Therapeutic Advances in Medical Oncology最新文献

Background: Systemic corticosteroids (SCs) are associated with reduced survival in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitor (ICI) monotherapy. However, the current first-line standard of care usually involves combined chemotherapy (CT) and ICIs, and the effect of SCs on survival under combined CT and ICI has never been studied.

Objectives: To investigate the association between SC therapy and survival under CT-ICI in advanced-stage NSCLC patients.

Design: We performed a multicenter retrospective cohort study of all advanced-stage NSCLC patients receiving first-line CT-ICI.

Methods: The primary endpoint was progression-free survival (PFS) according to SC exposure status (⩾10 mg/day), adjusted in a multivariate Cox model for the following confounders: age, performance status, hospital admission prior to treatment, number of metastatic sites, brain metastases, bone metastases, PD-L1 status, and histological subtype. Multivariate analyses also explored the association between dosage and SC exposure duration and PFS.

Results: Of the 193 included patients, 43 (22.3%) were receiving SCs, mainly because of symptomatic brain metastases (in 25/43 cases, 58%). In multivariate analysis, SC therapy at a 10 mg/day threshold was not associated with PFS (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 0.77-2.03, p = 0.35). However, SC dose was negatively associated with PFS (HR = 1.08 per 10 mg/day increment, 95% CI 1.01-1.16, p = 0.01) especially at doses ⩾60 mg/day (HR = 3.27 per 10 mg/day increment, 95% CI 2.01-5.35, p < 0.001). Duration of SC therapy was not associated with PFS (HR = 0.97, 95% CI 0.81-1.15, p = 0.71), but SC therapy ⩾4 weeks prior to CT-ICI was associated with shorter PFS (HR = 1.07, 95% CI: 1.01-1.14, p = 0.028).

Conclusion: In this group of patients receiving first-line CT-ICI for advanced NSCLC, SCs at ⩾60 mg/day were associated with shorter PFS, but lower doses were not. Prolonged SC therapy prior to CT-ICI was associated with shorter PFS. Larger studies are required to confirm these results.

Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. It is the first FDA-approved drug to target hypoxia-inducible factor 2 alpha (HIF-2α). By inhibiting the HIF-2α transcription factor, belzutifan prevents HIF-2α from dimerizing with HIF-1β, thereby preventing the transcription of downstream oncogenes. Most clear cell renal cell carcinoma (ccRCC) tumors are associated with VHL deletion or inactivation resulting in HIF-2α overexpression that represents a key contributor to tumorigenesis, thereby making belzutifan a uniquely optimal drug for targeting ccRCC. Belzutifan has demonstrated activity in clinical trials as a front- and later-line therapy, and in combination with tyrosine kinase inhibitors. It has been largely well tolerated, although anemia represents a common on-target side effect and, along with hypoxia, requires monitoring during treatment. Ongoing phase III trials are investigating belzutifan in combination regimens in the relapsed/refractory, front-line, and adjuvant settings. Future studies will focus on identifying predictive biomarkers and resistance pathways.

Background: Transarterial chemoembolization (TACE) is a widely used treatment for hepatocellular carcinoma (HCC), combining targeted chemotherapy and embolization. While effective, TACE can be associated with significant gastrointestinal (GI) side effects, impacting a patient's quality of life.

Objectives: Quantify the prevalence of key GI complications (diarrhea, nausea, GI toxicity, abdominal pain) following TACE.

Design: Systematic review was performed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, focusing on studies that reported side effects of TACE. Studies not involving cTACE or drug-eluting bead TACE (DEB-TACE), non-HCC studies, meta-analyses or systematic reviews, and inaccessible publications were excluded.

Data sources and methods: A PubMed search for clinical and randomized trials was conducted. Extracted data included study identifiers, demographics, TACE details, and GI side effect prevalences. The Mixed Methods Appraisal Tool assessed study quality and bias.

Results: The analysis included data from 81 studies with 121 individual study arms and 9495 patients. Diarrhea was reported in 38 studies, with a mean prevalence of 23.46% (2.5; 95% confidence interval (CI): 18.39-28.544) and a weighted prevalence of 23.5%. Nausea was most frequently reported, mentioned in 67 studies, with a mean prevalence of 34.66% (2.4; 95% CI: 29.89-39.44) and a weighted prevalence of 32.5%. Abdominal pain was reported in 59 studies, with the highest mean prevalence of 48.07% (2.9; 95% CI: 42.20-53.93) and a weighted prevalence of 46.1%. GI toxicity was reported in 32 studies, with a mean prevalence of 8.85% (1.4; 95% CI: 5.99-11.70) and a weighted prevalence of 9.9%. DEB-TACE generally led to slightly higher rates of nausea, diarrhea, abdominal pain, and GI toxicity compared to conventional TACE. The type of chemotherapy agent influenced prevalence of GI-side effects, with high prevalences observed for agents such as zinostatin and cisplatin.

Conclusion: This meta-analysis synthesizes current evidence on managing GI side effects in TACE. Standardizing reporting and developing effective management strategies are crucial to improving patient outcomes.

Background and objectives: This study aimed to compare the efficacy of the second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and brigatinib in the treatment of advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements based on real-world data.

Design and methods: We conducted a multicenter retrospective study using the Clinical Data Warehouse from seven university hospitals affiliated with the Catholic Medical Center. Patients diagnosed with ALK-positive advanced NSCLC and treated with alectinib or brigatinib were included. Key outcomes such as time to discontinuation (TTD), duration of response (DOR), overall survival (OS), and objective response rate (ORR) were analyzed.

Results: A total of 143 patients were included (107 treated with alectinib, 36 with brigatinib). Alectinib was more frequently used as a first-line treatment (71% vs 44.4% for brigatinib, p = 0.008). Prior crizotinib treatment was more frequent in the brigatinib group (52.8% vs 22.4% for alectinib, p < 0.001). The best ORR was similar between the groups (84.1% for alectinib vs 83.3% for brigatinib, p = 0.518). The median TTD was 57.8 months (95% confidence interval (CI): 29.0-86.7) for alectinib and 39.6 months (95% CI: 21.7-57.4) for brigatinib (p = 0.462). No significant differences were observed in intracranial TTD, intracranial DOR, or OS between the groups. Prior crizotinib treatment significantly shortened TTD for second-generation TKIs (p = 0.025), but the overall TKI treatment duration did not show a significant difference between patients who received frontline second-generation ALK TKIs and those who received second-generation ALK TKIs sequentially after crizotinib.

Conclusion: Alectinib and brigatinib demonstrated comparable efficacy in ALK-positive advanced NSCLC. Undergoing crizotinib followed by a second-generation TKI was not significantly different from initiating a second-generation TKI without prior crizotinib in terms of outcomes.

Head and neck squamous cell carcinoma (HNSCC) remains a challenge due to limited prognostic biomarkers and therapeutic options. The tumor microenvironment (TME), particularly the desmoplastic reaction (DR) characterized by stromal fibrosis, plays a crucial role in cancer progression and resistance to therapy. This review aims to summarize the biological significance of DR in HNSCC initiation, progression, and treatment resistance. Histologically, DR in HNSCC correlates with invasion patterns and clinical outcomes, affecting disease-free and overall survival. The interaction between cancer-associated fibroblasts (CAFs) and TME influences immune responses, including resistance to immunotherapy. Notably, human papillomavirus-driven HNSCC exhibits distinct DR characteristics that further influence the prognosis. DR promotes epithelial-mesenchymal transition and cancer cell invasion through CAF-mediated extracellular matrix remodeling and signaling pathways such as transforming growth factor-beta. DR also affects bone invasion and chemotherapy resistance by modulating stromal responses. Therapeutic strategies targeting DR and stromal components show promise in overcoming therapeutic resistance including resistance to immune checkpoint inhibitors. Understanding the role of DR in HNSCC biology and its impact on treatment response is critical to developing effective therapeutic interventions.

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies.

Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer.

Design: This is an ongoing, international, phase III, open-label, randomized controlled study.

Methods and analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety.

Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent.

Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. The findings of this trial could lead to promising treatment options for these patients.

Trial registration: ClinicalTrials.gov identifier: NCT06112379.

Lung cancer is one of the most common malignancies and causes the most cancer deaths in the United States. Targeted therapies have improved the survival of patients with advanced disease. Neurotrophic tropomyosin receptor kinase (NTRK) fusions are a rare oncogenic driver that has been targeted with the tumor-agnostic drug, larotrectinib. There are limited data on the treatment of non-small-cell lung cancer (NSCLC) with larotrectinib because of the rarity of this fusion in this population. We present the case of a patient who was diagnosed with SQSTM1-NTRK1 fused NSCLC with polymetastatic disease involving the brain and subsequently treated with a multidisciplinary approach via neurosurgical resection, radiotherapy, and larotrectinib. The combination of aggressive local treatments and systemic therapy is a relatively new treatment paradigm and represents a new area of research to optimize local control of metastatic lesions and potentially improve progression-free survival compared to the trials that show the efficacy of systemic monotherapies. The patient has experienced a sustained complete response to treatment almost 3 years later, and he has tolerated the drug without any significant adverse effects. The combination of systemic therapy with larotrectinib and aggressive local treatments could benefit patients with targetable fusions even with multiple metastatic lesions.

Background: Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare subtype of non-small-cell lung cancer that predominantly affects younger, non-smoking individuals in southern and southeast Asia, where Epstein-Barr virus (EBV) prevalence is high. The efficacy and safety of immunotherapy in pLELC, especially in second-line settings, remain inadequately explored.

Objectives: This study aimed to evaluate the efficacy of immunotherapy, either alone or in combination with chemotherapy, in improving progression-free survival (PFS) and overall survival (OS) in patients with advanced pLELC.

Design: This was a multicenter retrospective study.

Methods: A retrospective analysis was conducted on 252 patients with stage IIIB-IV pLELC treated across six centers. Patients received chemotherapy, immunotherapy, or a combination of both (chemoimmunotherapy). The primary outcomes measured were PFS and OS across different treatment regimens.

Results: Chemoimmunotherapy significantly improved both PFS and OS compared to chemotherapy alone, in both first- and second-line settings. In first-line treatment, chemoimmunotherapy resulted in a median PFS of 17.6 months and OS of 26.1 months, compared to chemotherapy alone (PFS 8.7 months, OS 19.2 months). In the second-line setting, chemoimmunotherapy achieved a median PFS of 5.1 months and OS of 13.5 months, surpassing the outcomes with chemotherapy alone (PFS 3.3 months, OS 8.9 months). High baseline EBV-DNA levels (>2000 copies/mL) and low programmed death ligand 1 (PD-L1) expression (<50%) were associated with poorer outcomes. In addition, patients with high baseline serum tumor markers (STMs) and a dynamic reduction of ⩽20% in STMs exhibited significantly worse PFS and OS.

Conclusion: The study suggests that immunotherapy, particularly when combined with chemotherapy, offers significant survival benefits for patients with advanced pLELC. Baseline EBV-DNA levels, PD-L1 expression, and both baseline and dynamic STM changes serve as important predictors of treatment response, highlighting the need for personalized therapeutic approaches in this unique subtype of lung cancer.

Background: The poor prognosis of locoregionally advanced nasopharyngeal carcinoma (LANPC) due to the high incidence of metastasis necessitates effective treatment strategies. Synergistic effects have been observed when anti-programmed death-1 (PD-1) inhibitors are combined with chemotherapy or targeted therapy.

Objectives: To compare the efficacy and safety of induction chemotherapy in combination with nimotuzumab with or without anti-PD-1 inhibitors for LANPC.

Design: Retrospective study.

Methods: In total, 319 patients with LANPC were retrospectively enrolled between December 2017 and November 2022. The primary endpoint was progression-free survival (PFS). Propensity score matching was performed to adjust for potential confounders.

Results: Overall, 150 patients were included after propensity score matching. The immunotherapy + nimotuzumab + chemotherapy (INC) group (n = 50) had a higher 3-year PFS rate (96.6% (95% confidence interval (CI): 93.2-100.0)) than the nimotuzumab + chemotherapy (NC) group (n = 100) (79.8% (95% CI: 75.6-84.0)). The INC group had a hazard ratio of 0.16 (95% CI: 0.02-1.22; p = 0.04). The objective response rates were 100% and 99% for the INC and NC groups, respectively. Grade ⩾3 treatment-related adverse events were reported in eight (5.3%) patients, and hyponatremia (2.0%) was the most common. Grade ⩾3 immune-related adverse events (rash and reactive capillary proliferation) were reported in two (4.0%) patients.

Conclusion: INC demonstrated remarkable anti-tumor activity with acceptable safety for LANPC.

Gastric cancer (GC), one of the tumours with the highest mortality worldwide, is not a homogeneous disease, showing different features according to location, macroscopic aspect, histotype and molecular alterations. Adenocarcinoma is the most frequent epithelial GC (95%), the remaining 5% comprising rare epithelial tumours with their peculiarities, behaviour and incidence <6 cases/100,000/year. Due to the low number of cases, many aspects must be elucidated in this context. In this narrative review, we highlight the importance of a better understanding of rare GCs to personalize the cures in the light of the precision medicine concept. Our main aim is to translate the scarce evidence from the literature into daily clinical practice, never forgetting that all the clinicians dedicated to rare GCs should encourage such patients' enrolment in clinical trials and promote international collaborations. Hence, we focused on the treatment of the following rare GCs: rare gastric adenocarcinomas (hepatoid adenocarcinoma, medullary carcinoma with lymphoid stroma, Paneth cell carcinoma and Salivary Gland carcinoma); squamous cell carcinoma; adenosquamous carcinoma; neuroendocrine gastric neoplasms; gastroblastoma.