Second-line Treatment Option Research Articles

Comparative efficacy and safety of anlotinib and topotecan as second-line treatment in small cell lung cancer: a retrospective cohort study.

Small cell lung cancer (SCLC) presents considerable challenges regarding the availability of second-line treatment options, which remain limited. The paucity of effective therapeutic choices at this setting emphasizes the urgent requirement for rigorous research and investigation into novel treatment strategies. To address this clinical gap, the current study aimed to compare the efficacy and safety of anlotinib with the standard second-line treatment, topotecan, in patients with relapsed SCLC. This retrospective collected data from SCLC patients who received either anlotinib or topotecan as second-line treatment. The primary endpoints were progression-free survival (PFS), while the secondary endpoints included the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety assessment. The study included 46 SCLC patients, with 20 receiving anlotinib and 26 receiving topotecan as second-line treatment. The anlotinib group showed a significantly longer median PFS compared to the topotecan group [5.6 vs. 2.2 months; hazard ratio (HR) =0.50; 95% confidence interval (CI): 0.27-0.92; P=0.02]. However, there was no statistically significant difference in OS between the two groups (9.1 vs. 7.7 months; HR =0.88; 95% CI: 0.46-1.70; P=0.71). The ORRs were 20.0% and 7.7% (P=0.48), and the DCRs were 70.0% and 23.1% (P=0.007) for the anlotinib and topotecan groups, respectively. Treatment-related adverse events (TRAEs) occurred in 13 patients (65.0%) in the anlotinib group and 20 (76.9%) in the topotecan group (P=0.49). Anlotinib shows the potential to extend PFS and manageable adverse events (AEs) compared to topotecan in the second-line setting for relapsed SCLC.

PP51 Strengths And Limitations Of Migraine Management Guidelines In The USA and Europe: A Targeted Literature Review

IntroductionMigraine, the second leading cause of disability worldwide, remains underdiagnosed and undertreated. Considering the high burden of migraine, we analyzed the strengths and limitations of existing migraine management guidelines.MethodsA targeted literature review was conducted using MEDLINE on 24 March 2021 to identify current migraine management guidelines (including policies and position statements) published in the English language from France, Germany, Italy, Spain, the United Kingdom, and the USA. This was supplemented by a gray literature search. Disease state or pharmacological management guidelines for adults with migraine comprising any of the following perspectives were included: health economics; payer; health technology assessment; treatment access; and impact of guideline implementation on economic or disease burden. Guidelines were analyzed using the Centers for Disease Control and Prevention (CDC) policy analytical framework, which comprises three domains: problem identification, policy analysis, and strategy or policy development, with ranking criteria for each.ResultsOf 39 selected guidelines, 25 adequately identified problems related to migraine, 35 sufficiently reviewed the literature on migraine treatment, three failed to cite literature, and one lacked sufficient content. Twenty-three guidelines targeted healthcare professionals. Almost all guidelines lacked a stepwise migraine treatment approach; only the American Academy of Family Physicians guideline offered first- and second-line treatment options. Four guidelines mentioned current political forces, and coverage of economic or budgetary impact aspects was limited. Numerous guidelines described the substantial economic burden of migraine and were categorized as ‘high’ for benefits. Public health impact was categorized as ‘high’ for 28 guidelines and budgetary impact was rated as ‘more favorable’ for 27 guidelines. Thirteen guidelines defined a strategy for the intended purpose. Only the United States Department of Health and Human Services pain management guideline met all of the CDC criteria.ConclusionsFuture policies on migraine management may benefit from the inclusion of information on economic data, political feasibility, and public health impact. Furthermore, migraine management guidelines could potentially be improved by considering a comprehensive treatment approach and guideline implementation, as well as addressing knowledge gaps in disease state, public health, and economic aspects.

Prevalence and Antimicrobial Resistance of Bacterial Uropathogens Isolated from Dogs and Cats.

Bacterial urinary tract infection (UTI) is a common diagnosis in companion animal practice and is one of the leading reasons for antimicrobial prescriptions. We analysed 1862 samples from the urinary tract of dogs and cats, submitted to a veterinary microbiological diagnostic laboratory in 2019 and 2020 in Germany. Susceptibility of 962 uropathogenic isolates to 15 antimicrobials, suggested as first- and second-line treatment options for UTI, was determined according to CLSI recommendations. Bacterial growth of uropathogens was detected in 43.9% of dog and in 38.5% of cat samples. Escherichia (E.) coli was the most frequently isolated pathogen (48.4%), followed by Enterococcus spp. (11.9%) and coagulase-positive staphylococci (CoPS; 11.5%). Females were more likely to exhibit a positive microbiological culture. Regarding first-line antibiotics, 93.4% of the most commonly isolated uropathogenic species were susceptible to the first-line antibiotics amoxicillin/clavulanic acid (AMC) and 87.6% to trimethoprim-sulfamethoxazole (SXT), while 76.1% showed decreased susceptibility to ampicillin (AMP). Multidrug resistance (MDR) was detected in 11.9% of E. coli, 50.4% of enterococci, and 42.7% of CoPS; 90.6% of these isolates were susceptible to nitrofurantoin (NIT). Our data indicate that empiric treatment of UTI with AMC or SXT could be recommended and is preferable to treatment with AMX. NIT should be considered for the treatment of MDR uropathogens.

Rituximab in the treatment of Graves' orbitopathy: latest updates and perspectives.

Graves' orbitopathy (GO) is a potentially sight-threatening and disfiguring, extrathyroidal manifestation of Graves' disease. It often impairs patients' quality of life, causing severe social and psychological sequelae. Intravenous glucocorticosteroids is currently the mainstay of therapy, but the efficacy is often underwhelming and recurrence rate is high. For many years, clinicians have been searching for new methods of treatment. Rituximab (RTX) is a chimeric monoclonal antibody targeted against CD20 which is a surface antigen present on B cells. It is frequently used to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, or various types of vasculitis. Numerous clinical trials employing RTX in the treatment of GO have shown promising results. RTX is currently considered to be a valid second-line treatment option in patients unresponsive to previous interventions or in disease reactivation. This review summarizes the available literature on this topic, including two largest, randomized, controlled studies. Potential benefits, as well as the limitations of RTX therapy, are discussed.

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Of 994 ICI-treated patients screened, a total of 58 patients (male, n= 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n= 26, 45%; ICI-2, n= 4, 7%), dual ICI regimens (n= 1, 2%; n= 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n= 31, 53%; n= 42, 72%). Most patients discontinued ICI-1 due to progression (n= 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n= 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.

The efficacy and safety of immune checkpoint inhibitors combined with chemotherapy or anti-angiogenic therapy as a second-line or later treatment option for advanced non-small cell lung cancer: a retrospective comparative cohort study.

Although immune checkpoint inhibitor (ICI) monotherapy remains the standard of second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) , the objective response rate (ORR) is low. There is an urgent need to increase the response population of second-line immunotherapy, and ICI combination therapy may be a possible option. However, the evidence is insufficient. We retrospectively collected the medical records of patients who received ICI monotherapy or ICI combination therapy as a second-line or later treatment option. We further analysed baseline clinical characteristics, evaluated treatment efficacy, assessed treatment-related adverse events (AEs) and followed up survival. The outcome variables assessed in the study were ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. A total of 145 patients were ultimately enrolled in this study, including the ICI monotherapy group (n=63) and ICI combination therapy group (n=82). The ICI combination therapy group was further divided into the ICI/chemotherapy group (n=57) and ICI/anti-angiogenic therapy group (n=25). The baseline was comparable among the three subgroups. The ICI combination therapy groups showed a higher ORR (29.3% vs. 11.1%, P=0.008) and DCR (85.4% vs. 61.9%, P=0.001) and a longer PFS (6.77 vs. 3.47 months, P<0.001) and OS (18.60 vs. 8.47 months, P<0.001) than the ICI monotherapy group. The ICI/chemotherapy group showed a significantly higher ORR (31.6% vs. 11.1%, P=0.006) and DCR (84.2% vs. 61.9%, P=0.006) and a longer PFS (6.37 vs. 3.47 months, P<0.001) and OS (18.60 vs. 8.47 months, P<0.001) than the ICI monotherapy group. The ICI/anti-angiogenic therapy group showed a significantly higher DCR (88.0% vs. 61.9%, P=0.021) and a longer PFS (8.17 vs. 3.47 months, P<0.001) and OS (19.20 vs. 8.47 months, P=0.005) than the ICI monotherapy group. Neither of the combined ICI therapy groups showed a significant increase in the incidence of AEs compared to the ICI monotherapy group. ICI combined with chemotherapy or anti-angiogenic therapy as second-line or later treatment demonstrated superiority over ICI monotherapy in advanced NSCLC patients without prior immunotherapy. These results provide a potentially superior treatment strategy and require verification in prospective clinical trials.

Nintedanib plus docetaxel after progression on first-line immunochemotherapy in patients with lung adenocarcinoma: Cohort C of the non-interventional study, VARGADO.

Immune checkpoint inhibitors (ICIs) with or without chemotherapy represent first-line standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The most appropriate second-line therapy after failing immunochemotherapy remains an open question. Nintedanib, an oral triple angiokinase inhibitor that targets the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and, platelet-derived growth factor receptor, in combination with docetaxel, is approved for treatment of advanced NSCLC (adenocarcinoma histology) following progression on first-line chemotherapy. VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study investigating the efficacy and safety of nintedanib plus docetaxel following first-line chemotherapy with or without ICIs in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology. This analysis focuses on Cohort C, which enrolled patients who had received prior first line chemotherapy with ICIs. Patients received second-line docetaxel (75 mg/m²) by intravenous infusion on Day 1, plus oral nintedanib (200 mg twice daily) on Days 2-21 of each 21-day cycle during routine clinical care. The primary endpoint is overall survival (OS) rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary endpoints include progression-free survival (PFS), OS, and disease control rate (DCR). Safety was also assessed. Among 137 patients treated, the median age was 63 years (range, 37-84); 57 patients (41.6%) were female, most patients had Eastern Cooperative Oncology Group performance status of 0 (28.5%) or 1 (43.1%); 118 (86.1%) had stage IV NSCLC and 27 (19.7%) had brain metastases. Most (n=120, 87.6%) patients had received pembrolizumab/pemetrexed/platinum-based chemotherapy as first-line treatment. In 80 patients with available response data, the DCR was 72.5% (complete response: 1.3%; partial response: 36.3%; stable disease: 35.0%). Median progression-free survival was 4.8 months (95% confidence interval: 3.7-6.6). OS data were immature. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were reported in 62 (45.3%), 50 (36.5%), and 40 patients (29.2%), respectively. This analysis indicates that nintedanib plus docetaxel represents an effective second-line treatment option in patients with advanced adenocarcinoma NSCLC following progression on first-line immunochemotherapy. The safety profile was manageable with no unexpected signals.

Treatment of Infantile Spasm Syndrome: Update from the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society of Neuropediatrics.

The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. A literature search was performed using the Cochrane and Medline Databases (2014 to July 2020). All studies were objectively rated using the Scottish Intercollegiate Guidelines Network. For recommendations, the evidence from these studies was combined with the evidence from studies used in the 2014 guideline. If ISS is suspected, electroencephalography (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatment should be evaluated clinically and electroencephalographically after 14 days. The preferred first-line treatment for ISS consists of either hormone-based monotherapy (AdrenoCorticoTropic Hormone [ACTH] or prednisolone) or a combination of hormone and vigabatrin. Children with tuberous sclerosis complex and those with contraindications against hormone treatment should be treated with vigabatrin. If first-line drugs are ineffective, second-line treatment options such as ketogenic dietary therapies, sulthiame, topiramate, valproate, zonisamide, or benzodiazepines should be considered. Children refractory to drug therapy should be evaluated early for epilepsy surgery, especially if focal brain lesions are present. Parents should be informed about the disease, the efficacy and adverse effects of the medication, and support options for the family. Regular follow-up controls are recommended.

Systemic therapies for metastatic renal cell carcinoma in the second-line setting: A systematic review and network meta-analysis.

Objectives:To perform a systematic review and network meta-analysis to compare the survival benefit and safety profile of current available second-line treatment options of metastatic renal cell carcinomav.Methods:PubMed, EMBASE, Web of Science, and Cochrane Library were systematically researched for eligible articles which were published before July 20, 2021. Studies comparing overall/progression free survival (OS/PFS), objective response rate (ORR), and/or adverse events (AEs) in patients with metastatic renal cell carcinomav were included.Results:Nine trials (with 4911 patients) were finally included for final network meta-analysis. Cabozantinib, lenvatinib, and lenvatinib plus everolimus were associated with significantly better PFS, OS, and ORR compared with everolimus, and lenvatinib plus everolimus emerged as the best option. As for grade 3 to 4 AEs, nivolumab showed significantly lower risk of AEs compared with everolimus. Other included treatments were associated with significantly increased risk of AEs. When comprehensively assessed the efficacy and safety of included treatments based on the ranking analysis of PFS, ORR, and grade 3 to 4 AEs, lenvatinib plus everolimus, cabozantinib, and nivolumab showed superior efficacy over other treatments, with relatively lower risk of grade 3 to 4 AEs.Conclusions:Among all included therapies, Lenvatinib plus everolimus was identified as the most effective treatment approach, with the best PFS, OS, and ORR. nivolumab was associated with decreased incidence of grade 3 to 4 AEs among included treatment therapies. When comprehensively evaluated the efficacy and safety of included treatment options, lenvatinib plus everolimus, cabozantinb, and nivolumab were associated with better survival benefits and lower risk of AEs. Future studies should focus on the direct comparison of different second-line treatment in real-world populations.

Correlation Between Tumor Response and Survival Outcomes in Patients with Advanced Gastric Cancer Receiving Ramucirumab and Paclitaxel as Second-Line Therapy.

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The first-line treatment for GC is a combination of platinum and fluoropyrimidine-based therapy. Based on the positive results of RAINBOW and REGARD trials, ramucirumab either alone or in combination with paclitaxel has proved to be a safe and active option for second-line treatment in GC patients. Advanced GC patients who received a 28-day cycles of ramucirumab and paclitaxel until disease progression or unacceptable toxicity were evaluated. Eligible patients had ECOG PS ≤ 1 and adequate organ function. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. In our single institution experience, we included a total of 67 patients. A median OS of 8months and a median PFS of 4months, were recorded. In patients experiencing an initial partial response (PR), we observed a significant association between tumor response and survival outcomes (OS and PFS). The OS and PFS were 15 and 11months in patients who experienced PR compared to 8 and 4months in patients without PR (p = 0.02; p = 0.04). Treatment with ramucirumab plus paclitaxel yielded the highest overall response rate reported to date for patients with previously treated advanced GC. In our experience, the initial tumor response is associated with a greater survival benefit which could be further improved by the identification of biomarkers predicting response.

IL-2/IL-2R signaling and IL-2Rα-targeted therapy in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is aCD30-positive non-Hodgkin's T‑cell lymphoma. Despite the implementation of CD30 antibody-drug conjugate-targeted therapy into front-line treatment regimens, the prognosis of some subtypes of the disease remains unsatisfactory. In the relapsed/refractory setting, effective second-line treatment options are still lacking. However, it has been reported that blockade of direct downstream targets of activator protein‑1 (AP-1) transcription factors, which are highly dysregulated in ALCL, results in complete and sustained remission in late-stage relapsed/refractory anaplastic lymphoma kinase (ALK)-positive ALCL patients. Moreover, it has been identified that involvement of the BATF3/AP‑1 module promotes lymphomagenesis via oncogenic BATF3/IL-2/IL-2R signaling through hyperphosphorylation of ERK1/2, STAT1, and STAT5 in ALCL cells regardless of their ALK status. Therefore, targeting BATF3/IL-2/IL-2R signaling may represent anovel therapeutic alternative for ALCL patients.

P10.04.A The development of a potent, tumour-specific heptamethine cyanine dye-palbociclib conjugate with novel mechanisms of action for the treatment of glioblastoma

Abstract Background Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-cancer agents for brain tumours is challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery Material and Methods We conjugated palbociclib, a cyclin-dependent kinase 4/6 inhibitor to the HMCD, MHI 148 for the treatment of GBM. Patient-derived GBM cell lines were established from surgically resected biopsy GBM tissue. Results High-throughput drug screening revealed an almost 100-fold increase in cytotoxicity of the palbociclib-MHI 148 conjugate compared to palbociclib alone. Moreover, the palbociclib-MHI 148 conjugate was synergistic with radiation, but not with temozolomide. Further analysis revealed the palbociclib-MHI 148 conjugate was superior to other cyclin-dependent kinase inhibitors in vitro. The shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI 148 prompted further investigation. We revealed that palbociclib-MHI 148-dependent inhibition of cell-cycle progression resulted in increased DNA damage. This preceded increased transcription of key extrinsic apoptosis genes and caused a time-dependent upregulation of TNFR1 endocytosis-dependent cell death signalling. Notably, inhibition of endocytosis and siRNA knockdown of TNFR1 prevented palbociclib-MHI 148-induced cell death. Conclusion: These results highlight a novel mechanism of action of palbociclib when conjugated to MHI-148 that induced autocrine-driven TNFR1-mediated apoptosis. In addition, we highlight the potential application of HMCDs in repurposing tyrosine kinase inhibitors, to overcome the current limitations preventing the expansion of second-line treatment options for GBM.

Novel pharmacological therapies for the treatment of endometriosis

Introduction Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease. Areas covered This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews. Expert opinion Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis.

Treatment considerations for patients with advanced squamous cell carcinoma of the lung: a plain language summary.

This plain language summary reports the key points of a recent review article that discussed current treatment options for a type of cancer called squamous cell carcinoma (SCC) of the lung. SCC of the lung is a type of non-small-cell lung cancer (NSCLC for short) that is usually linked with smoking. It can be difficult to treat because it is often diagnosed after it has spread to other parts of the body. Most patients receive a combination of chemotherapy and immunotherapy as their first-line treatment (the first treatment they receive after their diagnosis). Immunotherapy drugs have improved how long people with SCC of the lung can live for. However, for most patients, they eventually stop working. At this point, other second-line treatments are considered, meaning treatments patients receive after their first-line treatment is stopped due to side effects or because it no longer works. Immunotherapy drugs were originally developed as second-line options after chemotherapy. However, immunotherapy drugs are now used with chemotherapies as first-line treatments. This has left a gap for second-line treatment options. There are some drugs available for second-line treatment, such as afatinib, which comes as a tablet, and docetaxel with or without ramucirumab, which is given as an infusion. Other potential treatments are being developed. Some early clinical trials of potential treatments have shown promise, but more results are needed. Research into the genetic mutations linked with the development of SCC of the lung is also ongoing. It is hoped that this will help identify patients who might benefit from specific treatments. People with SCC of the lung and their caregivers, patient advocates, and healthcare professionals, including those who are helping people learn about scientific discoveries and potential new therapeutic strategies.

1261TiP CARMEN-GC01: Phase II, open-label, single-arm study of tusamitamab ravtansine in combination with ramucirumab in pretreated patients with gastric or gastroesophageal junction adenocarcinoma (GA/GEJA)

Tusamitamab ravtansine (tusa; SAR408701), an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) antibody conjugated to the potent cytotoxic antitubulin DM4, showed promising antitumor activity and was well tolerated in heavily pretreated patients (pts) with advanced non-small cell lung cancer (NSCLC) and high CEACAM5 expression (immunohistochemistry intensity ≥ 2+ in ≥ 50% of tumor cells). High CEACAM5 expression occurs in 30% of pts with gastric cancer (GC). Ramucirumab, an antibody antagonist of vascular endothelial growth factor receptor 2 (VEGFR2), combined with paclitaxel is a standard of care option for second-line (2L) treatment of GA or GEJA. Preclinical studies with tusa and a VEGFR2 antagonist have shown synergistic activity in gastric patient-derived xenografts, supporting clinical investigation of tusa in combination with ramucirumab. This combination may lead to improved 2L outcomes in pts with GC, with a better safety profile compared with that of paclitaxel plus ramucirumab. A phase II study (NCT04394624) of tusa in combination with ramucirumab is also ongoing in pts with NSCLC and high CEACAM5 expression. CARMEN-GC01 (NCT05071053) is a phase II, open-label, single-arm, multicenter, 2 part study to evaluate tusa combined with ramucirumab in pts pretreated for GA/GEJA with high CEACAM5-expressing tumors. Part 1 is a safety run-in, followed by a Part 2 expansion. Inclusion criteria include age ≥ 18, metastatic or locally advanced GA/GEJA, and ≥ 1 measurable lesion. Key exclusion criteria are untreated brain metastases, unresolved previous corneal disorders, concurrent anticancer therapy, and prior CEACAM5-targeted, DM1- or DM4-containing, anti-VEGF/VEGFR, or taxane treatment. The primary objectives are to confirm the recommended tusa loading dose in combination with ramucirumab (Part 1) and to assess the antitumor activity of tusa (Part 2). Secondary objectives include safety, duration of response, progression-free survival, disease control rate, pharmacokinetics, and immunogenicity. As of April 13, 2022, 22 sites in 6 countries are recruiting. EudraCT: 2021-001967-26; NCT05071053. Medical writing support was provided by Zeshan Mahmood, PharmD, and Elizabeth Strickland, PhD, inScience Communications (Philadelphia, PA). This work was performed in accordance with current Good Publication Practices and funded by Sanofi. Sanofi.

Unmet Needs and Treatment of Relapsing-Remitting Multiple Sclerosis in Saudi Arabia: Focus on the Role of Ofatumumab.

Treatment-pattern data suggest that some patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) may not be receiving optimal treatment. A virtual meeting of ten expert Saudi neurologists, held on October 23, 2020, discussed unmet needs in relapsing–remitting MS (RRMS), and the role of ofatumumab as a suitable treatment in the KSA. Multiple unmet needs were identified: poor quality of life, with high rates of depression and anxiety; a negative impact of MS on work ability; treatment choices that may compromise efficacy for safety or vice versa; inconvenient or complex dosage regimens; and limited access to patient education and support. Early use of highly effective disease-modifying treatments (DMTs) results in better patient outcomes than starting with less effective treatments and downstream escalation, but this strategy may be underutilized in the KSA. B cells are important in MS pathogenesis, and treatments targeting these may improve clinical outcomes. Ofatumumab differs from other B cell–depleting therapies, being a fully human monoclonal antibody that binds to CD20 at a completely separate site from the epitope bound by ocrelizumab, and being administered by subcutaneous injection. When compared with teriflunomide in two randomized, phase 3 clinical trials in patients with RRMS, ofatumumab was associated with significant reductions in annualized relapse rates, rates of confirmed disability worsening, and active lesions on magnetic resonance imaging. The incidence of adverse events, including serious infections, was similar with the two treatments. Ofatumumab is a valuable first- or second-line treatment option for RRMS in the KSA, particularly for patients who would benefit from highly effective DMTs early in the disease course, and for those who prefer the convenience of self-injection. Future research will clarify the position of ofatumumab in RRMS treatment, and comparative cost data may support the broad inclusion of ofatumumab in formularies across the KSA.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience – A Multicenter Retrospective Study

Introduction: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. Methods: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). Results: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261–315), and the PFS was 117 days (95% CI: 105–129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264–385] vs. 285 days [95% CI: 252–317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264–385] vs. 264 days [95% CI: 229–298]; p = 0.042). Discussion/Conclusion: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

Optimization of the treatment of moderate to severe and active thyroid orbitopathy considering the recommendations of the European Group on Graves' Orbitopathy (EUGOGO) [Optymalizacja leczenia umiarkowanej do ciężkiej i aktywnej orbitopatii tarczycowej z uwzględnieniem zaleceń European Group on Graves' Orbitopathy (EUGOGO)]

Graves' disease (GB), also known as Basedow's disease, is the most common cause of hyperthyroidism, and thyroid orbitopathy (TO) is its most common non-thyroid manifestation with an incidence of 42.2/million people/year. Based on the guidelines of the European Graves' Orbitopathy Group (EUGOGO), certain management standards presented in our publication should be used to optimize and improve the efficacy of TO treatment. Deciding on the optimal treatment for both hyperthyroidism and TO requires a cooperative team of specialists: endocrinologist, ophthalmologist, radiation therapist, and surgeon, as well as consideration of the risk of relapse and possible complications of the treatment method. The inflammatory activity and severity of TO should be diagnosed based on the investigator's own experience and according to standard diagnostic criteria. Assessment of the inflammatory activity of TO can be performed using the clinical activity score (CAS) and using imaging methods - mainly MRI. The severity of TO is assessed using a seven-grade NOSPECS classification and a three-grade EUGOGO scale. In moderate to severe and active TO, i.v. methylprednisolone pulses are the treatment of choice. It is important to maintain the standard and regimen of treatment. The recommended standard as first-line treatment in most patients with moderate to severe and active TO is the combined use of methylprednisolone i.v. (cumulative dose of 4.5 g over 12 weeks) with concurrent administration of mycophenolate sodium 0.72 g per day for 24 weeks. In more severe forms of moderate to severe and active TO, a higher cumulative dose of methylprednisolone i.v. is recommended as an alternative first-line treatment (7.5 g) as monotherapy starting with a dose of 0.75 g once a week for 6 weeks and 0.5 g for a further 6 weeks. EUGOGO guidelines recommend that in cases of no clinical response after 6 weeks of first-line treatment with i.v. methylprednisolone and mycophenolate, after 3-4 weeks, a second course of i.v. methylprednisolone monotherapy should be started with a higher cumulative dose of 7.5 g. Other second-line treatment options are orbital radiotherapy with or without oral or i.v. systemic glucocorticosteroid therapy, cyclosporine, or azathioprine in combination with p.o. glucocorticosteroid, methotrexate monotherapy, and a group of biologic drugs rituximab, tocilizumab, teprotumumab). Keeping in mind that TO is a sight-threatening disease, we expect, through the treatment applied, to maintain full visual acuity, pain relief, single vision in the useful part of the visual field, and a positive cosmetic effect.

Dynamics of Circulating CD14/CD16 Monocyte Subsets in Obstructive Sleep Apnea Syndrome Patients upon Hypoglossal Nerve Stimulation.

Background: Obstructive sleep apnea syndrome (OSAS) is a widespread respiratory disease that is associated with recurrent breathing intermissions at night. The corresponding oxidative stress triggers a low-grade systemic inflammation which leads to alterations of different immune cells in the peripheral blood. The current standard treatment for OSAS is continuous positive airway pressure (CPAP), whereas hypoglossal nerve stimulation (HNS) has been established as a second-line treatment option for CPAP failure. The aim of the study was to investigate the influence of HNS for OSAS patients on the distribution and differentiation of circulating monocyte subsets in connection with the clinical parameters. Materials and Methods: Therefore, a detailed analysis of the distribution of CD14/CD16 characterized monocyte subsets in the peripheral blood of OSAS patients before and after HNS therapy was performed by flow cytometry. Furthermore, values of BMI (body mass index), ODI (oxygen desaturation index), and ESS (Epworth Sleepiness Scale) were measured. Results: These OSAS patients significantly improved AHI and ESS scores under HNS. In addition, HNS revealed the potential to ensure normal distributions of blood monocyte subsets and even improved the monocyte dynamics in selected OSAS patients, but there were no significant correlations with AHI, ODI, HNS usage, and daytime sleepiness. Conclusions: We conclude that HNS-related positive effects on the oxygenation of the peripheral blood as well as affect the distribution of circulating monocyte subsets, but clinical OSAS correlations are missing. Far more individual clinical, cellular and molecular factors are involved in this sensitive and complex regulatory network and have to be elucidated in further studies.

Anti-PD-1 antibodies plus lenvatinib in patients with unresectable hepatocellular carcinoma who progressed on lenvatinib: a retrospective cohort study of real-world patients.

BackgroundLenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low.MethodsIn this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6–8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated.ResultsThe objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2–22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1–11.8] and 14.5 months (95% CI: 6.8–22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7, P=0.03; diarrhea, 12.3±20.9 vs. 18.5±16.8, P=0.01; pain, 5.5±10.3 vs. 11.1±13.9, P=0.01).ConclusionsThe combination of anti-PD-1 antibodies and lenvatinib may benefit patients with unresectable HCC who progressed on lenvatinib. This study provides a real-world data and treatment choice for patients progressed with lenvatinib.