Therapeutic Advances in Medical Oncology最新文献

Background: Gemcitabine plus capecitabine (GX) shows survival benefit and manageable safety in patients with advanced triple-negative breast cancer (TNBC) but there is a paucity of phase III trial evidence. We aimed to compare the efficacy and safety of GX with gemcitabine plus carboplatin (GC) as first-line treatment for patients with advanced TNBC and validate the prognostic value of tumor-infiltrating lymphocytes (TILs).

Methods: Patients with advanced TNBC were randomly assigned 1:1 to receive gemcitabine (1000 mg/m²) on days 1 and 8 plus oral capecitabine (1000 mg/m² twice a day) on days 1-14, or gemcitabine (1000 mg/m²) on days 1 and 8 plus carboplatin area under curve 2 on days 1 and 8. The primary endpoint was progression-free survival (PFS). TILs were analyzed by immunohistochemistry. The margin used to establish non-inferiority was 1.2.

Results: In all, 187 patients were randomly assigned, with 93 in GX and 94 in GC. Median PFS was 6.1 months in the GX arm compared with 6.3 months in the GC arm. The hazard ratio for PFS was 1.148, and a 95% CI was 0.856-1.539, exceeding the non-inferiority margin of 1.2. The median overall survival (OS) was 21.0 months in the GX arm compared with 21.5 months in the GC arm. The safety profile for the GX regimen was superior to the GC regimen, especially regarding hematological toxicity. Patients with high CD8⁺ TILs had significantly longer PFS and OS compared with patients with low CD8⁺ TILs. In the high CD8⁺ TIL group, the GC arm had prolonged PFS and OS compared with the GX arm.

Conclusion: The trial did not meet the prespecified criteria for the primary endpoint of PFS in patients with advanced TNBC. Moreover, the GC regimen showed better efficacy compared with the GX regimen in patients with high CD8⁺ TILs. However, the GX regimen should be considered in patients who cannot tolerate hematological toxicity.

Trial registration: ClinicalTrials.gov identifier: NCT02207335.

Background and objectives: Atypical thymic carcinoids (ATCs) are rare mediastinal malignancies that lack established treatment guidelines. Capecitabine and temozolomide (CapTem) has demonstrated significant efficacy in pancreatic neuroendocrine neoplasms (NENs), while its applicability and effectiveness in ATCs remain underexplored. This study seeks to investigate the efficacy, safety, and prognostic factors associated with CapTem in ATC patients.

Design and methods: Thirty-eight ATC patients treated with CapTem at our center were analyzed. We assessed the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse effects. We also examined patients' clinicopathological characteristics and their correlations with CapTem efficacy.

Results: The cohort achieved a 15.8% ORR and 89.5% DCR, with a median PFS of 13.0 months. Multivariate analysis identified the platelet-to-lymphocyte ratio (PLR) as a significant independent prognostic factor for PFS, with a PLR ⩾ 235 associated with shorter PFS (7 months vs. undefined, p = 0.0004). Age was an independent prognostic factor for OS, with patients over 50 years experiencing shorter OS (36 months vs. undefined, p = 0.015). Safety analysis showed rare severe toxicities and no treatment-related fatalities.

Conclusion: CapTem is an effective and well-tolerated treatment for ATC patients. Pretreatment PLR and age appear to be potential prognostic markers for CapTem therapy; however, these results warrant validation in larger patient cohorts.

Background: The incidence of prostate cancer (PC) is increasing in Asian countries. The epidemiology of PC, its treatment including the use of novel therapeutic options, impacts on quality of life, and clinical outcomes of patients with PC in Asia, are not well documented.

Objectives: To describe the demographic and disease features of the full cohort of patients enrolled in the United in Fight against prOstate cancer (UFO) registry.

Design: The UFO registry was a multi-national, longitudinal, observational study of patients with PC presenting to participating tertiary care hospitals in eight Asian countries/regions.

Methods: Patients with high-risk localized PC (HRL), non-metastatic biochemically recurrent, or metastatic PC were consecutively enrolled from September 14, 2015 until September 1, 2020 and followed for up to 5 years.

Results: Among the full cohort of 3635 patients, 425 had HRL, 389 had non-metastatic biochemically recurrent, and 2821 had metastatic PC. Median follow-up time was 4.2, 4.2, and 2.6 years, respectively. At first diagnosis, the mean age ranged from 65.7 to 69.1 years, 38.5% had extra-capsular tumor extension, 34.0% had regional lymph node metastases, and 65.1% had distant metastases. Quality-of-life scores at enrollment were significantly worse in patients with metastatic disease. Decisions to start therapy were mainly driven by treatment guidelines and disease progression. The decision to discontinue hormonal therapy was often due to disease progression. Few patients received novel hormonal therapies despite their availability.

Conclusion: The UFO registry provides a detailed, contemporary picture of the characteristics, treatment, and outcomes of patients with PC in Asia. There is an unmet medical need to improve access to novel agents in Asia, aiming to improve quality of life and clinical outcomes.

Trial registration: Clinicaltrials.gov Identifier: NCT02546908, Registry Identifier: NOPRODPCR4001.

Background: Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies.

Objectives: This study presents the first results of ipilimumab-nivolumab in invasive mucinous or non-mucinous lepidic adenocarcinoma (invasive mucinous adenocarcinoma (IMA) or invasive non-mucinous lepidic adenocarcinomas (INLA), respectively) of the lung.

Design: Dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks).

Methods: Participants histologically diagnosed with advanced IMA or INLA, who had not responded to at least one line of therapy, were included in the bronchioloalveolar carcinoma cohort. The primary endpoint was the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (confirmed complete and partial responses (CR and PR)). Secondary endpoints were progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) ⩾ 6 months plus ORR), and toxicity.

Results: Eight evaluable patients (median age: 77 years; the number of prior therapies ranged from 0 to 4; one patient with prior exposure to a PD-1 inhibitor; comprising six IMA and two INLA) were treated. One IMA had a 40% regression (PFS 45.2+ months, PD-L1 0%, KRAS G12C mutated, tumor mutational burden [TMB] 13 mut/Mb). One INLA had 66% regression (PFS 23.8 months, PD-L1 unknown, no actionable mutations, TMB 3 mut/Mb). Overall ORR was 25.0% (2/8) and CBR, 62.5% (5/8); PFS for the patients with SD > 6 months was 43.4+, 11.7+, and 8.3 months. The median PFS was 16 months (5.3-not reached) and the median OS was 32.2 months (14.6-not reached). The toxicity profile was similar to previous reports.

Conclusion: Ipilimumab plus nivolumab in the bronchioloalveolar carcinoma cohort (IMA, INLA) resulted in a durable ORR of 25.0% and CBR of 62.5% (PFS, 8.3 11.7+. 23.8 (PR), 43.4+ and 45.2+ (PR) months). Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies are warranted.

Trial registration: ClinicalTrials.gov registry: NCT02834013.

Pheochromocytomas and paragangliomas (PPGLs) are orphan tumors with the potential to spread to distant organs such as the lymph nodes, the skeleton, the lungs, and the liver. These metastatic tumors exhibit high rates of morbidity and mortality due to their frequently large tumor burden, the progression of the disease, and the excessive secretion of catecholamines that lead to cardiovascular disease and gastrointestinal dysmotility. Several molecular drivers responsible for the development of PPGLs have been described over the last 30 years. Although therapeutic options are limited, substantial progress has been made in the recognition of effective systemic therapies for these tumors. Successful clinical trials with radiopharmaceuticals such as high-specific-activity meta-iodobenzylguanidine and tyrosine kinase inhibitors such as cabozantinib and sunitinib have been recently published. This review will discuss the results of these studies and their impact on current clinical practices. In addition, this review will provide valuable information on how to design clinical trials to treat patients with metastatic PPGLs with novel medications.

Background: Until recently, targeted therapies have failed to benefit patients with human epidermal growth factor receptor 2 (HER2)-low-expressing breast cancer (BC). Nevertheless, antibody-drug conjugates (ADCs) have reshaped their prognosis.

Objectives: We performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) BC.

Design: This study is a systematic review and meta-analysis.

Data sources: We searched PubMed, Embase, and Cochrane databases as well as the American Society of Clinical Oncology, European Society for Medical Oncology, and San Antonio Breast Cancer Symposium conference proceedings.

Methods: Studies evaluating ADCs (trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), MRG002, and RC48-ADC) in patients with HER2-low a/mBC were included. We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using the I ² test.

Results: Overall, 14 studies were included (five real-world studies and nine clinical trials (CTs)), with 2883 HER2-low a/mBC patients: 808 received treatment of physician's choice (TPC), and 2075 ADCs. Most were treated with T-DXd (n = 1691), followed by SG (n = 310), MRG002 (n = 56), and RC48-ADC (n = 18). Patients treated with T-DXd achieved a significantly higher objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) than those receiving other ADCs. In the pooled analysis of four randomized CTs, ADCs statistically prolonged progression-free survival (n = 1828, hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.36-0.68, I ² = 82%, p < 0.001) and overall survival (n = 1546, HR 0.70, 95% CI 0.57-0.86, I ² = 43%, p < 0.001) compared with TPC. Patients on ADCs also achieved a greater antitumor response than TPC, including better ORR (odds ratio (OR), 3.7, 95% CI 2.5-5.6, I ² = 59%, p < 0.001), DCR (OR, 2.7, 95% CI 2.1-3.5, I ² = 0%, p < 0.001), and CBR (OR, 3.6, 95% CI 2.6-5.2, I ² = 56%, p < 0.01).

Conclusion: Our systematic review and meta-analysis confirms the efficacy of ADCs in HER2-low a/m BC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population.

Trial registration: This study was registered in PROSPERO (CRD42024452962).

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and aggressive subtype of inflammatory myofibroblastic tumor. The disease is associated with rearrangements of the anaplastic lymphoma kinase (ALK). In this paper, we present the clinicopathological features and treatment of a female patient diagnosed with EIMS. In 2019, an 18-year-old female patient was admitted to the hospital with abdominal pain. Radiological examinations confirmed a large pelvic mass which was subsequently resected. After re-evaluation of the initial histologic diagnosis, the final diagnosis of EIMS was established. Consequently, due to the lack of response to chemotherapy and deteriorating clinical condition, she began the therapy with ALK inhibitors. In total, the patient was treated with crizotinib, alectinib, and lorlatinib. As a result, after over 4 years since the initial diagnosis, she is still alive with significantly improved clinical condition and quality of life. This paper demonstrates the clinical benefits of sequential therapy of ALK inhibitors and an exceptionally long response to lorlatinib, a third-generation tyrosine kinase inhibitor.

Background: Chemoradiotherapy (CRT) is the main treatment for elderly patients with non-metastatic rectal cancer who are ineligible for or decline surgery, but the optimal modality remains unclear.

Objectives: This study was to validate the safety and efficacy of comprehensive geriatric assessment (CGA) guided radiotherapy in older patients.

Design: An exploratory analysis of a single-arm, multicenter, Phase II trial.

Methods: Patients aged over 70 and diagnosed with rectal cancer were enrolled and evaluated by CGA. CGA-guided radiotherapy was individually conducted in a multidisciplinary setting. Patients in fit, intermediate, and frail groups were scheduled to receive CRT, long-course radiotherapy, and short-course radiotherapy (SCRT) alone respectively. Patients who were unfit for or refused surgery were analyzed for acute toxicities and survival outcomes.

Results: In a total of 109 enrolled patients, 47 individuals who did not undergo surgery were included, with 26, 9, and 12 categorized into fit, intermediate, and frail groups. Only 11 (23.4%) grade 3 or above toxicities were observed overall. Within a median follow-up of 69.0 months, the 3-year overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS) rates were 44.3% (95% CI: 32.1%-61.2%), 25.5% (95% CI: 15.7%-41.6%) and 61.0% (95% CI: 47.8%-77.6%) in total. The 5-year OS, PFS, and CSS reached 15.0% (95% CI: 7.4%-30.3%), 14.6% (95% CI: 7.3%-29.4%), and 36.2% (95% CI: 22.0%-59.4%), with no significant difference among the three subgroups. SCRT (p < 0.001) and dose boost (p = 0.045) contributed to lower tumor-related death rates in multiple competing risk regressions.

Conclusion: Radiotherapy guided by CGA was effective and well-tolerated in non-surgical elderly patients. SCRT alone seemed to achieve similar clinical outcomes as CRT in corresponding subgroups. However, given the limited size of this study, further investigation in a larger population is still needed for this strategy.

Background: There are currently limited real-world data on the effectiveness and safety of first-line pembrolizumab combined with chemotherapy in patients with advanced/recurrent or metastatic esophageal squamous cell carcinoma (ESCC) in China. This study was conducted to address this knowledge gap.

Methods: This multicenter retrospective cohort study was conducted at 17 hospitals in China and included adults (⩾18 years) with stage IV primary ESCC, or recurring 6 months after radical radiotherapy/surgery-based combination therapy, who had received first-line pembrolizumab plus chemotherapy. Data were collected from electronic medical records. Endpoints included objective response rate (ORR), disease control rate (DCR) progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses were conducted to identify patient characteristics and treatment patterns associated with treatment response.

Results: In total, 202 patients who had received treatment from 2018 to 2023 were included: 125 (61.9%) newly diagnosed and 77 (38.1%) with recurrence, 181 (89.1%) were male. Pembrolizumab was most commonly combined with paclitaxel + platinum (69.8%) or fluorouracil + platinum (19.3%). After a median follow-up of 22.6 months (95% confidence interval (CI) 20.1-25.4), the ORR and DCR were 60.9% and 87.6% and the median PFS and OS were 10.8 months (95% CI 9.1-13.5) and 17.3 months (95% CI 14.9-19.9), respectively. OS was similar in patients with treatment-naïve and recurrent disease. Among the combination chemotherapy regimens, paclitaxel + platinum was associated with the longest median OS (18.2 months, 95% CI 16.1-22.5). Favorable survival outcomes were observed in patients with oligometastases. No new safety signals were observed.

Conclusion: These real-world data indicate that the first-line treatment with pembrolizumab plus chemotherapy is effective and safe in Chinese patients with advanced ESCC and show that paclitaxel + platinum is the most commonly used and most effective partner chemotherapy in China.

Background: Early changes in alpha-fetoprotein (AFP) are a promising surrogate endpoint for systemic treatment outcomes in hepatocellular carcinoma (HCC).

Objectives: We sought to investigate the utility of AFP response across first-line sorafenib (1L SOR) and later-line checkpoint inhibitor (CPI) therapies.

Design: We conducted a multicenter, retrospective cohort study of patients with advanced HCC who received 1L SOR and any subsequent CPI.

Methods: The primary outcomes were overall survival (OS) and time on treatment (TOT). Pre-treatment AFP and the lowest AFP within 3 months of treatment initiation were used to calculate the percent change in AFP for each treatment. AFP response was defined as an AFP reduction by ⩾20% within 3 months, and AFP progression was defined as an increase in AFP by ⩾20% within 3 months. Patients with baseline AFP < 20 ng/mL were considered not evaluable for AFP change.

Results: Of 176 study patients, 46 (28%) received CPI after SOR, and 125 (71%) had a baseline AFP ⩾ 20. Patients who experienced AFP response on SOR had significantly longer OS and TOT than those who did not and those who were not evaluable (OS: median 689 vs 320 vs 452 days, log-rank p < 0.001; TOT: median log of days 5.2 vs 4.5 vs 4.9, p < 0.001). Patients with AFP progression following SOR had significantly shorter OS than those who did not and those who were not evaluable (median 304 vs 557 vs 452, log-rank p = 0.008). Similarly, patients with AFP response following CPI therapy had a significantly reduced risk of death compared with those who did not have an AFP response (hazard ratio 0.13, 95% confidence interval 0.03-0.60, p = 0.009).

Conclusion: Early AFP response with 1L SOR and any subsequent CPI was associated with longer OS and TOT, and early AFP progression was associated with shorter OS and TOT. These data support utilizing longitudinal AFP changes as a surrogate endpoint in HCC systemic therapy.