity. The primary endpoints included safety and objective response rate. This study was not powered for formal hypothesis testing. A total of 40 and 63 patients were enrolled in cohorts 1A and 1B, respectively. The median age was 63 years in both cohorts. An Eastern Cooperative Oncology Group performance status of 1 was observed in 97.5% and 85.7% of patients in cohorts 1A and 1B, respectively. In cohorts 1A and 1B, the most common grade ≥3 treatment-related adverse events were decreased neutrophil count (30.0% and 34.9%), decreased white blood cell count (5.0% and 19.0%) and anemia (5.0% and 19.0%). No treatment-related deaths were observed. After median follow-ups of 19.3 months for cohort 1A and 13.0 months for cohort 1B, the confirmed objective response rate in the full analysis set was 40.0% (16 of 40) and 66.7% (42 of 63), the disease control rate was 85.0% and 92.1% and median progression-free survival was 15.4 months (95% confidence interval 6.7–17.9) and not reached for cohorts 1A and 1B, respectively. sac-TMT plus tagitanlimab showed promising efficacy as a first-line treatment for advanced or metastatic non-small-cell lung cancer, with a manageable safety profile. ClinicalTrials.gov registration:NCT05351788. Cancer immunotherapy Non-small-cell lung cancer Cancer Drug Development Clinical Human
