Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study.

Background: The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. Methods: We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. Results: Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. Conclusions: Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer.

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management.

AIM: Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS: We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS: Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION: Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.

First-Line Treatments and Management of Metastatic Renal Cell Carcinoma Patients: An Italian Interdisciplinary Uro-Oncologic Group Algorithm.

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice.

First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

Efficacy of rituximab-containing regimens used as first-line and rescue therapy for giant cell hepatitis with autoimmune hemolytic anemia a retrospective study.

OBJECTIVE: To evaluate the efficacy of rituximab (RTX)-containing therapy as first-line as well as rescue treatment for giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA). METHODS: This retrospective study recruited patients diagnosed with GCH-AHA and treated with conventional immunosuppressor regimens consisting of prednisone or RTX-containing regimes consisting of RTX and prednisone, with or without another immunosuppressor. The primary outcomes were the complete remission (CR) rate and time-period required for CR. The secondary outcomes included relapses and adverse events. RESULTS: Twenty patients (8 females and 12 males; age range 1-26 months), 15 receiving conventional regimens and 5 receiving RTX-containing regimens, were included. The CR rates were 73.3 % (11/15) and 100 % (5/5) in the conventional and RTX-containing groups, respectively. The time-period required for CR was significantly shorter in the RTX-containing group than in the conventional group (6 (3-8) versus 14 (5-25) months, P = 0.015). Relapses occurred in 30.8 % (4/13) of patients in the conventional group; all achieved CR after adding RTX. Relapses occurred in 40.0 % (2/5) of patients in the RTX-containing group; both achieved CR after adding intravenous immune globulins or tacrolimus. Transient low immunoglobulin and infections were recorded in both groups. Treatment withdrawal was achieved in 73.3 % (11/15) and 60.0 % (3/5) of patients receiving conventional and RTX-containing regimens after 36 (2-101) and 22 (4-41) months, respectively. Two patients in conventional group died of disease progression and infection. CONCLUSIONS: RTX-containing first-line therapy achieves CR of GCH-AHA more quickly than the conventional therapy. RTX is efficacious when added to rescue therapy.

Comparative efficacy of immune checkpoint inhibitors combined with chemotherapy in patients with advanced driver-gene negative non-small cell lung cancer: A systematic review and network meta-analysis.

Objective: To evaluate the efficacy of different combinations of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: We obtained relevant randomized controlled trials (RCTs) from databases such as PubMed, Embase, Web of Science, and The Cochrane Library up to May 31, 2023. The analysis of clinical prognostic factors was performed using R 4.2.3 and STATA 15.0. The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events of grade 3-5 severity (Grade ≥3 TRAE). Results: A total of 17 randomized controlled trials (RCTs) were conducted between 2012 and 2023, involving 7792 patients. These trials evaluated 11 different treatment methods. The results of these trials showed that in terms of overall survival (OS) and progression-free survival (PFS), the combination of tislelizumab with chemotherapy and the combination of camrelizumab with chemotherapy were particularly effective. Moreover, when compared with other combination therapies, pembrolizumab combined with chemotherapy showed superiority in terms of disease control rate (DCR) and objective response rate (ORR). Subgroup analyses further demonstrated that the addition of immune checkpoint inhibitors (ICIs) to chemotherapy significantly improved PFS and OS in patients without liver metastasis and in those with brain metastasis. Additionally, carboplatin-based combination therapy was found to confer favorable survival benefits in terms of PFS, while cisplatin-based combination therapy showed the most favorable outcomes in terms of OS. The results of subgroup analyses for overall survival (OS) showed that the combination of immunotherapy and chemotherapy yielded positive outcomes in specific subgroups. These subgroups were characterized by PD-L1 Tumor Proportion Score (TPS) of 50 % or higher, usage of anti-PD-1 medications, age below 65, male gender, smoking history, and non-squamous cell carcinoma histology. Superior effectiveness was demonstrated only in extending the progression-free survival (PFS) of female patients and patients with squamous carcinoma. Meanwhile, other patient cohorts did not show the same level of improvement. Conclusions: Tislelizumab, camrelizumab or pembrolizumab combined with chemotherapy may be the optimal first-line treatment strategies for NSCLC.

Treatment options in first-line metastatic renal carcinoma: A meta-analysis of 2556 patients treated with immune checkpoint inhibitors-based combinations in randomised controlled trials.

BACKGROUND & AIMS: The average five-year survival of metastatic renal cell carcinoma (mRCC) is 71%. However, there is significant variability in patient prognosis. Immune checkpoint inhibitors (ICIs) have been introduced into the treatment landscape of mRCC. This meta-analysis aimed to estimate progression-free and overall survival probabilities and identify possible outcome predictors of mRCC patients treated with ICI combination as first-line treatment. METHODS: Studies comparing the combination of ICI combinations versus standard of therapy for first-line treatment of advanced renal-cell carcinoma were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through September 2023. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using the DerSimonian and Laird methods. RESULTS: Six studies met the inclusion criteria. Globally, 5121 patients were included in this meta-analysis: 2556 patients treated with immune checkpoint inhibitors and 2565 with sunitinib as control. The ICI combination was associated with improved PFS (hazard ratio (HR) 0.68; 95 % confidence interval (CI), 0.56-0.81, p < 0.0001). Furthermore, ICI combination was also associated with OS improvement (HR 0.85; 95 % CI, 0.78-0.92, p = 0.001). There is no statistical increase in adverse events. CONCLUSIONS: Our findings show that PFS and OS are statistically increased in mRCC with ICI combination treatment by 32% and 15%, respectively.

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

[Box: see text].

New Insights into First-Line Therapy in Diffuse Large B-Cell Lymphoma: Are We Improving Outcomes?

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of lymphoma, comprising heterogeneous patient subgroups with distinctive biological and clinical characteristics. The R-CHOP combination (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard initial treatment, yielding prolonged remissions in over 60% of patients with advanced-stage disease. Several attempts to enhance the outcomes of this regimen over the last two decades have shown limited success. Various novel therapeutic approaches have recently emerged in lymphoma, demonstrating promising results. These include small molecules, novel monoclonal antibodies, antibody-drug conjugates (ADC), bispecific antibodies (BsAbs), and chimeric antigen receptor (CAR) T-cell therapy. This review explores recent advancements in therapeutic strategies for DLBCL and their potential impact on the initial management of DLBCL patients.

Real-life clinical management patterns in extensive-stage small cell lung cancer across France: a multi-method study.

BACKGROUND: We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice. METHODS: A 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers. RESULTS: In ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2-7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI. CONCLUSIONS: There is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting.

Long-Term Follow-Up of Combination Therapy with Sintilimab and Anlotinib in Gallbladder Follicular Dendritic Cell Sarcoma: A Rare Case Report.

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm for which a standardized treatment approach has yet to be established. The prevailing therapeutic strategy typically involves resection followed by adjuvant chemotherapy or radiation. This case report details the long-term follow-up of a 59-year-old Chinese male diagnosed with gallbladder FDCS and liver metastases. The patient received a combination therapy of sintilimab and anlotinib, resulting in a substantial partial response (PR) lasting for a noteworthy duration of 30 months. Notably, this is the first documented instance of gallbladder FDCS with liver metastases being treated with PD-1 antibody and antiangiogenic agents as first-line therapy. These findings suggest that this treatment regimen may offer a potential therapeutic option for patients with gallbladder FDCS and liver metastases, with a duration of PR lasting up to 30 months.

Clinical features and treatment outcomes of PD-1 inhibitor therapy in elderly patients (≥ 65 years) with advanced esophageal squamous cell carcinoma: a real-world study.

PURPOSE: This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65 years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). RESULTS: A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2 months (95% CI: 5.1-7.3), and the median OS was 15.3 months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. CONCLUSION: The study demonstrated that individuals older than 65 years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.

The Butterfly Flies - Practice Changing Results of PAPILLON, First Line Chemotherapy and Amivantamab for the Treatment of NSCLC Patients with EGFR Exon 20 Insertions.

Epidermal growth factor receptor (EGFR) exon 20 insertions are a rare subtype of EGFR mutations that do not respond to EGFR tyrosine kinase inhibitors developed for sensitizing mutations. In 2021, two drugs, amivantamab and mobocertinib each received FDA accelerated approval for second line use after platinum based therapy. These drugs were then brought to first line setting clinical trials; PAPILLON and EXCLAIM2. PAPILLON, which compared amivantamab plus chemotherapy to chemotherapy was positive, whereas EXCLAIM2, which compared mobocertinib to chemotherapy was negative. The PAPILLON regimen received subsequent FDA approval. In this commentary, we review the details of PAPILLON and also discuss why the rival trial, EXCLAIM2, may have failed.

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1-negative metastatic lung adenocarcinoma: a real-world data.

BACKGROUND: Chemotherapy combined with immune checkpoint inhibitors (IC), bevacizumab (BC), or both (IBC) is the preferred first-line therapy for PD-L1-negative and oncogenic-driver wild-type metastatic lung adenocarcinoma. However, the optimal strategy is still undetermined. METHODS: This retrospective study enrolled PD-L1-negative metastatic lung adenocarcinoma patients from four cancer centers between January 1, 2018 and June 30, 2022. All the patients received IC, BC, or IBC as the first-line therapies. The efficacy and safety were evaluated. RESULTS: A total of 205 patients were included, with 60, 83, and 62 patients in IC, BC, and IBC groups, respectively. The baseline characteristics among three groups were well balanced. Patients treated with IBC had the highest objective response rate (ORR) (43.5%) and disease control rate (DCR) (100%) relative to those treated with IC (40.4%, 84.2%) or BC (40.5%, 96.2%) (ORR: P = 0.919, DCR: P < 0.01). Compared with the IC (6.74 m) or BC (8.28 m), IBC treatment significantly improved median progression-free survival (mPFS) (9.53 m, P = 0.005). However, no difference in overall survival (OS) was observed. When stratified by different clinical and molecular information, we found that male gender, ever smoking, wild-type genes mutations, and adrenal metastasis predict superior PFS benefit when treated with IBC. In patients with liver metastasis, IBC or BC treatment displayed better PFS compared with IC. No additional adverse reactions were observed in IBC group compared with other two groups. CONCLUSION: Combined IBC treatment achieved superior DCR and PFS compared with IC or BC in patients with PD-L1-negative metastatic lung adenocarcinoma, while did not increase the adverse events.

Immune checkpoint inhibitors or anti-claudin 18.2 antibodies? A network meta-analysis for the optimized first-line therapy of HER2-negative gastric cancer.

Background: Multiple anti-programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and zolbetuximab, an anti-claudin 18.2 antibody, have shown efficacy in the first-line treatment of HER2-negative gastric cancers. How to choose the best regimen remains an unsolved question. Objectives: We aimed to conduct a comparative analysis of the therapeutic advantages between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers. Design: Network meta-analysis was employed to systematically compare efficacy and safety data derived from various clinical trials. Data sources and methods: We included phase III randomized controlled trials in PubMed, Embase, Web of Science, Cochrane Library, and major conference abstracts. Network meta-analysis was used to compare the efficacy of each first-line therapeutic agent and to indirectly compare immunotherapy with anti-claudin-18.2-targeted therapy. Results: Eight trials comprising a total of 6455 patients were included. For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94-1.07], sintilimab (HR = 0.99, 95% CI: 0.89-1.09), sugemalimab (HR = 0.98, 95% CI: 0.87-1.10), tislelizumab (HR = 0.97, 95% CI: 0.87-1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91-1.07), and nivolumab (HR = 1.00). For the progression-free survival (PFS) analysis, no statistically significant differences were observed between pembrolizumab (HR = 1.00, 95% CI: 0.93-1.06), sintilimab (HR = 0.91, 95% CI: 0.83-1.00), sugemalimab (HR = 0.92, 95% CI: 0.84-1.02), tislelizumab (HR = 0.93, 95% CI: 0.84-1.03), zolbetuximab (HR = 0.96, 95% CI: 0.88-1.05), and nivolumab (HR = 1.00). For the overall response rate analysis, all regimens presented similar effects on ORR. In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95-1.04) and PFS (HR = 1.01, 95% CI: 0.91-1.12) compared to immunotherapy, although their toxicity profiles were distinct. Conclusions: Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers.

Sequential versus Standard Triple Therapy for First-Line Helicobacter pylori Eradication: An Update.

BACKGROUND: non-bismuth sequential therapy (SEQ) was suggested as a first-line anti-Helicobacter pylori treatment alternative to standard triple therapy (STT). METHODS: We conducted a systematic review with a meta-analysis of randomized controlled trials (RCTs) comparing the efficacy of 10-day SEQ vs. STT (of at least 7 days) using bibliographical searches up to July 2021, including treatment-naïve adult or children. The intention-to-treat (ITT) eradication rate and the risk difference (RD) were calculated. RESULTS: Overall, 69 RCTs were evaluated, including 19,657 patients (9486 in SEQ; 10,171 in STT). Overall, SEQ was significantly more effective than STT (82% vs. 75%; RD 0.08; p < 0.001). The results were highly heterogeneous (I2 = 68%), and 38 studies did not demonstrate differences between therapies. Subgroup analyses suggested that patients with clarithromycin resistance only and all geographical areas but South America could benefit more from SEQ. Both therapies have evolved over the years, showing similar results when STT lasted 14 days; however, a tendency toward lower SEQ efficacy was noted from 2010 onwards. CONCLUSIONS: Prior to 2010, SEQ was significantly more effective than STT, notably when 7-day STT was prescribed. A tendency toward lower differences between SEQ and STT has been noted, especially when using 10-day STT. None of the therapies achieved an optimal efficacy and therefore cannot be recommended as a valid first-line H. pylori treatment.

Efficacy of first-line treatment options beyond RET-TKIs in advanced RET-rearranged non-small cell lung cancer: A multi-center real-world study.

BACKGROUND: Although RET-tyrosine kinase inhibitors (RET-TKIs) are the preferred first-line therapy for advanced RET-arranged NSCLC, most patients cannot afford them. In this population, bevacizumab, immunotherapy, and chemotherapy are the most commonly used regimens. However, the optimal scheme beyond RET-TKIs has not been defined in the first-line setting. METHODS: This retrospective study included 86 stage IV NSCLC patients harboring RET rearrangement from six cancer centers between May 2017 and October 2022. RET-TKIs, chemotherapy, or one of the combination therapies (including immune checkpoint inhibitor (ICI) combined with chemotherapy (I + C), bevacizumab combined with chemotherapy (B + C), ICI and bevacizumab combined with chemotherapy (I + B + C)), were used as the first-line therapeutics. The clinical outcomes and safety were evaluated. RESULTS: Fourteen of the 86 patients received RET-TKIs, 57 received combination therapies, and 15 received chemotherapy alone. Their medium PFS (mPFS) were 16.92 months (95% CI: 5.9-27.9 months), 8.7 months (95% CI: 6.5-11.0 months), and 5.55 months (95% CI: 2.4-8.7 months) respectively. Among all the combination schemes, B + C (p = 0.007) or I + B + C (p = 0.025) gave beneficial PFS compared with chemotherapy, while I + C treatment (p = 0.169) generated comparable PFS with chemotherapy. In addition, I + B + C treatment had a numerically longer mPFS (12.21 months) compared with B + C (8.74 months) or I + C (7.89 months) schemes. In terms of safety, I + B + C treatment led to the highest frequency of hematological toxicity (50%) and vomiting (75%), but no ≥G3 adverse effect was observed. CONCLUSIONS: I + B + C might be a preferred option beyond RET-TKIs in the first-line therapy of RET-arranged NSCLC. Combination with Bevacizumab rather than with ICIs offered favorable survival compared with chemotherapy alone.

Early Changes in LIPI Score Predict Immune-Related Adverse Events: A Propensity Score Matched Analysis in Advanced Non-Small Cell Lung Cancer Patients on Immune Checkpoint Blockade.

In advanced cancer patients undergoing immune checkpoint blockade, the burden of immune-related adverse events (irAEs) is high. The need for reliable biomarkers for irAEs remains unfulfilled in this expanding therapeutic field. The lung immune prognostic index (LIPI) is a noninvasive measure of systemic inflammation that has consistently shown a correlation with survival in various cancer types when assessed at baseline. This study sought to determine whether early changes in the LIPI score could discriminate the risk of irAEs and different survival outcomes in advanced non-small cell lung cancer (NSCLC) patients receiving PD-(L)1 blockade-based therapies. We included consecutive patients diagnosed with metastatic NSCLC who received pembrolizumab, nivolumab, or atezolizumab as second-line therapy following platinum-based chemotherapy, or first-line pembrolizumab either alone or in combination with platinum-based chemotherapy. The LIPI score relied on the combined values of derived neutrophil/lymphocyte ratio (dNLR) and lactate dehydrogenase. Their assessment at baseline and after two cycles of treatment allowed us to categorize the population into three subgroups with good (LIPI-0), intermediate (LIPI-1), and poor (LIPI-2) prognosis. Between April 2016 and May 2023, we enrolled a total of 345 eligible patients, 165 (47.8%) and 180 (52.2%) of whom were treated as first- and second-line at our facility, respectively. After applying propensity score matching, we considered 83 relevant patients in each cohort with a homogeneous distribution of all characteristics across the baseline LIPI subgroups. There was a noticeable change in the distribution of LIPI categories due to a significant decrease in dNLR values during treatment. Although no patients shifted to a worse prognosis category, 20 (24.1%) transitioned from LIPI-1 to LIPI-0, and 7 (8.4%) moved from LIPI-2 to LIPI-1 (p < 0.001). Throughout a median observation period of 7.3 (IQR 3.9-15.1) months, a total of 158 irAEs (63.5%) were documented, with 121 (48.6%) and 39 (15.7%) patients experiencing mild to moderate and severe adverse events, respectively. Multivariate logistic regression analysis showed that the classification and changes in the LIPI score while on treatment were independent predictors of irAEs. The LIPI-0 group was found to have significantly increased odds of experiencing irAEs. Following a median follow-up period of 21.1 (95% CI 17.9-25.8) months, the multivariable Cox model confirmed LIPI categorization at any given time point as a significant covariate with influence on overall survival, irrespective of the treatment line. These findings suggest that reassessing the LIPI score after two cycles of treatment could help pinpoint patients particularly prone to immune-related toxicities. Those who maintain a good LIPI score or move from the intermediate to good category would be more likely to develop irAEs. The continuous assessment of LIPI provides prognostic insights and could be useful for predicting the benefit of PD-(L)1 checkpoint inhibitors.