Efficacy, safety, and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.

Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS)

Background Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age. Methods In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years. Results Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51–0.89), 0.73 (95% CI 0.52–1.02), and 0.67 (95% CI 0.33–1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]. Conclusions The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.

Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial

PURPOSE Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene ( ERBB2 or HER2) exon 20 occur in 2%-5% of non–small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions. METHODS ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed. RESULTS Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range: 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients. CONCLUSION Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.

Endometriumkarzinom: Kombination aus Lenvatinib und Pembrolizumab zeigt Wirksamkeit unabhängig vom Mikrosatellitenstatus

<b>Purpose:</b> Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. <b>Methods:</b> Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. <b>Results:</b> At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. <b>Conclusion:</b> Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile. <b>Trial registration:</b> ClinicalTrials.gov NCT02501096.

Efficacy And Safety of Ramucirumab and Docetaxel In Previously Treated Patients With Squamous Cell Lung Cancer: A Multicenter Retrospective Cohort Study

Objective: Ramucirumab plus docetaxel therapy (RAM/DOC) is currently the standard for previously treated advanced non-small cell lung cancer (NSCLC), irrespective of histology. However, the safety data of anti-angiogenic agents for squamous cell NSCLC (Sq) is lacking, with a higher reported rate of severe hemoptysis in a clinical trial setting. We conducted a multicenter retrospective cohort study to confirm the efficacy and safety of RAM/DOC for Sq in real-world settings.Methods: We retrospectively analyzed previously treated patients with advanced NSCLC who underwent RAM/DOC at four institutions. Clinical data on the initiation of RAM/DOC were collected from medical records. Treatment outcomes of RAM/DOC were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Incidence of pulmonary hemorrhage was assessed according to the Common Terminology Criteria for Adverse Events version 5.0.Results: Overall, 237 patients with NSCLC were included and 38 (16%) had squamous cell carcinoma. There were no significant differences in median progression-free survival and overall survival between Sq and non-Sq patients (5.8 months vs. 4.3 months, P=0.0937; 15.2 months vs. 13.4 months, P=0.714, respectively). Of all patients, 13 (5%) developed pulmonary hemorrhage. According to histology, there was no significant difference in pulmonary hemorrhage proportion between Sq and non-Sq cohorts (2/38 vs. 11/199, respectively, P=0.947).Conclusion: For previously treated patients with Sq, efficacy and safety data of RAM/DOC were confirmed in a real-world setting and were similar to non-Sq. Ramucirumab is the only vascular endothelial growth factor-blocker available for Sq.

Efficacy, safety, and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.