Landscape of immune-checkpoint inhibitors in hepatocellular carcinoma: A systematic review with meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16632-e16632
Author(s):  
Dmitrii Shek ◽  
Scott A. Read ◽  
Adnan Nagrial ◽  
Bo Gao ◽  
Golo Ahlenstiel
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Forest Plot ◽  
Second Line ◽  
First Line ◽  
Advanced Hcc

e16632 Background: The WHO estimates that liver cancer will cause 1 million deaths by 2030. Hepatocellular carcinoma (HCC) is a primary liver malignancy causing 4.3% of all cancer deaths in 2019 in Australia. Kinase inhibitors are standard of care (SoC) for metastatic HCC with median overall survival (mOS) of < 13 months. This meta-analysis primarily aimed to determine objective response rate (ORR) of immune-checkpoint inhibitors (ICIs) in advanced HCC. Methods: Potentially relevant clinical studies were identified through PUBMED, Scopus, ASCO and ESMO databases. Studies evaluating ICIs in patients with HCC and reporting efficacy outcomes were considered as eligible. Publication bias was assessed with Funnel plots. Data analysis was performed employing fixed and random effects model depending on study heterogeneity evaluating by I2 statistic. STATA v16 software was used for all statistical considerations. Results: 12 single arm phase II/III studies and 2 randomized clinical trials on ICIs in HCC were included into this analysis. First-line ICI: Primary forest plot established the median ORR was 26.2% (95% CI 24.7 to 27.9) in patients treated with first line ICIs monotherapy; in comparison, ORR of current SoC sorafenib is 2-3% and lenvatinib 18.8%. Moreover, nivolumab resulted in 9.8 months of OS in Child-Pugh class B (CPB) patients, previously eligible only for supportive care due to a low efficacy of sorafenib (mOS < 4.5 months). Second-line ICI: Secondary forest plot established that nivolumab at 1 mg/kg with ipilimumab 3 mg/kg Q3W resulted in mOS of 23 months with ORR of 32% in sorafenib-progressors. In comparison, current second line SoC regorafenib has mOS of 10.6 months and ORR of 17%. Conclusions: This meta-analysis suggests that ICIs may be superior (ORR) to SoC sorafenib in advanced HCC, particularly nivolumab. Secondly, nivolumab with ipilimumab were confirmed to provide higher OS in sorafenib progressors as compared to regorafenib. Of note, many of the studies included were only available in abstract form and final reporting is pending. Nevertheless, our results support higher efficacy of ICIs in HCC patients.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

scholarly journals Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 131
Author(s):  
Antonio Lopez-Beltran ◽  
Alessia Cimadamore ◽  
Ana Blanca ◽  
Francesco Massari ◽  
Nuno Vau ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Durable Response ◽  
First Line Therapy ◽  
Line Therapy

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

scholarly journals Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3025
Author(s):  
Piera Federico ◽  
Angelica Petrillo ◽  
Pasqualina Giordano ◽  
Davide Bosso ◽  
Antonietta Fabbrocini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Critical Evaluation ◽  
Phase Iii ◽  
Current Status ◽  
Small Subset ◽  
Second Line

Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an “ill-defined” small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

scholarly journals Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaozhun Huang ◽  
Lin Xu ◽  
Teng Ma ◽  
Xin Yin ◽  
Zhangkan Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
New Strategy

BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

Is there a benefit of immune checkpoint inhibitors for patients over 75 years of age with advanced cancer in first and second line setting: A meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12031-12031 ◽  
Author(s):  
Thierry Landre ◽  
Gaetan Des Guetz ◽  
Christos Chouaid ◽  
Jean F. Morere ◽  
Kader Chouahnia ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Line Setting ◽  
The Impact

12031 Background: The impact of aging on Immune Checkpoint Inhibitors (ICIs) effectiveness is controversial. Currently, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We propose to compare the clinical benefit of ICIs in those over 75 and in those under 75. Methods: We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumours. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients ( < 75 years) in first and second line setting. Hazard ratios (HRs) with their 95% confidence interval (CI) were collected from the studies and pooled. Results: Fifteen phase III studies evaluating anti-PD-1 (nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab or avelumab) or anti-CTLA-4 (ipilimumab) were included. Patients were enrolled for Non-Small-Cell-Lung-Cancer, Renal-Cell-Carcinoma, Melanoma, Head-and-Neck-Squamous-Cell-Carcinoma or Gastric-Cancer. Eight studies assessed treatment in first line setting and seven in second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 younger. In first line setting, HRs for death were 0.78 (95% CI: 0.61-0.99) in patients ≥75 years versus 0.84 (95% CI: 0.71-1.00) in younger. In second line setting, HRs for death were 1.02 (95% CI: 0.77-1.36) in patients ≥75 years versus 0.68 (95% CI: 0.61-0.75) in younger with a statistically significant difference observed between subgroups (p interaction = 0.009). Conclusions: ICIs appears to be effective in patients over 75 years of age. However, the survival benefit comes mainly from the first line of treatment. This result encourages the use of ICIs early in the therapeutic management of patients over 75 years of age.

scholarly journals Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

2019 ◽  
Vol 11 ◽  
pp. 175883591986190 ◽  
Author(s):  
Giandomenico Roviello ◽  
Silvia Paola Corona ◽  
Gabriella Nesi ◽  
Enrico Mini
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

scholarly journals Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting

2021 ◽  
Vol 10 (15) ◽  
pp. 3201
Author(s):  
Maria Corina Plaz Torres ◽  
Quirino Lai ◽  
Fabio Piscaglia ◽  
Eugenio Caturelli ◽  
Giuseppe Cabibbo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Advanced Hepatocellular Carcinoma ◽  
Second Line ◽  
First Line ◽  
Advanced Hcc ◽  
Real Life Setting ◽  
Line Setting

Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab—an anti-vascular endothelial growth factor monoclonal antibody—demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.

Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 330-330
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
Roland Ching-Yu Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Objective Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

330 Background: Programmed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICI) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in advanced HCC patients with progression on prior ICIs. Methods: Advanced HCC patients with documented tumour progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analysed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Twenty-five patients were included. The median age was 62 (range 51-83). 68% were of Child-Pugh (CP) grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range 2.76-30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% C.I. 1.61-4.31). Median OS was 10.9 months (95% C.I. 3.99-17.8) and the 1-year, 2-year and 3-year survival rates were 42.4%, 32.3% and 21.6% respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) grade 1 or 2. CP and ALBI grades were significantly associated with OS (p=0.006 and p<0.001 respectively). Overall, 52% of patients experienced TRAEs and 12% experienced grade 3 or above TRAEs. Conclusions: Ipilimumab and nivolumab/pembrolizumab can achieve durable antitumour activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

scholarly journals Treatments of Advanced Non‑Small Cell Lung Cancer (NSCLC) in an Italian Center: Drug Utilization and the Treatment Costs of Innovative Drugs

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Francovito Piantedosi ◽  
Raffaela Cerisoli ◽  
Ciro Battiloro ◽  
Francesca Andreozzi ◽  
Fabiana Vitiello ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Multivariate Analyses ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Small Cell ◽  
Line Treatment ◽  
Second Line ◽  
Small Cell Lung ◽  
First Line

AIM: To provide an updated picture of the therapies most commonly used in the advanced Non-Small Cell Lung Cancer (NSCLC) setting, together with the relevant costs.METHODS: This study considered the clinical records of patients affected by stage IIIb and IV NSCLC treated in the AORN dei Colli - Plesso Monaldi in Naples during the period January 2016-July 2017 and diagnosed since 2014, as well as the pathology lab database. Multivariate analyses were performed in order to identify the main predictors of time to next treatment and the main cost drivers.RESULTS: Data were collected on 575 patients, who were mainly affected by adenocarcinoma (62%) and squamous cell carcinoma (34%). 64% of patients were reported having been tested for molecular biomarkers (among the patients tested, 13% were EGFR+, 4% Alk t, and 1% ROS1 t). In accordance with the international guidelines, chemotherapy – as single agent or platinum-based doublets – was the prevalent first-line treatment, except among EGFR+ and ROS1 t patients, for whom the target therapy was authorized as first-line therapy. As second-line treatment, the target therapy and immune checkpoint inhibitors (nivolumab) were the most commonly used treatments. Drug expenditure per patient was remarkably higher in mutated patients (€ 29,053) versus wild-type patients, or patients with unknown mutational status (€ 11,854), who received just chemotherapy. The costs sustained in 2017 are proportionally higher than those sustained in 2016, mainlydue to the increasing eligibility to target therapy and immune checkpoint inhibitors and the wider biomarker analysis performed. From multivariate analyses, among the predictors of a longer time to next treatment (TTNT) were a better performance status and target therapy both in first and second line. The therapy for squamous cell carcinoma and other nonadeno histotypes turned out to be less expensive in patients treated just in the first line than that for adenocarcinoma and adenosquamous carcinoma. The use of immune checkpoint inhibitors in the second line results in increased costs compared to the use of chemotherapy. Also the target therapy in the first line results in an increase in the total costs with respect to chemotherapy in patients who received just a first-line therapy.CONCLUSIONS: Generally, in this study population, the treatments administered are in accordance with the international guidelines. The costs borne by the Health Systems are higher for the target therapy and the immune checkpoint inhibitors.

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