First-line Therapy For Patients Research Articles

The impact of human epidermal growth factor receptor-2 (low) status on the efficacy of first line cyclin-dependent kinase 4/6 inhibitors in advanced breast cancer.

The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33 ± 0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, P = .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.

Outcome of 14-Day Sequential and Levofloxacin-Based Triple Regimen as the First-Line Therapy in Patients with Helicobacter pylori Infection: A Prospective Comparative Study from Southern Central Nepal

Outcome of 14-Day Sequential and Levofloxacin-Based Triple Regimen as the First-Line Therapy in Patients with Helicobacter pylori Infection: A Prospective Comparative Study from Southern Central Nepal

Cost-effectiveness analysis of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric/gastroesophageal junction cancer in the Chinese healthcare system

ABSTRACT Background This study compares first-line pembrolizumab plus chemotherapy with chemotherapy alone for patients with HER2-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC) in China. Methods A Markov state-transition model was developed based on the phase 3 randomized KEYNOTE-859 clinical trial data. The health state utility values and direct medical costs were derived from the KEYNOTE-859 clinical trial, the relevant literature, and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses (OWSA) were performed to assess the uncertainty of the model. Results In the base analysis, the incremental effectiveness and cost of pembrolizumab plus chemotherapy versus chemotherapy alone were 0.22 QALYs and $16,627.31, respectively, resulting in an ICER of $76,936.60/QALY, which is higher than the willingness-to-pay threshold in China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of pembrolizumab plus chemotherapy versus chemotherapy alone were $72,762.68 and $34,813.70 in the populations with PD-L1 CPS of 1 or higher (CPS ≥ 1) and PD-L1 CPS ≥ 10 (CPS ≥ 10), respectively. Conclusions As first-line therapy for patients with locally advanced or metastatic HER2-negative GC/GEJC in China, pembrolizumab plus chemotherapy is less cost-effective than chemotherapy alone, however, in the CPS ≥ 10 subgroup is more.

Which Is More Suitable for First-Line Treatment of Extensive-Stage Small Cell Lung Cancer, PD-L1 Inhibitors Versus PD-1 Inhibitors? A Systematic Review and Network Meta-Analysis.

In this network meta-analysis (NMA), the efficiency and safety of PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy were compared in the first-line therapy of patients with extensive-stage small cell lung cancer (ES-SCLC). We searched research databases, conference abstracts, and trial registries and subsequently chose relevant studies and extracted dates. The NMA was conducted to estimate the efficiency and safety of the PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy on overall survival (OS), progression-free survival (PFS), overall remission rate (ORR), and adverse events (AEs). Studies were assessed for quality. Subgroup analyses were used to evaluate study heterogeneity. We included six randomized trials with a total of 3163 patients. Direct comparisons showed that patients who received either PD-1 inhibitors + chemotherapy (HR: 0.71, 95% CI: 0.57-0.87) or PD-L1 inhibitors + chemotherapy (HR: 0.74, 0.61-0.89) demonstrated significantly longer OS than those who received placebo + chemotherapy. The results of the NMA showed that no significant differences in OS (HR 0.96 95% CI: 0.72-1.3), PFS (HR 0.83, 95% CI: 0.51-1.4), and ORR (OR 1.3 95% CI: 0.66-2.5) were observed for PD-1 inhibitors + chemotherapy compared with PD-L1 inhibitors + chemotherapy, but the Bayesian ranking revealed that patients receiving PD-1 inhibitors + chemotherapy tended to have longer OS, PFS benefit, and better treatment response than patients receiving PD-L1 inhibitors + chemotherapy. In terms of safety, no significant difference was observed in their safety profiles. In comparison to placebo + chemotherapy, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy significantly improved survival for ES-SCLC. According to the available data, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy had equivalent efficacy and safety; however, the level of evidence of this type of comparison is limited.

Analysis of the resistance profile of real-world alectinib first-line therapy in patients with ALK rearrangement-positive advanced non-small cell lung cancer using organoid technology in one case of lung cancer.

Alectinib has achieved excellent therapeutic efficacy in anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) patients, however, patients eventually develop resistance to it. Exploring the gene variant mapping after alectinib resistance provides a basis for the whole management of ALK-positive advanced NSCLC. This study aimed to characterize the mutation profiles of real-world ALK rearrangement-positive advanced NSCLC patients after first-line alectinib treatment resistance. The research also investigated the treatment options and coping strategies after resistance. Clinical data of patients with advanced NSCLC who received first-line alectinib treatment in the First Affiliated Hospital of Guangzhou Medical University between November 2018 and April 2022 were collected. Moreover, next-generation sequencing (NGS) data of the patient's baseline and post-resistance tissues were gathered. One patient underwent lung cancer organoid culture and drug sensitivity testing. Out of 35 first-line alectinib-treated patients with advanced NSCLC, 31 are presently in progression-free survival (PFS; 4.3-35.0 months). Four patients experienced progressive disease, and all of them were sequentially treated with ceritinib. Tissue NGS results before sequential treatment in three patients indicated an echinoderm microtubule-associated protein-like 4-ALK fusion that remained at the original baseline, and the PFS for ceritinib treatment was 0.5-1.3 months. One patient developed acquired resistance mutations in the structural domain of ALK protein kinase (V1180L and E1161D), and the PFS for ceritinib treatment was 6.7 months. For one patient who maintained original baseline ALK rearrangement positive without acquired mutation after progression of ceritinib resistance, lung cancer-like organ culture with sequential brigatinib and lorlatinib led to a PFS of 3.2 and 1.9 months, respectively, which aligned with the corresponding drug susceptibility testing results for this patient. For ALK rearrangement-positive patients, blind sequencing of other second-generation tyrosine kinase inhibitors (TKIs) or third-generation lorlatinib may not guarantee satisfactory tumor suppression following first-line second-generation ALK-TKI alectinib administration for treatment progression. NGS testing of patients' blood or tissue samples after disease progression may provide insight into the etiology of alectinib resistance. Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline.

Liposomal irinotecan, oxaliplatin, and S-1 as first-line therapy for patients with locally advanced or metastatic pancreatic adenocarcinoma (NASOX): A multicenter phase I/IIa study

IntroductionThis multicenter phase I/IIa study aimed to determine the recommended phase II dose (RP2D) and evaluate the safety and preliminary efficacy of liposomal irinotecan (nal-IRI), oxaliplatin, and S-1 (NASOX) as first-line treatment for advanced pancreatic adenocarcinoma. MethodsPatients with locally advanced or metastatic pancreatic adenocarcinoma without prior systemic treatment for advanced disease, aged ≥ 19 years, with measurable disease, and Eastern Cooperative Oncology Group performance status of 0–1 were eligible. The primary endpoints were to determine the dose-limiting toxicity (DLT) in the phase I cohort and overall response rate (ORR) in the phase IIa cohort. The intention-to-treat (ITT) analysis included patients who received the RP2D. ResultsIn phase I, seven patients were screened, and six were assessed for DLT. None experienced DLT during the first cycle. The RP2D was determined as nal-IRI 50 mg/m2 and oxaliplatin 60 mg/m2 on day 1, S-1 40 mg/m2 twice daily on days 1–7 every 14 days. For the ITT (N = 41; 7, and 34 from phases I and IIa, respectively), the most common grade 3–4 treatment-emergent adverse events were neutropenia (31.7 %), enterocolitis (9.8 %), anorexia (7.3 %), and diarrhea (2.4 %). The ORR was 58.5 % (1 complete, and 23 partial responses). Two underwent conversion surgery; both achieved R0 resection. With median follow-up of 17.5 months, median progression-free survival was 6.5 months (95 % confidence interval [CI], 5.0–8.1) and median overall survival was 11.4 months (95 % CI, 9.8–15.5). ConclusionNASOX exhibited a manageable safety profile and encouraging efficacy outcomes consistent with NALIRIFOX, showing potential to replace infusional 5-fluorouracil with oral S-1 in the triplet regimen.

Effect of cetuximab plus FOLFOX4 regimen on clinical outcomes in advanced gastric carcinoma patients receiving evidence-based care

BACKGROUND Although chemotherapy is effective for treating advanced gastric carcinoma (aGC), it may lead to an adverse prognosis. Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients. AIM To determine the efficacy and safety of cetuximab (CET) combined with the FOLFOX4 regimen (infusional fluorouracil, folinic acid, and oxaliplatin) as first-line therapy for patients with aGC, who received evidence-based care (EBC). METHODS A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled. Of these, 60 in the research group (RG) received CET + FOLFOX4 as first-line therapy, whereas 57 in the control group (CG) received FOLFOX4. The efficacy [clinical response rate (RR) and disease control rate (DCR)], safety (liver and kidney dysfunction, leukopenia, thrombocytopenia, rash, and diarrhea), serum tumor marker expression [STMs; carbohydrate antigen (CA) 19-9, CA72-4, and carcinoembryonic antigen (CEA)], inflammatory indicators [interleukin (IL)-2 and IL-10], and quality of life (QOL) of the two groups were compared. RESULTS A markedly higher RR and DCR were observed in the RG compared with the CG, with an equivalent safety profile between the two groups. RG exhibited notably reduced CA19-9, CA72-4, CEA, and IL-2 levels following treatment, which were lower than the pre-treatment levels and those in the CG. Post-treatment IL-10 was statistically increased in RG, higher than the pre-treatment level and the CG. Moreover, a significantly improved QOL was evident in the RG. CONCLUSION The CET + FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC. It facilitates the suppression of STMs, ameliorates the serum inflammatory microenvironment, and enhances QOL, without increased adverse drug effects.

Nab-paclitaxel plus platinum versus paclitaxel plus platinum as first-line therapy in patients with metastatic or recurrent cervical cancer

PurposeThis study aimed to assess the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus platinum versus paclitaxel plus platinum as first-line therapy in patients with metastatic or recurrent cervical cancer.MethodsBetween October 2020 and March 2022, consecutive patients with diagnosed with metastatic or recurrent cervical cancer were retrospectively recruited in our hospital. Fifty-four patients were treated with nab-paclitaxel plus cisplatin or carboplatin. Twenty-four patients were treated with paclitaxel plus cisplatin or carboplatin. A propensity score matching (PSM) analysis was done using a multivariable logistic regression model. The two groups were compared for objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in the raw and matched dataset.ResultsThe nab-paclitaxel group showed a higher ORR than the paclitaxel group both in the raw dataset (72.2% vs. 45.8%; P = 0.025) and matched dataset (81.1% vs. 47.6%; P = 0.008). The median PFS was significantly longer in the nab-paclitaxel group than in the paclitaxel group both in the raw and matched dataset (12 vs. 7 months; P < 0.05). The median OS was not reached in the nab-paclitaxel group compared with 15 months in the paclitaxel group, with a trend toward prolongation. The most common toxicity was hematological adverse events, including grade 3–4 neutropenia, grade 3 anemia and thrombocytopenia in both groups and no statistical differences were observed between the groups (all P > 0.05).ConclusionCompared with paclitaxel plus platinum, nab-paclitaxel plus platinum may be an effective and tolerable option as first-line therapy for patients with metastatic or recurrent cervical cancer.

Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real‑world practice.

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first-line therapy for patients with unresectable hepatocellular carcinoma (u-HCC), its outcomes in real-world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u-HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression-free survival (PFS), therapeutic response and adverse events (AEs) were assessed. The objective response rate (ORR) and disease control rates (DCR) were 15.8 and 53.3%, respectively. The median PFS was 3.9 months. The incidence rates of AEs of any grade and those grade 3 or higher were 83.3 and 36.7%, respectively. Liver injury was the most frequent AE of any grade and grade 3 or higher. Although there was no significant difference in ORR and PFS between the first and later line groups (ORR 15.8 vs. 15.7%, P=0.986; PFS 4.5 vs. 3.6 months, P=0.213), there was a significant difference in DCR between the two groups (65.8 vs. 45.9%, P=0.034). No significant differences were noted between the first- and later-line treatment groups regarding the incidence rate of AEs. Decision tree analysis revealed that poor liver function and advanced age were significant variables for discontinuation owing to AEs. In conclusion, Dur/Tre as first-line therapy had better disease control responses compared with later-line therapy; however, this regimen should be carefully administered to patients with deteriorating hepatic function or advanced age.

Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer

Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80mg once daily or gefitinib 250mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Three hundred and fifty-seven patients (furmonertinib group, n=178; gefitinib group, n=179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25-4.04], p=0.027), nausea/vomiting (-1.56 [95% CI-2.62 to-0.49], p=0.004), appetite loss (-2.24 [95% CI-4.26 to-0.23], p=0.029), diarrhoea (-3.36 [95% CI-5.19 to-1.54], p < 0.001), alopecia (-2.62 [95% CI-4.54 to-0.71], p=0.007), and pain in other parts (-4.55 [95% CI-7.37 to-1.74], p=0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42-0.94], p=0.021), cognitive functioning (0.73 [95% CI 0.54-0.98], p=0.034), nausea/vomiting (0.64 [95% CI 0.41-0.99], p=0.042), appetite loss (0.63 [95% CI 0.43-0.92], p=0.016), diarrhoea (0.63 [95% CI 0.46-0.85], p=0.002), dyspnoea (0.72 [95% CI 0.53-0.98], p=0.034), cough (0.67 [95% CI 0.44-1.00], p=0.049), dysphagia (0.54 [95% CI 0.35-0.83], p=0.004), and alopecia (0.62 [95% CI 0.42-0.90], p=0.012) was longer with furmonertinib versus gefitinib. In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

The therapeutic features of EGFR L858R exon 21 mutation in non-small cell lung cancer

Introduction. Monotherapy with EGFR tyrosine kinase inhibitors (TKIs) results in a worse prognosis for patients with the exon 21 L858R mutation than for patients with exon 19 Del. Thus, the search for alternative drug strategies that improve treatment outcomes for patients with NSCLC with the L858R mutation is an urgent problem. This article presents preliminary results of a pilot study of the effectiveness of chemotherapy integrated into targeted anti-EGFR therapy for patients with non-small cell lung cancer (NSCLC) with a mutation in exon 21 of the EGFR gene.Aim. To improve progression-free survival results on first-line therapy in patients with NSCLC with the L858R mutation.Materials and methods. From 2015 to 2021 23 patients were included in the study with advanced L858R 21 exon mutation NSCLC for the first line of treatment. Patients received TKI therapy for the first 2 months, followed by discontinuation of targeted therapy and receiving 3 courses of paclitaxel and carboplatin. Target therapy was then resumed until disease progression. The follow up period was 36 months.Results. The objective response rate (ORR) was 59.1%. Median progression-free survival 23 months [95% CI: 16–36]. Four (18.1%) patients developed grade 3-4 toxicity during chemotherapy, and therefore the 3rd course of chemotherapy was canceled in one patient. Due to toxicity during targeted therapy, gefitinib dose was reduced in one patient and the drug was changed from gefitinib to afatinib in the other one patient.Conclusion. Preliminary results of our study showed that integrating chemotherapy into targeted treatment for this category of patients may become a new worthy option to increase median PFS.

Teprotumumab for the treatment of Thyroid eye disease.

Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves' disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.

The continuing value of mesalazine as first-line therapy for patients with moderately active ulcerative colitis

Mesalazine is an established and recommended first-line treatment for mild-to-moderate ulcerative colitis (UC). For patients with moderately active UC, the choice to use mesalazine or to initiate treatment with an oral corticosteroid or anti-tumor necrosis factor (TNF) agent is not clearly informed from current guidelines. The use of mesalazine is supported by robust clinical evidence supporting its efficacy at inducing remission in patients with moderately active disease. A key advantage of mesalazine is its tolerability profile being similar to that of placebo, which contrasts with that of the corticosteroids and advanced therapies, where there is the potential for significant toxicities. Mesalazine also has cost advantages over anti-TNFs and other advanced therapies. Evidence supports the consideration of all patients with moderately active UC for first-line mesalazine therapy at an optimized dose of ≥4g/d (± 1g/d rectal). Patients responding to treatment within 2 weeks should continue at ≥4g/d for at least 6 months before a dose reduction is considered, since this then alters the pattern of disease.

Update results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase II clinical trial.

e16035 Background: Recent studies have demonstrated encouraging efficacy in patients with ESCC when combining PD-1 blockades with chemotherapy in the first-line setting. However, the safety profile of conventional chemotherapy remains unsatisfactory, suggesting the chemotherapy-free regimen a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, has shown therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China. TQB2450 is a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China). This study aims to investigate the efficacy and safety of anlotinib plus TQB2450 as first-line therapy for patients with advanced ESCC. Preliminary results were presented at the 2023 ASCO-GI Symposium (Abs 377), the 2023 ASCO (Abs 4041) and the 2023 ESMO (1531P), the consecutively updated results were presented in this report. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 score and life expectancy of &gt; 3 months were inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR, secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Sep 2022, a total of 46 patients were enrolled. At the data cut-off date (Dec, 2023), there were 1 CR (2.2%), 31 PR (67.4%), 10 SD (21.7%), 1 PD (2.2%) and 3 NE (6.5%). Therefore, the preliminary ORR was 69.6% (95%CI: 54.2%~82.3%), DCR was 91.3% (95%CI: 79.2%~97.6%). At the data cut-off date, 16 patients discontinued treatment due to PD, the preliminary prognostic result exhibited that the median PFS of the 46 pts was 15.44 months (95%CI: NA~NA). Additionally, safety profile exhibited that the regimen was tolerable. The common grade ≥3 treatment-related adverse events in 46 patients were hypertension (8.7%), neutrophil count decreased (4.3%), hyponatremia (4.3%), lymphocyte count decreased (4.3%), white blood cell count decreased (2.2%), platelet count decreased (2.2%), hand-foot syndrome (2.2%), hemoptysis (2.2%) and toothache (2.2%). Conclusions: The preliminary results highlighted that anlotinib plus TQB2450 as a first-line therapy for advanced ESCC showed encouraging efficacy and manageable safety profile. Furthermore, these conclusions required to be confirmed in subsequent trials. Clinical trial information: NCT05038813 .

Comparison of checkpoint inhibitor–based regimens as first-line therapy in advanced hepatocellular carcinoma: A Frequentist Network meta-analysis of randomized clinical trials.

e16136 Background: Multiple immune checkpoint inhibitor (ICI) based regimens have shown better responses and survival rates than previously used sorafenib/lenvatinib in advanced hepatocellular carcinoma (HCC). However, there was no direct comparison done among different ICI-based regimens. This network meta-analysis focuses on the efficacy of different ICI-based regimens in advanced HCC as first-line therapy. Methods: A comprehensive literature search was performed on PubMed, and Embase from the inception of data till 12/30/2023 with keywords for “Hepatocellular carcinoma” AND “Immune Checkpoint Inhibitors”. We screened 5120 articles and included 8 randomized clinical trials (RCTs, N = 5834). “R” software and netmeta package was used to conduct this network meta-analysis. Atezolizumab + cabozantinib was randomly chosen as the comparator group. Results: 2208 patients were treated with ICI-based two-drug regimens, 1102 patients were treated with ICI monotherapy, 1937 patients were treated with sorafenib, and 399 patients were treated with lenvatinib. Overall survival (OS) was 0.63 (0.43-0.93), 0.64 (0.43-0.98), and 0.69 (0.48-0.99) in favor of sintilimab + bevacizumab, atezolizumab + bevacizumab, and camrelizumab + rivoceranib, respectively, as compared to atezolizumab + cabozantinib. Progression free survival (PFS) was 0.83 (0.54-1.27), 0.89 (0.58-1.35), and 0.94 (0.61-1.45) in favor of camrelizumab + rivoceranib, sintilimab + bevacizumab, and atezolizumab + bevacizumab, respectively, as compared to atezolizumab + cabozentinib. Odds ratio of overall response rate (ORR) 2.03 (0.67-6.13), 1.7 (0.65-4.43), and 1.46 (0.58-3.67) in favor of sintilimab + bevacizumab, camrelizumab + rivoceranib, and tremlimumab + durvalumab, respectively, as compared to atezolizumab + cabozantinib. P-scores for each regimen are in Table. Conclusions: Among ICI combinations, better survival and response rates were reported with sintilimab + bevacizumab, atezolizumab + bevacizumab, and camrelizumab + rivoceranib. Therefore, these regimens should be preferred for treatment of advanced HCC as first line therapy in patients who can tolerate these regimens. [Table: see text]

Randomized phase II evaluation of nivolumab (nivo), or relatlimab (rela), or combined nivo-rela lead-in followed by nivo-rela as first line therapy for patients (pts) with advanced melanoma (mel).

9525 Background: A phase II study of nivo and rela was designed to evaluate the separate antitumor activity of nivo and rela vs. the combination for first-line treatment of pts with advanced mel. We report objective response rate (ORR) at week (wk) 4 and 16, progression-free survival (PFS) for pts receiving lead-in with nivo or rela vs. combination, and correlations with immune-related pathological response (irPR) at wk 4 tumor biopsy. Methods: Pts were randomized (1:1:1) to lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy in all pts. The primary endpoint was ORR to nivo-rela by RECISTv.1.1 at wk 16. Secondary endpoints included progression-free survival (PFS), ORR according to lead-in therapy at wk4, safety, and major pathological response on biopsy at 4wk (MPRbx) per Stein et al, Ann Oncol (2019). Results: The trial enrolled 43 advanced mel pts, median age=67 years, female=15 (35%), ECOG PS 0=34 (79%), BRAFmutant=18 (42%), Stage IV=35 (81%), and LDH &gt;ULN=37 (86%). Pts were randomized to nivo=15, rela=14, and nivo-rela=14 lead-in arms. ORR at wk 4 were 3 (20%), 1 (7.1%), and 0 (0%) in nivo, rela, and nivo-rela lead-in arms, respectively. Among 41 evaluable pts who received at least one cycle of nivo-rela radiological assessment at wk16 was partial response (PR)=14 (34.2%), stable disease (SD)=15 (36.6%), and progressive disease (PD)=12 (29.3%). ORR at wk 16 were 6 (42.9%), 2 (15.4%), and 6 (42.9%) for nivo, rela, and nivo-rela lead-in arms, respectively. Median PFS for the whole cohort was 6.5 mos (95%CI 2.2-not reached [NR]), 4.7 mos, 1.8 mos, and NR in nivo, rela, and nivo-rela lead-in arms, respectively. After adjusting for BRAF status, rela lead-in was significantly associated with worse PFS (HR=3.41, 95% CI 1.11-10.4, p=0.03). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 14 (32.6%) pts. &amp; TRAEs (any grade) leading to treatment discontinuation were observed in 9 (20.9%). After 1 cycle of nivo one pt developed myocarditis leading to death without proceeding to nivo-rela. MPRbx at wk 4 was observed in 11 (31.4%) of 35 evaluable pts and were 50%, 0%, and 43% in nivo, rela, and nivo-rela lead-in arms, respectively. MPRbx was associated with wk16 radiological response (p=0.04) and improved PFS (HR=0.29, 95% CI 0.10-0.87, p=0.03). Nivo-rela resulted in increased CD8 and CD4+FOXP3- cell densities at wk4 (p&lt;0.01 and p=0.03, respectively) and CD8 density at wk 4 was associated with improved PFS (p=0.02). Conclusions: Nivo-rela results in 34.2% ORR and median PFS of 6.5m in pts with advanced mel after lead-in nivo, rela or combination therapy. This first single agent lead-in rela evaluation demonstrated wk 4 ORR of 7%, wk 16 ORR of 15.4% and median PFS 1.8 mos. MPRBx and CD8 density at wk4 are associated with improved PFS. Clinical trial information: NCT03743766 .

Effectiveness and safety of first-line serplulimab in patients with metastatic/locally advanced esophageal carcinoma (EC): A real-world study.

e16044 Background: The prognosis of metastatic/locally advanced EC has significantly improved with the development of immune checkpoint inhibitors. Serplulimab has been approved in the treatment of various solid tumors (e.g. esophageal squamous cell carcinoma [ESCC], small cell lung cancer). Considering the lack of real-world evidence, this study aimed to explore the real-world effectiveness and safety of serplulimab as first-line therapy in patients with metastatic/locally advanced EC. Methods: Thismulticenterretrospective study included patients with metastatic/locally advanced EC who received first-line serplulimab-containing therapy from March 2022 to December 2023. The demographic and disease characteristics, chemotherapy regimens selected by physicians, treatment response and adverse events were collected from medical record. The outcomes included progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DoR), time to treatment discontinuation (TTD) and safety. Results: A total of 57 patients were included, 45 (78.9%) were male with a mean age of 68 years. A majority of patients had ESCC (n=40, 70.2%) and metastatic disease (n=35, 61.4%). The most common chemotherapy regimens combined with serplulimab were paclitaxel plus cisplatin (n=27, 39.1%) and etoposide and platinum (n=13, 23.6%). With a median follow-up of 4.8 month (range: 0.7-19.7), the median PFS was 7.4 months (95% confidence interval [CI]: 3.7-11.1). The ORR and DCR were 22.8% and 96.5% in all patients, respectively. The median DoR and TTD were 4.7 months (95% CI: 4.3-not estimated [NE]) and 13.9 months (95% CI: 3.6-24.1), respectively, while the median OS was not reached (NR). The mPFS was 11.1 months (95% CI: 7.0-NE) in patients with ESCC, which was numerically longer than those with neuroendocrine carcinoma (6.5 months, 95% CI: 5.8-7.3, P=0.052). Other effectiveness outcomes in ESCC are presented in Table. Patients &gt; 65 years had a significant improved mPFS compare to those ≤ 65 years (5.9 vs. 11.1 months, P=0.001). The rate of any grade adverse events (AEs) was 26.3% (n=15), while grade 3 or higher AEs was 10.5% (n=6), thrombocytopenia (7.0%, n=4), myelosuppression and pulmonary infection (both 5.3%, n=3) being the most common. Conclusions: First-line serplulimab combined with chemotherapy demonstrated promising effectiveness and favorable safety profile in patients with metastatic/locally advanced EC, especially in ESCC. The current real-world evidence indicates that serplulimab combined with chemotherapy could provide survival benefit for patients with advanced first-line EC. [Table: see text]

Mycophenolate Mofetil with Steroid, a Reasonable Alternative to Current First-line Therapy, for Idiopathic Membranous Nephropathy in Resource-constrained Settings: A Randomized, Open-label Study.

The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile. Though mycophenolate mofetil (MMF) + steroid (S) is not recommended by Kidney Disease Improving Global Outcomes guidelines, it can be used as an alternative to mPR due to higher tolerability and steroid-sparing effect. Thus, we compared the safety and effectiveness of MMF + S and mPR regimens in patients with IMN. This randomized, open-label study enrolled patients with adult-onset nephrotic syndrome (NS) and biopsy-proven IMN. Forty-two patients were allocated to MMF + S group (MMF 1 gm twice daily + oral prednisolone 0.5 mg/kg/day; n = 21) and mPR group [methylprednisolone (1 gm intravenous) for 3 days followed by alternating monthly cycles of oral prednisolone (0.5 mg/kg/day) for the next 27 days and cyclophosphamide (2 mg/kg/day) for 6 months; n = 21]. The primary outcome measure was change in urinary protein creatinine ratio (UPCR). At 6 months, both groups demonstrated a significant increase in serum albumin levels and estimated glomerular filtration rate (eGFR) (both p-values <0.0001) as well as a decrease in 24-hour proteinuria (MMF + S group: p-value = 0.003, and mPR group: p-value <0.0001) and UPCR (both p-values <0.0001). However, the groups did not differ in any of these parameters at any of the monthly follow-up visits. Moreover, the groups did not differ significantly in terms of the composite remission rates (61.91% for MMF + S group and 71.43% for mPR group). MMF + S and mPR had comparable tolerability and effectiveness, with MMF-associated advantage of reduced steroid exposure.

Contemporary management of patients with advanced melanoma: Utility of an online interactive decision support tool to assess concordance of healthcare professional treatment patterns with expert recommendations.

e13548 Background: The treatment landscape for patients with melanoma continues to evolve with approvals of novel therapeutic agents for advanced disease and new indications for therapy in earlier-stage disease. Using an online decision support tool, we compared practice patterns and treatment recommendations between community healthcare professionals (HCPs) and key opinion leaders (KOLs). Methods: The online decision support tool was developed with input from 5 KOLs who provided treatment recommendations for 151 hypothetical patients. Case scenarios covered a spectrum of stages (III, IV), central nervous system (CNS) metastases, BRAF mutation status, and treatment histories. HCPs entered specific patient criteria into the tool to define a case and their intended therapy choice and the tool then showed 5 KOL recommendations for that patient case. An analysis of KOL recommendations and HCP-selected therapy was performed. Results: Between August 2023 and January 2024, 156 patient cases were entered by 100 HCPs. HCP and KOL recommendations were concordant in 51% (80/156) of cases. The highest level of discord among HCPs and KOLs was 72% for patients with completely resected stage IIIA melanoma and no positive lymph nodes having a metastatic focus ≥1mm (n = 25) (Table). A lower level of discordance (31%, n = 35) was observed in therapy selection for patients with stage IIIA melanoma and ≥1 positive lymph node. For first-line therapy in patients with unresectable stage III or IV BRAF wild-type melanoma (n = 16), discordance was 50% between HCPs and KOLs. The level of discordance was higher for first-line therapy for patients with BRAF-mutant melanoma (68%, n = 19). For the management of patients with CNS metastases, 40% of HCP therapy selections were not aligned with KOLs (n = 40). More than one half (56%) of HCPs noted that the tool confirmed their treatment plan, and 21% intend to change practice to align with KOLs. Conclusions: This analysis identified areas of discordance in clinical practice between HCPs and KOLs for advanced melanoma that can guide further education and enhance communication of evolving evidence to HCPs. Our data suggest that use of the decision tool can confirm best practices with KOL recommendations and improve alignment of treatment choices with KOLs. [Table: see text]

Preliminary data of a phase Ib/II trial evaluating the efficacy and safety of adebrelimab, camrelizumab plus apatinib as first-line therapy in patients with advanced hepatocellular carcinoma.

e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .