First-line Treatment Option For Patients Research Articles

Efficacy and safety of apatinib versus sorafenib/placebo in first-line treatment for intermediate and advanced primary liver cancer: A systematic review and meta-analysis.

Background: Apatinib is a novel tyrosine kinase inhibitor used in the treatment of advanced hepatocellular carcinoma (HCC). For decades, sorafenib has been a classic first-line treatment option for patients with HCC. This meta-analysis aimed to assess the efficacy and safety of apatinib versus sorafenib/placebo as first-line treatment for intermediate and advanced primary liver cancer (PLC). Methods: A literature search was performed via PubMed, Web of Science, CENTRAL, Embase, CNKI, VIP, and CBM. Data extraction from databases of other languages is not restricted. The Cochrane risk of bias tool, modified Jadad scale, Newcastle-Ottawa scale (NOS), and non-randomized studies of interventions (ROBINS-I) tool were employed to evaluate methodological qualities in original studies. Influence analysis was applied to assess the reliability of pooled results. Publication bias was evaluated using the funnel plot with Begg's test and Egger's test. Results: Seven studies were included in the systematic review and meta-analysis. Four randomized controlled trials (RCTs) and one clinical controlled trial (CCT) were used for comparing apatinib with placebo, and two retrospective clinical studies (RCSs) were used for comparing apatinib with sorafenib. Apatinib led to higher overall effects in objective response rate (ORR), disease control rate (DCR), and mean survival time (MST) over placebo (RR = 2.03, 95% CI = 1.46-2.81, p < 0.0001, I2 = 0%; RR = 1.17, 95% CI = 1.04-1.33, p = 0.009, I2 = 45.8%; SMD = 2.63; 95% CI = 1.47-3.78, p < 0.0001, I2 = 92.7%, respectively). Compared to sorafenib, apatinib showed no superiority in ORR and DCR but was inferior in the 6-month and 1-year survival rate (RR = 1.99, 95% CI = 0.85-4.65, p = 0.111, I2 = 68.3%; RR = 1.04, 95% CI = 0.73-1.47, p = 0.840, I2 = 0.0%; RR = 0.63, 95% CI = 0.42-0.97, p = 0.036, I2 = 0.0%; RR = 0.47, 95% CI = 0.29-0.79, p < 0.0001, I2 = 0.0%, respectively). Apatinib had similar adverse effects over placebo but possessed a greater incidence rate of proteinuria and hypertension over sorafenib. Conclusion: In the first-line setting, apatinib might be an alternative treatment approach for patients with intermediate and advanced PLC. Sorafenib alone showed a better survival rate within 1 year and a lower incidence rate in hypertension and proteinuria than apatinib monotherapy.

Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial

BackgroundIn the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. MethodsPatients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. ResultsConsistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. ConclusionResults from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma.

RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome

Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY. Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated. Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type. This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status.

Comparison of hematopoietic stem cell transplantation and immunosuppressive therapy as the first-line treatment option for patients with severe hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia (HAAA) is a rare variant of acquired aplastic anemia characterized with a syndrome of bone marrow failure after hepatitis. We retrospectively analyzed the outcomes of consecutive severe HAAA patients who received immunosuppressive therapy (IST, n = 70), matched-sibling donor hematopoietic stem cell transplantation (MSD-HSCT, n = 26) or haploidentical-donor (HID) HSCT (n = 11) as the first-line treatment. In the IST group, the hematologic response (HR) rate was 55.71% at 6 months. In contrast, HSCT recipients exhibited significantly more rapid and sustained hematopoiesis (HR 76.92%, 96.15% and 96.15% at 3, 6 and 12months, respectively). The 5-year overall survival (OS) was not different among IST (83.7 ± 4.9%), MSD-HSCT (93.3 ± 6.4%) and HID-HSCT group (80.8 ± 12.3%). Compared with IST, MSD and HID-HSCT demonstrated a trend of superiority in the estimated 5-year failure-free survival rates (93.3 ± 6.4% vs 64.3 ± 6.0%, p = 0.05; 80.8 ± 12.3% vs 64.3 ± 6.0%, p = 0.57). In subsequent stratified analysis on age, we found that HID-HSCT showed its efficacy and safety among young patients. In sum, MSD-HSCT remains first-line treatment choice for HAAA, whereas HID-HSCT represents an alternative treatment choice in addition to IST for young patients (< 40 years) without a matched sibling donor.

Abstract P1-04-01: High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results

Abstract Background: Dual HER2 blockade with trastuzumab and pertuzumab combined with docetaxel (DHP) is the standard first-line treatment option for patients with HER2-positive metastatic breast cancer. However, HER2 positivity alone often fails to predict treatment outcome of HER2 targeted therapy. The magnitude of HER2 immunohistochemical staining (IHC) and HER2/CEP17 ratio from in situ hybridization (ISH) is a well-known predictive biomarker for HER2 targeted therapy. In the neo-adjuvant setting, patients with HER2 IHC 3+ have higher pathologic complete response (pCR) rate compared to HER2 IHC&amp;lt; 3+ with HER2 ISH positive. In addition, higher HER2/CEP17 ratio is associated with higher pCR rate in HER2-positive breast cancer patients treated with dual HER2 blockade regimens. However, there is no data whether there is an association between HER2/CEP17 ratio and treatment outcome of DHP regimen in patients with advanced of metastatic breast cancer especially among those with HER2 IHC 3+. Methods: We performed a retrospective cohort study with patients with locally advanced or metastatic HER2-positive breast cancer who were treated with first-line palliative DHP regimen between August 2008 and January 2021 at Seoul National University Hospital. In the clinical setting, HER2 IHC 3+ is defined as HER2 positive and no further ISH testing is required. Additional ISH was performed in patients with HER2 IHC 3+ without archival HER2 ISH results. The association between HER2/CEP17 ratio and treatment outcome was assessed. Results: In total, 165 patients were included with a median follow-up duration of 28.0 months. Among the 165 patients, 35 patients had archival ISH result and additional ISH was performed in 53 patients. The correlation between HER2/CEP17 ratio and treatment outcome was assessed in 88 patients. Cox proportional hazard analysis revealed that HER2/CEP17 ratio is correlated with PFS (HR 0.23, 95% CI 0.11-0.49, p &amp;lt; 0.001). When dichotomized by the median HER2/CEP17 ratio of 4.17, patients with higher HER2/CEP17 ratio had significantly longer PFS (37.5 vs. 17.4 months, p = 0.003) and numerically higher ORR (54.5% vs. 34.1%, p = 0.085). Multivariate analysis revealed that HER2/CEP17 ratio is an independent prognostic factor for PFS (HR 0.72, p = 0.001). Of 88 patients with ISH results, 25 had HER2 IHC 1+ or 2+ and 63 had HER2 IHC 3+. HER2/CEP17 ratio was associated with PFS in both HER2 IHC 1+/2+ patients (HR 0.12, 95% CI 0.02-0.88, p = 0.037) and HER2 IHC 3+ patients (HR 0.18, 95% CI 0.07-0.49, p = 0.001). Patients with higher HER2/CEP17 ratio had longer PFS in both HER2 IHC 1+/2+ patients (28.6 vs. 12.9 months, p = 0.003) and HER2 IHC 3+ patients (Not reached vs. 18.3 months, p = 0.005) when dichotomized by the median HER2/CEP17 of 2.95 and 4.75, respectively. Conclusion: This is the first study to report that higher HER2/CEP17 ratio is associated with longer PFS in HER2-positive advanced breast cancer patients treated with palliative first-line DHP. The strength of this study is that we identified prognostic role of ISH even in patients with HER2 IHC 3+. It would be helpful to perform ISH not only in patients whose HER2 IHC is ambiguous, but also in patients with HER2 IHC 3+ to make better prediction of treatment outcome. Table 1. Patient characteristics. Citation Format: Jeongmin Seo, Jiwon Koh, Dae-Won Lee, Han Suk Ryu, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-01.

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma.

TPS747 Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697 .

An open-label, multi-center phase IIIb study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (TREMENDOUS study).

TPS628 Background: Hepatocellular carcinoma (HCC) is of high incidence and mortality rate in China, with nearly half of them are diagnosed as advanced or metastatic stage at the initial diagnosis. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors and immune checkpoint inhibitors in combination with vascular endothelial growth factor. Recently, the phase III HIMALAYA trial investigated the STRIDE regimen, tremelimumab 300mg × 1 dose and durvalumab 1500mg every 4 weeks, compared to sorafenib in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved overall survival (OS) (16.4 mos vs 13.8mos, HR=0.78) and a well-tolerated safety profile (≥grade 3 treatment-related adverse events 25.8% vs 36.9% ). Notably, the HIMALAYA trial did not enroll subject from mainland China and excluded patients with class Child-Pugh B liver dysfunction or ECOG performance status (PS) 2. We hypothesize the STRIDE regimen will be safe and well tolerated in Chinese patients with locally advanced or metastatic HCC with Child-Pugh class A or B liver dysfunction or ECOG PS 0-2. In addition, the study will also assess efficacy and explore biomarkers. Methods: This will be an open label, multi-center phase IIIb study investigating the safety and efficacy of the STRIDE regimen in Chinese unresectable HCC patients without prior systemic therapy. Patients with Child-Pugh A liver dysfunction and ECOG PS 0-1 will be enrolled in cohort 1, while patients with Child-Pugh B liver dysfunction or ECOG PS 2 will be enrolled in cohort 2. Patients with main portal vein tumor thrombosis (Vp4), clinically significant ascites or hepatic encephalopathy, or active or prior documented gastrointestinal bleeding within 12 months will be excluded. We plan to enroll 300 patients with the primary endpoint of grade 3-5 adverse event (AE) rate by CTCAE v5.0 and adverse events of special interest (AESI). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), OS, OS rate at 6 months and 12 months. Patients of both cohorts will receive a single dose of tremelimumab 300 mg and durvalumab 1500 mg at Cycle 1 (Week 0), followed by durvalumab 1500 mg monotherapy every 4 weeks until confirmed disease progression or unacceptable toxicity. Archival or fresh tumor biopsy will be required at baseline. The trial is currently screening eligible subjects. Clinical trial information: CTR20222433 .

Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of claudin 18.2–positive metastatic pancreatic cancer (mPC): Phase 2, open-label, randomized study.

TPS782 Background: GN is a first-line treatment option for patients (pts) with mPC. Poor prognosis and low 5-year survival rate ( &lt; 5%) with mPC highlight the need for new therapeutics. Claudin 18.2 (CLDN18.2), a tight junction protein expressed exclusively on normal gastric epithelial cells, is maintained during malignant transformation in gastric cancers and is frequently expressed in some carcinomas from organs that do not normally express it, such as pancreatic cancer. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase 2 study (NCT03816163) will assess safety and efficacy of GN alone or with zolbetuximab in CLDN18.2-positive mPC. Methods: The study was expanded to enroll approximately 369 pts with histologically confirmed mPC and high CLDN18.2 expression (moderate-to-strong IHC staining intensity in ≥75% of tumor cells). The study included a safety lead-in that enrolled 3-12 pts to assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W, then expand/de-escalate using a 3+3 design) plus GN. Dose-limiting toxicities (DLTs, defined as a specified zolbetuximab-related toxicity that occurs during DLT assessment period) will be assessed after Cycle 1 (28 days). Based on the recommended phase 2 dose (RP2D), confirmed during the safety lead-in, approximately 357 pts will be randomized 2:1 to zolbetuximab Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle (Arm 1), or GN alone on Days 1, 8, and 15 of each cycle (Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). At sites in Japan, DLTs (assessed from Cycle 1 Day 1 to Cycle 2 Day 1) will be evaluated in ≤6 pts randomized to the RP2D in Arm 1. Pts will undergo imaging (CT/MRI) at baseline and Q8W until investigator-assessed disease progression (RECIST v1.1) or the start of another systemic anticancer treatment, whichever comes earlier. In addition to confirming the RP2D during the safety lead-in, primary objectives are to assess whether treatment with zolbetuximab plus GN, versus GN alone, improves overall survival (randomization phase) and to establish the safety/tolerability profile of zolbetuximab plus GN (across the study). Secondary endpoints include progression-free survival, objective response rate, disease control rate, duration of response, pharmacokinetics, and health-related quality of life (per protocol amendment). Descriptive statistics will be used for continuous endpoints and frequency and percentage for categorical endpoints. Original protocol enrollment completion was in October 2021. Under the expanded protocol amendment, 95 of ~140 sites in North America, Latin America, Europe, and Asia Pacific were activated. Clinical trial information: NCT03816163 .

Optimal first-line treatment for metastatic ALK+ non-small cell lung cancer-a narrative review.

First-line treatment options for patients with advanced non-small cell lung cancer (aNSCLC) whose tumors harbour anaplastic lymphoma kinase (ALK) gene rearrangements have rapidly evolved from chemotherapy, to the first in class ALK-targeted tyrosine kinase inhibitor (TKI) crizotinib in 2011, and now include no fewer than five Food and Drug Administration (FDA)-approved ALK inhibitors. However, while superiority to crizotinib has been established, head-to-head clinical trials comparing newer generation ALK inhibitors are lacking, and decisions on optimal first-line treatment must be based on analysis of the relevant trials, with attention to systemic and intracranial efficacy, toxicity profile as well as consideration of patient factors and preferences. Here we aim to synthesise findings from review of these trials and to describe options for optimal first-line treatment for ALK+ NSCLC. A literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied. Crizotinib was established as the standard of care first-line treatment for patients with ALK+ aNSCLC in 2011. Since this time, alectinib, brigatinib, ensartinib and lorlatinib have all demonstrated superiority as first-line treatments compared to crizotinib, based on progression free survival, intra-cranial efficacy, and side-effect profiles. Options for optimal first-line treatment for ALK+ aNSCLC include alectinib, brigatinib and lorlatinib. This review serves as a resource summarizing data from key clinical trials with ALK inhibitors to aid in decision making when tailoring treatment for patients. Future research in the field includes real world analysis of efficacy and toxicity of next-generation ALK-inhibitors, identification of mechanisms of tumor persistence and acquired resistance, development of novel ALK inhibitors, and use of ALK-TKIs in earlier stage disease.

Adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an extremely refractory peripheral T-cell lymphoma that develops after persistent human T-lymphotropic virus type 1 (HTLV-1) infection. In recent years, the number of HTLV-1 carriers has decreased due to lifestyle changes and different measures. Rapid progression in comprehensive genetic analysis techniques has revealed the molecular basis of ATL. Therefore, in addition to conventional prognostic indices based on clinical parameters, prognostic indices incorporating genetic mutations have been proposed. The standard treatment for untreated aggressive ATL is combination chemotherapy such as VCAP-AMP-VECP or CHOP, followed by allogeneic hematopoietic stem cell transplantation, as appropriate. Combined mogamulizumab and chemotherapy is a promising first-line treatment option for patients not eligible for transplantation. Salvage treatment with lenalidomide, brentuximab vedotin, tucidinostat, and valemetostat, in addition to mogamulizumab, has been introduced over the last decade. Advancements in allogeneic transplantation therapy, including early induction and transplantation with post-transplant cyclophosphamide for GVHD prophylaxis, have also improved patient outcomes. This article highlights recent developments in the field of ATL.

Integrin β3 Mediates Sepsis and Mechanical Ventilation-Associated Pulmonary Fibrosis Through Glycometabolic Reprogramming

Mechanical ventilation (MV) has become a clinical first-line treatment option for patients with respiratory failure. However, it was unclear whether MV further aggravates the process of sepsis-associated pulmonary fibrosis and eventually leads to sepsis and mechanical ventilation-associated pulmonary fibrosis (S-MVPF). This study aimed to explore the mechanism of S-MVPF concerning integrin β3 activation in glycometabolic reprogramming of lung fibroblasts. We found that MV exacerbated sepsis-associated pulmonary fibrosis induced by lipopolysaccharide, which was accompanied by proliferation of lung fibroblasts, increased deposition of collagen in lung tissue, and increased procollagen type I carboxy-terminal propeptide in the bronchoalveolar lavage fluid. A large number of integrin β3- and pyruvate kinase M2-positive fibroblasts were detected in lung tissue after stimulation with lipopolysaccharide and MV, with an increase in lactate dehydrogenase A expression and lactate levels. S-MVPF was primarily attenuated in integrin β3-knockout mice, which also resulted in a decrease in the levels of pyruvate kinase M2, lactate dehydrogenase A, and lactate. In conclusion, MV aggravated sepsis-associated pulmonary fibrosis, with glycometabolic reprogramming mediated by integrin β3 activation. Thus, integrin β3-mediated glycometabolic reprogramming might be a potential therapeutic target for S-MVPF.

Bioinformatics analysis of an immunotherapy responsiveness-related gene signature in predicting lung adenocarcinoma prognosis.

Immune therapy has become first-line treatment option for patients with lung cancer, but some patients respond poorly to immune therapy, especially among patients with lung adenocarcinoma (LUAD). Novel tools are needed to screen potential responders to immune therapy in LUAD patients, to better predict the prognosis and guide clinical decision-making. Although many efforts have been made to predict the responsiveness of LUAD patients, the results were limited. During the era of immunotherapy, this study attempts to construct a novel prognostic model for LUAD by utilizing differentially expressed genes (DEGs) among patients with differential immune therapy responses. Transcriptome data of 598 patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) database, which included 539 tumor samples and 59 normal control samples, with a mean follow-up time of 29.69 months (63.1% of patients remained alive by the end of follow-up). Other data sources including three datasets from the Gene Expression Omnibus (GEO) database were analyzed, and the DEGs between immunotherapy responders and nonresponders were identified and screened. Univariate Cox regression analysis was applied with the TCGA cohort as the training set and GSE72094 cohort as the validation set, and least absolute shrinkage and selection operator (LASSO) Cox regression were applied in the prognostic-related genes which fulfilled the filter criteria to establish a prognostic formula, which was then tested with time-dependent receiver operating characteristic (ROC) analysis. Enriched pathways of the prognostic-related genes were analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and tumor immune microenvironment (TIME), tumor mutational burden, and drug sensitivity tests were completed with appropriate packages in R (The R Foundation of Statistical Computing). Finally, a nomogram incorporating the prognostic formula was established. A total of 1,636 DEGs were identified, 1,163 prognostic-related DEGs were extracted, and 34 DEGs were selected and incorporated into the immunotherapy responsiveness-related risk score (IRRS) formula. The IRRS formula had good performance in predicting the overall prognoses in patients with LUAD and had excellent performance in prognosis prediction in all LUAD subgroups. Moreover, the IRRS formula could predict anticancer drug sensitivity and immunotherapy responsiveness in patients with LUAD. Mechanistically, immune microenvironments varied profoundly between the two IRRS groups; the most significantly varied pathway between the high-IRRS and low-IRRS groups was ribonucleoprotein complex biogenesis, which correlated closely with the TP53 and TTN mutation burdens. In addition, we established a nomogram incorporating the IRRS, age, sex, clinical stage, T-stage, N-stage, and M-stage as predictors that could predict the prognoses of 1-year, 3-year, and 5-year survival in patients with LUAD, with an area under curve (AUC) of 0.718, 0.702, and 0.68, respectively. The model we established in the present study could predict the prognosis of LUAD patients, help to identify patients with good responses to anticancer drugs and immunotherapy, and serve as a valuable tool to guide clinical decision-making.

Pembrolizumab: first anti-PD-1/L1-based regimen for first-line treatment of advanced esophageal cancer in Japan

ABSTRACT Introduction Esophageal cancer (EC) is the ninth most common cancer in Japanese men. Esophageal squamous cell carcinoma (ESCC) is the major histological type and accounts for 90% of EC cases in Japan. The prognosis of advanced ESCC remains poor. The standard treatment for advanced ESCC was palliative chemotherapy with 5-fluorouracil plus cisplatin as first-line chemotherapy. After failure of first-line chemotherapy, taxanes were used as second-line chemotherapy. Recently, pembrolizumab monotherapy has demonstrated benefits as a second-line treatment in patients with advanced ESCC and a combined positive score of ≥10. Survival was found to be improved in patients with advanced EC who received first-line treatment with pembrolizumab plus doublet chemotherapy than in those who received doublet chemotherapy alone. Areas covered This overview of immune checkpoint inhibitors focuses on pembrolizumab in combination with chemotherapy and shares key clinical data relevant to the treatment of patients with EC in Japan. Expert opinion Pembrolizumab plus doublet chemotherapy is now an established first-line treatment for advanced EC in Japan. Recently, nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab have also become first-line treatment options for patients with advanced ESCC. Further investigations are needed to identify biomarkers that would be useful for selecting candidates for these treatments.

Comparison of ultrasonography and fluoroscopy as guides for extracorporeal shock wave lithotripsy in nephrolithiasis patients: a systematic review

BACKGROUND Extracorporeal shock wave lithotripsy (ESWL) is one of the first-line treatment options for patients with renal stones &lt;2 cm. The large variability in ESWL results may be due to the stone visualization methods using ultrasonography (USG), fluoroscopy, or a combination of both. This study aimed to review the efficacy and safety of the stone visualization method on the stone-free rate (SFR) and postprocedural complications in nephrolithiasis patients.&#x0D; METHODS We conducted a systematic review of USG and fluoroscopy on ESWL until July 2022, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We assessed and collected summaries of the screened papers. The main outcomes assessed were the SFR of renal stones and postprocedural complications between imaging modalities.&#x0D; RESULTS A total of 7 studies were assessed, including 6 comparative assessments of USG versus fluoroscopy and 1 comparative assessment of USG and fluoroscopy versus fluoroscopy only. Although all studies showed that USG had a higher SFR than fluoroscopy, only 1 study showed a significant difference (p = 0.008). Additionally, superior results were obtained using a combination of USG and fluoroscopy compared with fluoroscopy only. Most studies agreed that USG was not inferior in post-ESWL complication results.&#x0D; CONCLUSIONS Overall, the use of USG is comparable to fluoroscopy because it does not provide a significant difference in the SFR and complications. In most cases, USG is preferred because of the absence of radiation. The combination of fluoroscopy and USG also provides more promising results than a single modality.

Clinical outcomes of reverse shoulder arthroplasty and rotator cuff repair in patients with massive rotator cuff tears without osteoarthritis: comparison using propensity score matching.

The optimal management for massive rotator cuff tears (MRCTs) without osteoarthritis (OA) remains controversial. The purpose of this study was to evaluate and compare the clinical outcomes of reverse shoulder arthroplasty (RSA) vs. rotator cuff repair (RCR) in patients with MRCTs without OA. We conducted a retrospective data analysis of 68 patients treated for MRCTs via RSA and 215 patients treated for MRCTs via arthroscopic RCR between January 2014 and April 2019. Through propensity score matching, patients were matched for sex, age, tear size, and global fatty degeneration index. Thirty-nine patients in each group were included, and all patients had completed minimal 2-year follow-up. Postoperative radiologic evaluations of healing failure were performed. The visual analog scale score for pain, range of motion, and functional outcome measures including the American Shoulder and Elbow Surgeons score, QuickDASH (short version of Disabilities of the Arm, Shoulder and Hand questionnaire) score, Simple Shoulder Test score, and Constant score were assessed and compared between the 2 groups. Healing failure was observed in 10 patients in the RCR group (32.3%). No statistically significant differences in preoperative range of motion and functional scores were found between the RCR and RSA groups. Both groups showed significant pain relief and functional improvement at final follow-up. Patients in the RCR group showed significantly greater forward elevation (156.4°±23.8° vs. 139.7°±22.4°, P<.001) and internal rotation (thoracic vertebra, T8.2±1.2 vs. T9.7±2.6, P=.001). The average American Shoulder and Elbow Surgeons score was 88.3±12.2 in the RCR group and 81.8±16.1 in the RSA group (P=.045). The QuickDASH score was significantly higher in the RCR group (P=.019). A significantly higher Simple Shoulder Test score (9.7±2.8 vs. 8.1±3.0, P=.01) and a significantly higher Constant score (67.2±6.5 vs. 63.2±7.1, P=.011) were seen in the RCR group. Both RSA and RCR are effective and reliable treatment options for MRCTs without OA. However, the RCR group showed better shoulder function improvement than the RSA group. Considering the possible implications of RSA, RCR should be referred to as a first-line treatment option for patients with MRCTs without OA with proper indications.

P827: EFFICACY AND SAFETY OF ROMIPLOSTIM ADDED TO IMMUNOSUPPRESSIVE THERAPY AS A FIRST-LINE TREATMENT IN PATIENTS WITH APLASTIC ANEMIA: A PHASE 2/3 CLINICAL TRIAL

Background: Romiplostim, a thrombopoietin (TPO) mimetic protein, has been shown to promote tri-lineage hematopoiesis in patients with acquired aplastic anemia (AA) refractory to immunosuppressive therapy (IST) or eltrombopag; however, its effectiveness in the combination therapy with antithymocyte globulin (ATG) plus cyclosporine (CsA) as a first-line treatment remains unknown. Aims: To clarify this issue, we conducted a phase 2/3 clinical trial to evaluate the efficacy and safety of romiplostim combined with rabbit ATG plus CsA in patients with AA requiring transfusions who had not been exposed to IST. Methods: This study was a multi-national, open-label study with romiplostim in IST-naïve adult patients with AA (NCT03957694). 10 µg/kg of romiplostim was started on day 1 of ATG therapy (2.5mg/kg/day for 5 days) and was weekly given for the first 4 weeks. The dose was adjusted from 5 to 20 µg/kg according to the prespecified dose adjustment procedure. Treatment lasted until Week 26. For those who intend to continue treatment, romiplostim administration was extended to Week 52. The primary endpoint was the hematological response rate (HRR) at Week 27 based on the response assessment criteria (Table 1). The secondary endpoints included the HRR at Week 14; the time to the hematological response; the proportion of patients who achieved transfusion independence or who showed a reduction of transfusion requirement among patients who had received a transfusion within 8 weeks prior to the first romiplostim administration. The bone marrow and cytogenetic analyses were performed prior to enrollment and at Week 27 and 53. Results: Twenty-six patients were screened, of which 17 (9 Japan, 7 Korea, and 1 Taiwan; 5 transfusion dependent non-severe AA, 6 severe AA (SAA) and 6 very SAA) were enrolled in the study. The median age was 44.0 years (range: 25-70). Two patients discontinued romiplostim before Week 27. The HRR (CR or PR) at Week 27 was 76.5% (95% CI: 50.10%, 93.13%), of which 6 (35.3%) achieved CR. The HRR at Week 14 was 41.2% (95% CI: 18.44%, 67.03%). The median day to achieve the first hematological response was 93.0 (range: 63-181). Of the 16 patients who depended on platelet transfusion before romiplostim administration, 14 (87.5%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. In addition, of 16 who required erythrocyte transfusion at baseline, 13 (81.3%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. The frequently reported adverse events (AEs) were constipation (41.2%) followed by headache (35.6%). The frequently reported drug-related AEs were headache (12.9%) followed by muscle spasms (9.7%), alanine aminotransferase increased, fibrin D dimer increased, malaise, and pain in extremity (each 6.5%). In bone marrow examination, increases of reticuline grade (grade 1 to 2) were observed in 3 patients at Week 27 and 1 patient at Week 53. No chromosomal abnormality or transformation into MDS and/or AML was observed. Image:Summary/Conclusion: This is the first clinical trial of romiplostim combined with rabbit ATG plus CsA in patients with acquired AA requiring transfusions who were previously untreated with IST. This regimen produced higher HRR at Week 27 (76.5%) than those of historical control received rabbit ATG plus CsA (approximately 50% at 6 months), with manageable AEs, and could therefore serve as a new first-line treatment option in patients with AA.

Cost-effectiveness analysis of nivolumab plus ipilimumab plus two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States

Aim This economic analysis evaluated the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of platinum-doublet chemotherapy (PDC) compared with four cycles of PDC as first-line treatment for patients with advanced NSCLC in the United States (US). Methods A partitioned survival model was constructed with three mutually exclusive health states: progression free, progressed disease, and death. The analysis was conducted from a US healthcare payer perspective, using a time horizon of 25 years. Costs and outcomes were discounted at 3% annually. Survival outcomes from CheckMate 9LA were extrapolated with longer follow-up data from CheckMate 227 Part 1 (NIVO + IPI) and validated against data from other relevant clinical trials and real-world registries. Health-related quality of life utility values were derived from EQ-5D-3L data collected in CheckMate 9LA. US-specific costs (2020 dollars) were used for disease management; drug acquisition, administration, and monitoring; end-of-life care; adverse events; and subsequent treatments. Model outcomes included life years (LYs) gained, quality-adjusted LYs (QALYs) gained, and incremental cost-effectiveness ratio (ICER) for NIVO + IPI + PDC versus PDC. Sensitivity and scenario analyses were conducted. Results NIVO + IPI + PDC was associated with higher projected health benefits than PDC, including gains in LYs (3.71 vs 1.89) and QALYs (2.86 vs 1.37), and higher costs ($317,581 vs $119,909). The ICER was $132,960/QALY gained. NIVO + IPI + PDC had a 78–100% probability of being cost-effective at a willingness-to-pay threshold of $150,000–$250,000/QALY. Sensitivity and scenario analyses indicated that the results were robust to changes in key parameters. Limitations The inherent limitation in extrapolating clinical trial data was mitigated using data from the more mature CheckMate 227 Part 1 trial and validating the outcomes against data from other relevant trials and real-world registries. Conclusion NIVO + IPI + PDC (two cycles) provides a new first-line treatment option for patients with advanced NSCLC that is cost-effective within a range considered acceptable in the US.

Treatment-Resistant Depression – What is the Effective Maintenance Treatment

IntroductionTreatment-resistant depression (TRD) presents a significant challenge in clinical practice. Besides antidepressant medications, neurostimulation methods (ECT, rTMS) and ketamine are viable treatment options.ObjectivesTo objectively evaluate the real effectiveness of treatments within interventional psychiatry in the maintenance treatment.MethodsThe extensive literature review of the efficacy of ECT, rTMS, and ketamine treatment in the maintenance treatment of TRD and the author’s clinical and research experience will be included in this presentation.ResultsNeurostimulation, particularly ECT and ketamine treatment are usually effective treatments for patients with TRD. However, both of these treatment modalities do not have sustained benefits and after discontinuing treatment the majority of patients relapse. Ketamine has rapid therapeutic effects in depression, but these effects are short-lived. Continuation treatment with ketamine in the form of intranasal ketamine is an option, but concerns over cognitive impairment, interstitial cystitis and significant addictive potential related to longer use of ketamine are significant limiting factors. rTMS is a first-line treatment option for patients with TRD according to the Canadian CANMAT guidelines. However, the majority of patients may relapse following the course of rTMS. The maintenance rTMS over an extended period of time is usually not feasible as it may significantly affect the waiting time for newly referred patients. Portable TMS machine for home use would be an alternative option for a limited number of patients.ConclusionsMaintenance treatment has been always a big clinical challenge in mood disorder psychiatry. Only well-established multimodal treatment is a realistic option for getting long-term benefits in treating patients with TRD.DisclosureNo significant relationships.

Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of claudin 18.2-positive metastatic pancreatic cancer (mPC): Phase 2, open-label, randomized study.

TPS4186 Background: GN is a first-line treatment option for patients (pts) with mPC. Poor prognosis and low 5-year survival rate ( &lt; 5%) of pts with mPC highlight the need for new therapeutics. Claudin 18.2 (CLDN18.2), a tight junction protein expressed exclusively on normal gastric epithelial cells, is maintained during malignant transformation in gastric cancers and is frequently expressed in some carcinomas from organs that do not normally express it, such as pancreatic cancer. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Methods: This phase 2 study (NCT03816163), expanded to enroll approximately 369 pts, will assess safety and efficacy of GN alone or with zolbetuximab in pts with histologically confirmed mPC and high CLDN18.2 expression (moderate-to-strong IHC staining intensity in ≥75% of tumor cells). The study included a safety lead-in that enrolled 3-12 pts to assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W, then expand/de-escalate using a 3+3 design) plus GN. Dose-limiting toxicities (DLTs, defined as a specified zolbetuximab-related toxicity that occurs during DLT assessment period) will be assessed after Cycle 1 (28 days). Based on the recommended phase 2 dose (RP2D), confirmed during the safety lead-in, approximately 357 pts will be randomized 2:1 to zolbetuximab Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle (Arm 1), or GN alone on Days 1, 8, and 15 of each cycle (Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). At sites in Japan, DLTs (assessed from Cycle 1 Day 1 to Cycle 2 Day 1) will be evaluated in ≤6 pts randomized to the RP2D in Arm 1. Pts will undergo imaging (CT/MRI) at baseline and every 8 weeks until investigator-assessed disease progression (RECIST v1.1) or the start of another systemic anticancer treatment, whichever comes earlier. In addition to confirming the RP2D during the safety lead-in, primary objectives are to assess whether treatment with zolbetuximab plus GN, versus GN alone, improves overall survival (randomization phase) and to establish the safety/tolerability profile of zolbetuximab plus GN (across the study). Secondary endpoints include progression-free survival, objective response rate, disease control rate, duration of response, pharmacokinetics, and health-related quality of life (per protocol amendment). Data will be presented using descriptive statistics for continuous endpoints and frequency and percentage for categorical endpoints. At original protocol enrollment completion (October 2021), 84 sites were actively recruiting; sites are currently reopening for screening/enrollment pending protocol amendment approval. Clinical trial information: NCT03816163.

Colonoscopy Versus Catheter Angiography for Lower Gastrointestinal Bleeding After Localization on CT Angiography.

The aim of this study was to compare catheter angiography (CA) and colonoscopy outcomes after successful CT angiographic (CTA) localization for patients with overt lower gastrointestinal bleeding (LGIB). Seventy-one consecutive patients from two institutions between 2010 and 2020 had both contrast extravasation on CTA imaging in the lower gastrointestinal tract and subsequent CA or colonoscopy. The primary outcome was confirmation of active bleeding during CA or colonoscopy (defined as confirmation yield). The secondary outcomes were to determine therapeutic yield (hemostatic therapy), time to procedure, rebleeding rate, and adverse outcome rates (defined as surgery, acute kidney injury, initiation of dialysis, and overall mortality). Univariate analyses and multivariable analyses with P < .05 were used to determine statistical significance. Forty-four patients underwent CA and 27 underwent colonoscopy. CA had higher overall confirmation yield (55% vs 26%, P= .026), whereas therapeutic yields were similar (70% vs 56%, P= .214). Time to procedure was 5.1 ± 3.4 hours for CA and 15.5 ± 13.6 hours for colonoscopy (P < .001). On multivariable analysis, shorter time to procedure was the only statistically significant predictor of confirmation yield (P= .037) and therapeutic yield (P= .013), whereas procedure, hemoglobin, transfusions, and hemodynamic instability were not. Adverse events and rebleeding were not statistically different between patients who underwent CA and colonoscopy (P > .05). Shorter time to procedure was the only statistically significant predictor of confirmation and therapeutic yield after CTA localization of LGIB. Because CA can be performed sooner than colonoscopy without increased rates of adverse outcomes or rebleeding, CA may be a reasonable first-line treatment option in patients with CTA localization of LGIB.