Therapeutic Advances in Medical Oncology最新文献

The introduction of immune checkpoint inhibitors (ICIs) has represented a major therapeutic breakthrough for patients with mismatch repair-deficient (MMRd) endometrial cancer (EC). However, despite initial clinical success, a considerable subset of patients does not experience meaningful clinical benefit from these therapies. The lack of accurate predictive biomarkers to differentiate responders from non-responders remains a key clinical challenge. There is a pressing need for robust predictors of response that can more reliably identify patients with MMRd EC who are unlikely to benefit from ICIs, thereby guiding treatment decisions in routine practice and refining patient stratification in future clinical trials. A range of potential biomarkers has been explored in this context, including genomic, epigenomic, transcriptomic, and proteomic features of both the tumor and its microenvironment. In this review, we evaluate the predictive utility of conventional biomarkers, namely, programmed death-ligand 1 expression and tumor mutation burden, and survey emerging candidates, including proteomic immune signatures, for predicting response or resistance to ICIs in the MMRd EC population. We also examine machine-learning approaches that integrate multi-omics and clinicopathological data to improve stratification, and consider how mechanistic insights into ICI resistance may inform novel therapeutic strategies.

Background: Despite advancements in treatment of advanced testicular germ cell tumors (GCT), metastatic teratoma remains a significant challenge due to its intrinsic chemo- and radioresistance. Claudin-6 (CLDN6), a tumor-specific antigen, has shown promise in targeted therapies for various solid tumors, including metastatic GCT in early phase trials. Testicular GCT frequently exhibit a unique cytogenetic hallmark, isochromosome 12p (i12p), which is associated with tumor development and progression, underscoring its significance in oncogenesis and diagnosis, and potential as a potential biomarker.

Objectives: We aimed to understand the expression of CLDN6 during progression from germ cell neoplasia in situ (GCNIS) to primary GCT and postchemotherapy teratoma, and to investigate persistence of i12p in postchemotherapy teratoma.

Design: An observational cohort study.

Methods: Using matched pre- and postchemotherapy formalin-fixed paraffin-embedded tumor tissue from patients with primary GCT and postchemotherapy teratoma identified from a national GCT registry, iTestis, CLDN6 expression, and presence of i12p were evaluated.

Results: Twenty-two patients were eligible. The majority were diagnosed with mixed primary GCT (20/22, 91%) with teratoma the sole histologic component in 86% of postchemotherapy samples (19/22). CLDN6 expression was consistently observed in GCNIS (16/16, 100%) and primary nonteratoma GCT (20/20, 100%) though significantly lower in primary teratoma components (4/10, 40%) and metastatic teratomas (5/22, 23%). The mean proportion of CLDN6-positive cells was higher in primary nonteratoma components (87.5%) compared to primary (6.5%) and postchemotherapy teratoma (4.6%). i12p was also common in primary GCT (18/22, 82%), including pure teratoma (2/2, 100%), though concordance between i12p in primary orchidectomy and metastatic samples was lower (13/18, 72%).

Conclusion: Our results demonstrate early overexpression of CLDN6 in GCNIS and high expression in nonteratoma components in primary GCTs, but limited expression in primary and posttreatment teratomas. CLDN6-targeted therapies may not be effective for teratoma. In contrast, i12p was prevalent across all stages of GCT progression, suggesting its potential as a biomarker for identifying viable GCT.

Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment landscape of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC), with significant improvements in survival reported in clinical trials. However, limited data exist regarding its performance in real-world settings, particularly in lower-middle-income countries (LMICs).

Objectives: To evaluate the real-world effectiveness and safety of T-DXd in patients with HER2+ mBC in Türkiye.

Design: A multicenter retrospective cohort study.

Methods: This multicenter, retrospective cohort study, conducted by the Turkish Oncology Group, evaluated the real-world outcomes and tolerability of T-DXd in patients with HER2+ mBC across 27 oncology centers in Türkiye. The primary endpoints were real-world progression-free survival (rwPFS) and overall survival (rwOS). Secondary endpoints included response rate, safety (with adverse events (AEs) graded according to CTCAE v5.0), and evaluation of the first post-T-DXd treatments.

Results: A total of 269 patients were included. The median age was 49 years (interquartile range: 42-59), and the median follow-up was 12.9 months. The median rwPFS was 17.9 months (95% confidence interval: 13.3-22.5), and the median rwOS was 35.7 months (95% confidence interval: 27.8-43.6). The objective response rate was 71.4%, and the disease control rate was 95.2%. Patients receiving T-DXd in the second line experienced significantly longer rwPFS compared with those treated in later lines (p < 0.001). Treatment-related AEs of any grade occurred in 68.4% of patients. Interstitial lung disease was reported in 21 patients (7.8%), with 4 cases being grade ⩾3.

Conclusion: In this large national real-world cohort from an LMIC, T-DXd demonstrated robust antitumor activity and a manageable safety profile in patients with HER2+ mBC. These findings are consistent with prior clinical trial data and support the applicability of T-DXd in broader clinical settings.

Background: Postmenopausal breast cancer survivors treated with neo/adjuvant chemotherapy often experience persistent declines in physical function that fail to resolve after treatment. One mechanism thought to underlie this lasting impairment is cellular senescence, a fundamental process of aging that contributes to frailty and functional decline. Chemotherapy induces senescence, and preclinical studies show that targeting senescent cells with senolytics can reduce inflammation and improve physical function. These findings have generated a strong interest in translating senolytic therapies to humans; however, no study to date has evaluated the effects of senolytics on physical function in postmenopausal breast cancer survivors.

Objective: To evaluate the effects of targeting senescence with the oral senolytic agent fisetin on physical function in chemotherapy-treated postmenopausal breast cancer survivors.

Design: A multicenter, phase II, randomized, double-blind, placebo-controlled trial.

Methods and analysis: Eighty-eight postmenopausal women with early-stage, high-risk breast cancer who completed neo/adjuvant chemotherapy within the past 12 months and have diminished physical function, defined by a 6-minute walk distance (6MWD) <400 m, will be randomized 1:1 to receive either placebo or fisetin (20 mg/kg/day) on days 1-3 of a 14-day cycle for four cycles. The primary endpoint is the change in the 6MWD from baseline to end of treatment.

Ethics: The study has been approved by the institutional review boards at participating sites.

Discussion: This is one of the first studies to test whether targeting senescence with an oral senolytic agent, fisetin, can mitigate physical function decline in postmenopausal breast cancer survivors treated with neo/adjuvant chemotherapy. Promising results would provide the preliminary evidence needed to support a larger, confirmatory trial evaluating fisetin's efficacy in this population. If successful, this approach could fill an important unmet clinical need, as no pharmacological therapies currently exist to prevent or treat chemotherapy-related declines in physical function among postmenopausal breast cancer survivors.

Trial registration: ClinicalTrials.gov NCT05595499.

Background: The COMPASSION-15 trial showed that cadonilimab plus chemotherapy has significant clinical advantages in patients with HER2-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma compared to chemotherapy. This study evaluated the cost-effectiveness for patients in China and the United States.

Objective: To provide advice for patients on the use of cadonilimab.

Design: The cost-effectiveness analysis.

Methods: A partitioned survival model was conducted from perspective of the Chinese and U.S. healthcare systems over a lifetime horizon. Key parameters of the model were derived from COMPASSION-15 trial and published literature. In this study, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were taken as main outcomes. Sensitivity analyses, price simulations, and programmed death ligand 1 combined positive score (PD-L1 CPS) subgroup analyses were conducted to test robustness.

Results: In base-case analysis, cadonilimab plus chemotherapy group achieved an ICER of US dollars (USD) 32,630.84/QALY in China and USD 109,996.43/QALY in the United States, falling within the established willingness to pay (WTP) thresholds in both cases. At the current negotiated Chinese price (USD 208.94/100 mg), cadonilimab was cost-effective; in the United States, it remained cost-effective when priced below USD 437.87 (USD 100,000/QALY threshold) or USD 870.23 (USD 150,000/QALY threshold) per 100 mg. Subgroup analyses demonstrated that patients with PD-L1 CPS ⩾5 had 100% (China) and >94% (U.S.) probability of cost-effectiveness, whereas those with CPS <5 had reduced economic favorability. Sensitivity analyses identified progression-free survival utility, drug price, and body weight as key drivers of ICERs.

Conclusion: As a first-line strategy for patients with HER2-negative advanced G/GEJ adenocarcinoma, cadonilimab combined with chemotherapy represents a cost-effective option in both China and the United States. Its economic advantage is most pronounced in patients with high PD-L1 expression and at lower drug prices. These findings provide quantitative evidence supporting reimbursement negotiations and future pricing strategies for cadonilimab in global markets.

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced or unresectable hepatocellular carcinoma (HCC). However, the comparative clinical efficacy and cost-effectiveness of various ICI-based combination therapies remain unclear.

Objectives: This study aimed to evaluate the cost-effectiveness and clinical efficacy of the 12 first-line ICI-based therapies for advanced or unresectable HCC under two distinct healthcare systems-China and the United States.

Design: A model-based pharmacoeconomic analysis.

Methods: A network meta-analysis (NMA) was conducted to compare first-line ICI-based therapies in terms of overall survival (OS) and progression-free survival (PFS). A partitioned survival model with three health states (progression-free, progressive disease, death) was developed for cost-effectiveness analysis. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were primary outcomes. One-way and probabilistic sensitivity analyses were performed to assess model uncertainty.

Results: The NMA included 11 randomized clinical trials comprising 7289 patients. Four ICI-based regimens (atezolizumab plus bevacizumab, camrelizumab plus rivoceranib, sintilimab plus bevacizumab biosimilar, and penpulimab plus anlotinib) were associated with significantly improved OS and PFS compared with sorafenib. In China, camrelizumab plus rivoceranib and tislelizumab were cost-effective compared with sorafenib, with ICERs of $17,624.64 and $1971.14 per QALY, respectively. In the United States, no ICI-based therapy was cost-effective at a willingness-to-pay threshold of $150,000 per QALY; sorafenib remained the most cost-effective option. ICERs were most sensitive to drug costs, utility values, and discount rates.

Conclusion: Camrelizumab plus rivoceranib represents a cost-effective first-line therapy for advanced or unresectable HCC in China. In the United States, current ICI-based therapies are not cost-effective at existing prices. These findings may inform treatment selection and health policy decision-making in different healthcare systems.

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Background: Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma. Currently, high-dose methotrexate (HD-MTX)-based chemotherapy remains the standard first-line treatment. Previous clinical trials have reported that fotemustine-containing regimens offer promising efficacy and tolerability as an alternative option.

Objectives: To compare the efficacy, safety, and feasibility of fotemustine-containing regimens with HD-MTX-containing regimens for newly diagnosed PCNSL.

Design: A single-center, retrospective cohort study.

Methods: We retrospectively analyzed 114 newly diagnosed PCNSL patients treated between April 2011 and December 2021. Patients were classified into two cohorts: those receiving fotemustine-containing regimens (n = 72) and those receiving HD-MTX-containing regimens (n = 42). The primary efficacy endpoint was the objective response rate (ORR). Secondary endpoints included complete response rate, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Results: No significant difference in ORR was observed between the fotemustine-containing group and HD-MTX-containing group (68% vs 67%, p = 0.879). At a median follow-up of 28.5 months, the survival outcomes were comparable, with no statistically significant differences in either PFS (hazard ratio (HR) = 0.887, 95% confidence interval (CI): 0.522-1.508; p = 0.654) or OS (HR = 0.966, 95% CI: 0.494-1.888; p = 0.918). Notably, fotemustine-based therapy was associated with significantly fewer AEs, including leukopenia, thrombocytopenia, digestive tract toxicity, and mucositis (all p < 0.05).

Conclusion: Fotemustine-containing chemotherapeutics appear to confer a safer profile with comparable efficacy relative to HD-MTX-based regimens in newly-diagnosed PCNSL patients.

Background: The current predictive models for venous thromboembolism (VTE) have limitations in predicting VTE risk in patients with urological cancer.

Objectives: To establish and validate a risk stratification model for in-hospital VTE in patients with urological cancer.

Design: Retrospective, multicenter study.

Methods: The clinical data of 735 patients with urological cancer in the Department of Urology at four hospitals in China between January 2019 and December 2024 were analyzed. VTE (n = 147) and non-VTE (n = 588) groups were formed based on inclusion and exclusion criteria to develop a predictive model for VTE in patients with urological cancer.

Results: In this study, we developed a risk stratification model using a logistic regression based on variables selected by LASSO and constructed a nomogram to visualize the model. The areas under the receiver operating characteristic curve for the training, validation, and external validation cohorts were 0.933 (95% confidence interval (CI): 0.909-0.957), 0.900 (95% CI: 0.850-0.950), and 0.857 (95% CI: 0.776-0.938), respectively. The corresponding Brier scores for them were 0.070, 0.089, and 0.200. The calibration curve indicated good model performance. Decision curve analysis evaluated the clinical utility of the model and showed that it provided a higher net benefit than the "treat-all" and "treat-none" strategies across a wide range of threshold probabilities, supporting its potential clinical usefulness.

Conclusion: A predictive model was developed to estimate the risk of in-hospital VTE in patients with urological cancer, enabling personalized assessment and guiding preventive strategies. Further studies are needed to better validate our model.