Therapeutic Advances in Medical Oncology最新文献

Background: A newly generic microspheres, sustained-release formulation of triptorelin acetate 3.75 mg has been developed.

Objectives: To evaluate the efficacy, pharmacokinetics, and safety of triptorelin 1-month formulation in Chinese patients with prostate cancer.

Design: An open-label, multicenter clinical trial with one arm testing a 1-month sustained-release triptorelin formulation in prostate cancer patients.

Methods: Patients with prostate cancer received three consecutive 28-day injections of triptorelin acetate. The primary endpoint was the proportion of successful patients over the total number of evaluable patients. Treatment success was defined as testosterone suppression below the clinical castration level (i.e., <0.5 ng/mL) at day 28 and maintenance of clinical castration until study completion (day 84). The frequency of patients with testosterone concentrations <0.2 ng/mL was also studied.

Results: The study included 125 patients. All 125 patients received at least one dose of the study drug and 122 completed the study. The successful patient proportion among the evaluable patients was 97.6% (122/125; 95% CI, 92.7-99.2). 95.1% (116/122) achieved testosterone concentrations <0.2 ng/mL. The pharmacokinetic profile of triptorelin during the first 3 months of treatment, evaluated in a subset of the study population (n = 11), showed sustained release of triptorelin from the formulation. Values for AUC_0-τ calculated from day 0 to 28, and day 56 to 84 were 134.42 (28.76), and 154.72 (21.86) h*ng/mL, respectively. The most common treatment-related adverse events were increased alanine aminotransferase (18.4%), increased aspartate aminotransferase (16.0%), and hot flashes (9.6%). Prolonged QT interval on electrocardiogram, erectile dysfunction, and decreased libido each occurred in ⩽4% of the patients. The frequently reported local adverse reaction was pain at the injection site, experienced by 2.4% (3/125) of the patients.

Conclusion: 3.75-mg Triptorelin acetate microspheres for injection were effective in achieving and maintaining testosterone suppression and were well tolerated in patients with prostate cancer.

Trial registration: chictr.org.cn (ChiCTR2000033188).

Background: Complete pathological response to neoadjuvant treatment (NAT) in breast cancer is associated with prolonged survival. Compared to other breast cancer immunophenotypes, luminal tumors are the least chemosensitive with low rates of pathological response within this molecular subtype. Thus, finding predictors of response in this subset remains challenging. The emerging concept of low human epidermal growth factor receptor 2 (HER2) expression has led to a repurpose of the current prognostic system. Little is known about its correlation with response to NAT.

Objectives: This study aims to evaluate predictors of response in early-stage luminal breast cancer receiving neoadjuvant chemotherapy.

Design: A total of 252 luminal patients who received NAT were retrospectively assessed in this cohort study.

Methods: We analyzed the correlation of ki67 and HER2 low expression with the rate of pathologic response. Using ki67 as a continuous variable and applying the receiver operating characteristic curves method.

Results: We identified that in patients with a ki67 expression level >37%, the probability of having a complete pathological response was 4.80 times higher (odds ratio = 4.80, 95% confidence interval: 1.92-12.04). In Her2-low breast cancer patients, Her2 expression did not correlate with a better response rate.

Conclusion: In our study, a ki67 expression value greater than 37% constitutes a predictive biomarker of pathological complete response in the subgroup of patients with luminal B tumors and could be considered, therefore, an indicator for treatment decisions in this subgroup.

Background: Several studies have indicated that the use of immune checkpoint inhibitors (ICI) can prolong the survival of patients with advanced gastric cancer (AGC). However, it remains unclear whether the presence of liver metastasis leads to systemic immune suppression, resulting in poorer immune therapy outcomes. This study aims to investigate whether liver metastasis affects the efficacy of ICI in first-line treatment for AGC patients.

Methods: The data of AGC patients undergoing combined immunotherapy and chemotherapy treatment at Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University from January 2018 to January 2023 were collected. The Kaplan-Meier method and Cox proportional hazards regression analysis were employed to analyze the overall survival (OS) and progression-free survival (PFS) of the patients.

Results: A total of 162 patients with AGC who were human epidermal growth factor receptor 2 (Her 2) negative and treated with immunotherapy in the first line were included in the study. Patients were divided into two groups, the liver metastasis group (LM group, n = 40) and the group without liver metastasis (NLM group, n = 122) according to the presence of liver metastasis. The results of the present study indicate that there was no statistically significant difference in the median OS, with median OS of 17 and 15 months, respectively (p = 0.29). Similarly, no significant difference was observed in the median PFS between the two groups (p = 0.65).

Conclusion: This study suggests that the presence or absence of liver metastasis does not significantly affect the prognosis of AGC patients receiving first-line treatment with ICI.

Background: Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear.

Objectives: To analyze the association between bone metastatic sites and the clinical efficacy of the first-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKI), in these patients.

Design: Retrospective multicenter cohort study.

Methods: The clinical data of patients with advanced-NSCLC harboring EGFR mutation, who were treated by EGFR-TKIs as first-line treatment at five medical institutions (N = 411), were retrospectively assessed for bone metastatic sites, overall survival (OS), and progression-free survival (PFS).

Results: Bone metastases were found in 41.1% of the patients at diagnosis, including 13.1%, 8.0%, and 20.0 for single, double, and multiple lesions (⩾3), respectively. The vertebra (76.3%) and pelvis (60.9%) were the most frequent metastatic sites. Femoral-, sternum-, and scapula-metastases were remarkably increased in the patients with multiple-bone metastases. In the EGFR-mutant NSCLC patient treated with osimertinib, both the OS and the PFS of the patients with femoral bone metastasis were significantly shorter than those of the patients without femoral bone metastasis (OS: not reached vs 12.1 months, p < 0.0001; and PFS: 17.2 vs 9.3 months, p < 0.0018). Furthermore, a multivariable Cox regression analysis, including several poor prognostic factors, such as L858R mutation and liver metastasis, demonstrated that femoral bone metastasis was a statistically independent predictor of OS.

Conclusion: Femoral bone metastasis is associated with poor survival of EGFR-mutant NSCLC patients who were treated with EGFR-TKIs, including osimertinib, and is an independent prognostic factor of OS.

Background: Although the approval of immunotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) has significantly improved the patient's prognosis, synchronous chemoradiotherapy has always been the standard treatment for limited-stage small-cell lung cancer (LS-SCLC).

Objectives: Immuno-combined and radio-combined therapy in LS-SCLC has been applied in clinical practice, but what is the best for LS-SCLC?

Design: This was a retrospective cohort study.

Methods: Patients with LS-SCLC from January 2019 to December 2023 were retrospectively screened and divided into three groups according to the initial treatment regimen whether included immune-combined and radio-combined treatment. Univariate and multivariate Cox regression were used to analyze the predictors affecting the survival of LS-SCLC, and the progression pattern of patients and the occurrence of adverse events (AEs) were also recorded.

Results: In this study, the median overall survival (OS) was 15.8 months, not yet reached (NR) and NR, and the median progression-free survival (PFS) was 11.7, 20.9, and 18.9 months in the immunotherapy combined chemotherapy (N = 34), immune combined chemoradiotherapy (N = 26), and chemoradiotherapy (N = 53) groups, respectively. OS and PFS were significantly prolonged in the radio-combined groups compared with the non-radio-combined group, and there was no significant difference between the radio-combined groups, namely immunotherapy combined chemoradiotherapy and chemoradiotherapy groups. In this study, we also constructed some indexes to predict prognosis for LS-SCLC, derived neutrophil and lymphocyte ratios were significantly associated with worse survival, and systemic inflammatory index and neuron-specific enolase (NSE) levels were significantly associated with shorter PFS. The primary organs of progression remained the lung and brain, the main immune-related AE was hypothyroidism, and the radiation-related AE was pneumonia.

Conclusion: Radiation-combined therapy still plays an important role in LS-SCLC in the era of immunotherapy, and clinicians cannot abandon the use of radiation therapy in the initial treatment plan for LS-SCLC.

Background: In recent years, the combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has emerged as the standard first-line treatment for hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) patients. However, the comparison between the efficacy of CDK4/6i has been poorly explored before. Moreover, it remains unclear about the optimal choice of CDK4/6i in the first-line treatment for HR+/HER2- MBC patients in Asian, especially Chinese populations.

Objectives: Our study aims to compare the efficacy of three CDK4/6i widely used in the Chinese population (palbociclib, abemaciclib, and dalpiciclib) in the real world.

Design: From 2020 to 2023, the medical records of patients diagnosed with HR+/HER2- MBC were retrospectively assessed in seven institutions in China. Patients who received first-line palbociclib, abemaciclib, or dalpiciclib plus ET were included.

Methods: Demographic and clinical data were retrospectively collected and analyzed. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate were used to analyze the clinical outcome.

Results: In total, 209 HR+/HER2- MBC patients were eligible for this study. Eighty-eight (42.1%), 79 (37.8%), and 42 (20.1%) patients were administered first-line palbociclib, abemaciclib, or dalpiciclib plus ET. The overall median rwPFS was 19 months, with no significant difference between these three CDK4/6i (p = 0.84). The results were similar even after propensity score matching. The median OS was not reached. Cox univariate and multivariate regression analysis identified that higher KI67 index, liver metastasis, and primary endocrine resistance were independent risk factors for rwPFS in patients with initial CDK4/6i plus ET.

Conclusion: This study presents a comparison of the real-world efficacy between three CDK4/6i widely used in the Chinese population. Palbociclib, abemaciclib, and dalpiciclib demonstrated comparable efficacy in Chinese patients with advanced HR+/HER2- MBC.

Trial registration: ClinicalTrials.gov identifier: NCT06344780.

Background: While targeted therapies have transformed the treatment landscape of oncogene-addicted non-small cell lung cancer (NSCLC), the influence of sex on treatment outcomes remains insufficiently understood.

Objectives: This systematic review aimed to investigate the impact of sex on clinical outcomes in patients with NSCLC harboring driver fusions treated with targeted therapies enrolled in clinical trials.

Data sources and methods: A comprehensive literature search was conducted using PubMed, Embase, and relevant conference abstracts to identify phase III randomized and early clinical trials that reported sex-specific data, including progression-free survival (PFS), overall survival (OS), overall response rate, and adverse events (AEs), in patients with fusion-positive NSCLC treated with tyrosine kinase inhibitors (TKIs).

Results: This review involved 10 studies reporting PFS data and 3 studies with OS data, focusing on first-line treatments for ALK fusion (9 studies) and RET fusion-positive (1 study) NSCLC. Pooled analysis of hazard ratios (HRs) for PFS and OS in ALK inhibitors trials revealed no significant differences in survival outcomes based on sex. Additionally, none of the studies provided data on sex-based differences in response rates or toxicities, highlighting a significant knowledge gap regarding the impact of sex on secondary outcomes in targeted therapy.

Conclusion: This review found no significant sex-related differences in survival outcomes among patients treated with ALK inhibitors. However, the lack of data on sex-specific response and toxicity emphasizes the need for future research to better understand the role of sex in modulating treatment outcomes and treatment decisions with TKIs.

Background: Urothelial carcinoma is a significant health concern in the United States (US), with high mortality and economic burdens. The CheckMate-901 trial showed promising survival benefits for nivolumab combined with gemcitabine and cisplatin followed by nivolumab maintenance therapy (nivolumab-combination) as first-line treatment of unresectable or metastatic urothelial carcinoma (UC), but its cost-effectiveness is unclear.

Objectives: This study aimed to evaluate the cost-effectiveness of the nivolumab-combination versus standard chemotherapy (gemcitabine-cisplatin) for advanced UC from the perspective of healthcare payers in the US.

Design: A model-based pharmacoeconomic evaluation.

Methods: Based on the CheckMate-901 study, a three-state Markov model (progression-free, progression, and death) was developed to evaluate the cost-effectiveness of nivolumab-combination versus gemcitabine-cisplatin as a first-line treatment for unresectable or metastatic UC. The model's outputs included quality-adjusted life years (QALYs) and costs and were used to calculate the incremental cost-effectiveness ratio (ICER). Costs included drug prices, adverse event management, and healthcare resource utilization from a US healthcare payer's perspective. State utilities were derived from published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were used to test model robustness. Scenario analyses for drug costs in the UK and Australian health systems were performed.

Results: Compared with gemcitabine-cisplatin, the nivolumab-combination resulted in an additional 0.416 QALYs at an incremental cost of $90,523, yielding an ICER of $217,527 per QALY. Sensitivity analyses indicated significant impacts from the cost of nivolumab maintenance therapy.

Conclusion: Compared with gemcitabine-cisplatin, nivolumab-combination therapy is not cost-effective for unresectable or metastatic UC at a $100,000 per QALY threshold. High drug prices in the US significantly impact cost-effectiveness, highlighting the need for price negotiations and healthcare policy adjustments to balance innovation incentives and patient affordability.

Background: Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), primary and secondary resistance to current therapies remains. Elevated circulating sphingolipids are associated with poor outcomes in patients with mCRPC, including therapeutic resistance and shorter overall survival. PCPro is a clinically accessible, regulatory compliant plasma lipid biomarker of poor prognosis in mCRPC, which incorporates prognostic sphingolipids. We hypothesize that reversal of the PCPro signature in men with mCRPC by sphingolipid-lowering agents will improve their clinical outcomes. However, the first step is to determine whether this poor prognostic lipid signature can be modulated. A potential sphingolipid-lowering agent is the PCSK9-inhibitor evolocumab, which is used in the management of hypercholesterolemia.

Objectives: Our primary objective is to assess whether treatment with evolocumab during standard anticancer therapy can safely modify the PCPro signature in men with mCRPC.

Design: This is a multicenter, open label phase II trial.

Methods: Men with mCRPC commencing docetaxel, cabazitaxel, abiraterone, enzalutamide, olaparib, or lutetium-177 PSMA for disease progression will be screened for the presence of PCPro. Those who are PCPro positive will receive a 12-week course of evolocumab concurrent with their standard therapy. Dosage is as per cardiovascular guidelines (420 mg subcutaneously every 4 weeks). PCPro will be repeated after 12 weeks. The primary endpoint is reversal of PCPro. The secondary endpoint is the safety of combination therapy with exploratory endpoints characterizing changes in comprehensive lipid profiles pre- and post-treatment.

Discussion: This study will evaluate whether evolocumab can safely modify the PCPro signature in men with mCRPC, providing essential data to the development of precision metabolic therapy in the management of prostate cancer.

Trial registration: This study is approved by the Human Research Ethics Committee (X22-0072 and 2022/ETH00427). It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001003763).

Background: Despite the revolutionary impact of immune checkpoint inhibitors (ICIs) on the treatment of metastatic urothelial carcinoma (mUC), the clinical utility of reliable prognostic biomarkers to foresee survival outcomes remains underexplored.

Objectives: The purpose of this study was to ascertain the prognostic significance of serum inflammatory markers in mUC patients undergoing ICI therapy.

Design: This is a retrospective, multicenter study.

Methods: Data were collected from two independent medical centers in Taiwan, encompassing a validation and a training cohort (TC). Patients with histopathologically confirmed urothelial carcinoma who received at least one cycle of ICI monotherapy were included. Serum inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were calculated prior to ICI therapy. Statistical analyses involved the use of receiver operating characteristic (ROC) curves to determine optimal biomarker cutoffs and Cox proportional hazards models to evaluate the independent predictive capability of these markers.

Results: A total of 192 patients were enrolled. In the univariate analysis, serum markers such as NLR, PLR, SII, and Hb were significantly associated with overall survival (OS) in both the training and validation cohorts (VC). White blood cells, NLR, and SII demonstrated a robust correlation with progression-free survival across both cohorts. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status ⩾2 (p < 0.001), visceral metastasis (p < 0.001), leukocytosis (p < 0.001), Hb levels ⩾10 mg/dL (p = 0.008), and NLR ⩾5 (p = 0.032) as independent predictors of OS. A prognostic nomogram integrating these independent factors yielded a C-index for a 3-year OS of 0.769 in the TC and 0.657 in the VC.

Conclusion: Serum inflammatory markers, combined with clinicopathologic factors, provide a practical prognostic tool in mUC treatment with ICIs.