Aspirin boosts the synergistic effect of EGFR/p53 inhibitors on lung cancer cells by regulating AKT/mTOR and p53 pathways.

The regimen of afatinib and vinorelbine has been used to treat breast or lung cancer cells with some limitations. Aspirin alone or in combination with other agents has shown unique efficacy in the treatment of cancer. We designed a preclinical study to investigate whether the triple therapy of aspirin, afatinib, and vinorelbine could synergistically inhibit the growth of p53 wild-type nonsmall cell lung cancer (NSCLC) cells. Three NSCLC cells A549, H460, and H1975 were selected to study the effect of triple therapy on cell proliferation and apoptosis. Compared to single agents, triple therapy synergistically inhibited the proliferation of lung cancer cells with combination index <1. Meanwhile, the therapeutic index of triple therapy was superior to that of single agents, indicating a balance between efficacy and safety in the combination of three agents. Mechanistic studies showed that triple therapy significantly induced apoptosis by decreasing mitochondrial membrane potential, increasing reactive oxygen species, and regulating mitochondria-related proteins. Moreover, epidermal growth factor receptor (EGFR) downstream signaling proteins including JNK, AKT, and mTOR were dramatically suppressed and p53 was substantially increased after NSCLC cells were exposed to the triple therapy. We provided evidence that the triple therapy of aspirin, afatinib and vinorelbine synergistically inhibited lung cancer cell growth through inactivation of the EGFR/AKT/mTOR pathway and accumulation of p53, providing a new treatment strategy for patients with p53 wild-type NSCLC.

Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial.

INTRODUCTION: Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. METHODS: This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. RESULTS: Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3-4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). CONCLUSIONS: This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.

A meta-analysis of recombinant human endostatin combined with NP regimen for treating non-small cell lung cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of recombinant human endostatin in combination with vinorelbine + cisplatin (NPE) for the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Randomized controlled trials (RCTs) of NPE for advanced NSCLC in PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched using a computerized search of the database from the time of creation to May 2023. Two investigators independently extracted literature information and assessed the quality of the included literature. Meta-analysis was performed using RevMan 5.4.0 software. RESULTS: A total of 24 RCTs with 2114 patients with advanced NSCLC were finally included. The results of meta-analysis showed that the total effective rate in the group received NPE regimen was significantly higher than those in the group without NPE regimen (RR = 1.70, 95% CI: 1.48-1.95, P < .00001). Meanwhile, the clinical benefit rate in the group received NPE regimen was also significantly higher than those in the group without NPE regimen (RR = 1.22, 95% CI: 1.15-1.29, P < .00001). However, there was no significant difference in the incidence of adverse event rate between the 2 groups (RR = 0.98, 95% CI: 0.76-1.27, P = .88). CONCLUSIONS: Compared with NP (vinorelbine + cisplatin) regimens for patients with advanced NSCLC, NPE regimens improve the total effective rate and clinical benefit rate of treatment, but there can be no significant difference in adverse effects. Prospective randomized trials are needed to further validate the safety and efficacy of this treatment modality.

Phase II Trial of Adjuvant Atezolizumab Therapy in Elderly Patients with Completely Resected Stage II/III Non-Small Cell Lung Cancer: RELIANCE Trial.

INTRODUCTION: Atezolizumab following platinum chemotherapy and complete pulmonary resection has become the new standard of adjuvant care for patients with stage II-III non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1). However, the efficacy and safety of postoperative adjuvant therapy and subsequent atezolizumab in patients aged 75 and older have not been established. METHODS: Patients with completely resected stage II-III NSCLC aged 75 and older will be prospectively registered in this single-arm phase II study. The enrolled patients will receive cisplatin plus vinorelbine (CDDP + VNR) followed by atezolizumab for up to 12 months. PD-L1 expression in at least 1% of cells will be confirmed by immunohistochemical staining. We plan to enroll 33 patients over 1 year at 25 institutions in Japan. The primary endpoint is the completion rate of adjuvant treatment (CDDP + VNR initiation to atezolizumab completion). CONCLUSION: The present study represents the first prospective trial of the tolerability of postoperative adjuvant therapy with immune checkpoint inhibitors in elderly individuals. The results of this trial might help promote postoperative adjuvant immunotherapy in the future for the elderly.

The efficiency and safety of low-dose apatinib combined with oral vinorelbine in pretreated HER2-negative metastatic breast cancer.

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor-2. Oral vinorelbine is a semisynthetic chemotherapeutic agent of vinorelbine alkaloids. Apatinib and oral vinorelbine have been proved to be effective in the treatment of metastatic breast cancer (mBC). At present, several small sample clinical trials have explored the efficacy of apatinib combined with oral vinorelbine in the treatment of mBC. METHODS: This retrospective study included 100 human epidermal growth factor receptor-2 (HER2)-negative mBC patients who received low-dose apatinib (250 mg orally per day) plus oral vinorelbine until disease progression or intolerance during February 2017 and March 2023. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety were analyzed by SPSS 26.0 software and GraphPad Prism 8 software. Cox proportional hazards regression model for univariate and multivariate was used to identify factors significantly related to PFS and OS. RESULTS: The median follow-up time for this study was 38.1 months. Among 100 patients with HER2-negative mBC, 66 were hormone receptor (HR)-positive/HER2-negative and 34 were triple-negative breast cancer (TNBC). The median PFS and OS were 6.0 months (95% CI, 5.2-6.8 months) and 23.0 months (95% CI, 19.9-26.1 months). There were no statistical differences in PFS (p = 0.239) and OS (p = 0.762) between the HR-positive /HER2-negative and TNBC subgroups. The ORR, CBR, and DCR were 21.0%, 58.0%, and 78.0%, respectively. Ninety-five patients (95.0%) experienced varying grades of adverse events (AEs) and 38.0% of patients for Grades 3-4. The most common Grades 3-4 AEs that we observed were neutropenia (30.0%) and leukopenia (25.0%). CONCLUSION: Low-dose apatinib combined with oral vinorelbine demonstrates potential efficacy and well tolerated for pretreated HER2-negative mBC.

Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer / Eficácia e toxicidade da quimioterapia adjuvante em pacientes com câncer de pulmão de células não pequenas

ABSTRACT Objective: Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting. Methods: This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting. Results: The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity. Conclusions: These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.

RESUMO Objetivo: A quimioterapia adjuvante melhora a sobrevida de pacientes com câncer pulmonar de células não pequenas (CPCNP) ressecado. No entanto, o esquema cisplatina-vinorelbina está relacionado com risco significativo de toxicidade clinicamente relevante. Nosso objetivo foi avaliar a eficácia, segurança e viabilidade da quimioterapia adjuvante para pacientes com CPCNP em um cenário de mundo real. Métodos: Estudo retrospectivo de coorte realizado em um único centro com pacientes com CPCNP em estágio I-III submetidos a cirurgia com intuito curativo entre 2009 e 2018. A quimioterapia adjuvante foi administrada a critério dos médicos. Os pacientes foram divididos em dois grupos: quimioterapia adjuvante e sem quimioterapia adjuvante (grupo controle). Os desfechos estudados foram sobrevida global (SG) e sobrevida livre de recidiva (SLR), bem como o perfil de segurança e viabilidade do esquema cisplatina-vinorelbina em um cenário de mundo real. Resultados: O estudo envolveu 231 pacientes, 80 dos quais receberam quimioterapia adjuvante. Destes, 55 receberam o esquema cisplatina-vinorelbina. As análises de sobrevida estratificadas pelo estágio do tumor mostraram que os pacientes com CPCNP em estágio II que receberam quimioterapia adjuvante apresentaram melhor SLR (p = 0,036) e SG (p = 0,017) do que os do grupo controle. Entre os pacientes com CPCNP em estágio III que receberam quimioterapia adjuvante, a SLR foi melhor (p < 0,001) e houve uma tendência a melhor SG do que no grupo controle (p = 0,060). Dos que receberam o esquema cisplatina-vinorelbina, 29% apresentaram neutropenia febril de grau 3-4, e 9% morreram em virtude de toxicidade. Conclusões: Os resultados confirmam o efeito benéfico da quimioterapia adjuvante em pacientes com CPCNP em um contexto real. No entanto, o esquema cisplatina-vinorelbina relacionou-se com taxas alarmantes de toxicidade e alternativas mais eficazes e menos tóxicas devem ser investigadas.