scholarly journals Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Rohini Sharma ◽  
Leila Motedayen Aval
Keyword(s):  
Immune Checkpoint ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hepatocellular Cancer ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Second Line ◽  
Research Strategies ◽  
First Line ◽  
Line Setting

Until recently, the treatment landscape for hepatocellular cancer (HCC) was dominated by tyrosine kinase inhibitors (TKIs) which offered an overall survival (OS) benefit when used both in the first-and second-line setting compared to best supportive care. However, the treatment landscape has changed with the introduction of immune checkpoint inhibitors (ICIs) for the treatment of HCC with significant improvement in OS and progression free survival reported with combination atezolizumab and bevacizumab compared to sorafenib in the first-line setting. Nonetheless, the response to ICIs is 20–30% and invariably patients will progress. What remains unclear is which therapeutics should be used following ICI exposure. Extrapolating from the evidence base in renal cell carcinoma, subsequent therapy with TKIs offers both a response and survival benefit and are recommended by European guidelines. However, there are a number of novel therapies emerging that target mechanisms of ICI resistance that hold promise both in combination with ICI or as subsequent therapy. This paper will discuss the evidence for ICIs in HCC, the position of second-line therapies following ICIs and research strategies moving forward.

scholarly journals Timing of immune checkpoint inhibitors for metastatic patients over 75 years of age: the earlier the better

2020 ◽  
Author(s):  
Thierry Landre ◽  
Gaetan Des Guetz ◽  
Kader Chouahnia ◽  
Virginie Fossey-Diaz ◽  
Stéphane Culine
Keyword(s):  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Significant Difference ◽  
Line Setting ◽  
The Impact

Abstract Background The impact of ageing on Immune Checkpoint Inhibitors (ICIs) effectiveness remains controversial. However, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We focused our study on patients over 75 and looked at the potential impact of timing in the use of ICIs. Methods We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumors. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients (< 75 years). Hazard ratios (HRs) with their 95% confidence interval (CI) were collected 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 the second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 youngers. 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 is mainly observed in first-line treatment.

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 Second-Line Therapies in the Changing Landscape of First-Line Therapies for Metastatic Clear Cell Renal Cell Cancer

ONCOLOGY ◽  
2021 ◽  
pp. 306-310
Author(s):  
Tiffany Shaw ◽  
Hannah Lee ◽  
Robert Figlin
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Single Agent ◽  
Current Data ◽  
Treatment Modalities ◽  
Second Line ◽  
First Line ◽  
Line Setting

In recent years, first-line therapies for metastatic renal cell carcinoma (mRCC) have shifted to a combination of immune checkpoint inhibitors or a combination of antiangiogenesis tyrosine kinase inhibitors (TKIs) and immunotherapy. This has led to a need to address standard-of-care treatment in the second-line setting. Our review presents an analysis of current and upcoming data to guide treatment decisions. After progression on nivolumab plus ipilimumab, current data favor monotherapy TKI with cabozantinib or axitinib. Current literature for second-line therapy given after combination TKI plus immunotherapy shows the strongest evidence for either single-agent cabozantinib or combination everolimus with lenvatinib. Investigations are ongoing for the role of TKIs with immunotherapy in the second-line setting. Novel agents, such as HIF2α inhibitors, are currently being studied as single agents and in combination with other treatment modalities in efforts to improve patient outcomes in mRCC.

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.

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.

Phase II study of weekly scheduled irinotecan and capecitabine treatment in advanced colorectal cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14644-e14644
Author(s):  
Wenhua Li ◽  
Jin Li ◽  
Jianming Xu ◽  
Lin Shen ◽  
Tianshu Liu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Current Phase ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Severe Diarrhea ◽  
Grade 3 ◽  
Line Setting

e14644 Background: The clinical application of combination therapy of irinotecan and capecitabine is at a standstill due to the consideration on severe diarrhea. The aim of the current phase II study was to explore the optimal administration mode of these two drugs, and evaluate the safety and efficacy of weekly-scheduled XELIRI regimen (wXELIRI) in mCRC pts. Methods: Pts with unresectable, histologically confirmed mCRC were enrolled to receive wXELIRI: irinotecan 90mg/m(2) on Day 1 and capecitabine 1200 mg/m(2) bid on Days 1-5 weekly. Both the first-line pts and second-line treatment pts who failed with FOLFOX or XELOX were eligible. The primary endpoint was rate of Grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and other safeties. Results: From January 2011 to May 2012, totally 43 pts with measurable mCRC were enrolled, 18 of them were male and 25 were female. The median age was 60 yrs (range 32-70). No Grade 4 diarrhea was observed and the rate of grade 3 diarrhea was 4.7%. The most common Grade 3/4 toxicities included leucocyte(11.6%), neutrophile (18.6%), vomiting (4.7%), fatigue (2.3%), hand-foot-syndrome (2.3%) . With a median follow-up of 19.0 months, 23 PFS events were observed. The mPFS for all the 43 pts was 6.1 mons and the mOS was 15.5 mons. For the 31 first-line treatment pts, the mPFS was 7.5 mons and the mOS has not reached. In the second-line treatment group (12 pts), the mPFS was 5.4 mons and mOS was 13.8 mons. Conclusions: The weekly-scheduled irinotecan and capecitabine combination has a low rate of severe diarrhea and acceptable toxicity profile. It could be an alternative regimen for mCRC pts, especially in the second-line setting. Clinical trial information: NCT01322152.

Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 534-534 ◽  
Author(s):  
David Chan ◽  
Eva Segelov ◽  
Jeremy David Shapiro ◽  
Timothy Jay Price ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Biologic Therapy ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Biologic Agents ◽  
First Line ◽  
Grade 3 ◽  
Line Setting ◽  
The Impact

534 Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]

Efficacy of first-line immune checkpoint inhibitors in patients with sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 66-66
Author(s):  
Ziad Bakouny ◽  
Sarah Abou Alaiwi ◽  
Amin Nassar ◽  
John A. Steinharter ◽  
Xiao X. Wei ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Logistic Regressions

66 Background: Patients with mRCC with S/R components tend to have a poor prognosis with few therapeutic options available. Recent data suggest that immune checkpoint inhibitor (ICI)-based therapies may be especially effective for these patients. Our aim was to evaluate the efficacy of ICI-based therapies in patients with S/R mRCC. Methods: We retrospectively assessed objective response rate (ORR), progression free survival (PFS) & overall survival (OS) of patients with S/R mRCC treated at our institution with first-line ICI-based therapies and compared these to those of patients treated with first-line non-ICI-based therapies. Univariable and multivariable (adjusted for IMDC group) Cox and logistic regressions were performed. Results: 92 patients (70 S, 9 R, and 13 S&R) patients were included, of which 74 with a clear-cell component. For all patients (regardless of therapy), 74 (80.4%) patients experienced a PFS event (progression or death) and 52 (56.5%) died at 25.3 months (m) median follow-up. Overall median PFS was 5.3 m (95% CI= 3.4–7.2) and 24 m OS rate was 39.5% (27.4–51.7). Out of 78 patients in whom response was evaluable, ORR was 30.8% (20.4–41.2). Patients treated with ICI-based therapies had significantly better ORR, PFS, and OS on multivariable analysis (table). Conclusions: mRCC patients with S/R components have significantly better ORR, PFS, and OS with first-line ICI-based compared to non-ICI-based therapies. These data support the use of ICI-based therapies for patients with S/R mRCC. [Table: see text]

Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4002-4002 ◽  
Author(s):  
Shinya Ueda ◽  
Shuichi Hironaka ◽  
Hirofumi Yasui ◽  
Tomohiro Nishina ◽  
Masahiro Tsuda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Standard Regimen ◽  
Phase Iii Trials ◽  
Phase Iii Study ◽  
Third Line

4002 Background: A combination CT of FP has been regarded as the standard first-line treatment for AGC. Although two randomized trials showed a survival benefit of second-line CT (CPT-11 or docetaxel) compared with best supportive care, no standard regimen has been established. In Japan, wPTX has been used more frequently than docetaxel as the second‑line CT. The objective of this study was to compare CPT-11 with wPTX in patients (pts) with AGC refractory to FP. Methods: Patients with AGC refractory to the first‑line FP regimen were randomized 1:1 to either CPT-11 (150 mg/m2, q2w) or wPTX (80 mg/m2, days 1, 8, 15, q4w). The primary endpoint was overall survival (OS) and secondary endpoints were progression‑free survival (PFS), overall response rate (ORR), adverse events and receiving rates of third-line CT. To demonstrate an increase in median OS from 5 months (wPTX) to 7.5 months (CPT-11) with 2-sided alpha 5% and 80% power, 220 pts were required. Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled; 112 pts were randomized to CPT-11 and 111 pts to wPTX. Baseline characteristics were well balanced between arms. Median OS was 8.4 months for CPT-11 and 9.5 months for wPTX (HR 1.132; 95% CI, 0.86-1.49; p=0.38). Median PFS was 2.3 months for CPT-11 and 3.6 months for wPTX (HR 1.14; 95% CI, 0.88-1.49; p=0.33). The ORR was 13.6% (12/88) for CPT-11 and 20.9% (19/91) for wPTX (p=0.20). The most common grade 3/4 adverse events were neutropenia (39.1% for CPT-11 vs. 28.7% for wPTX), anemia (30.0% vs. 21.3%), anorexia (17.3% vs. 7.4%) and fatigue (12.7% vs. 6.5%). Four (4%) CPT-11 and three (3%) wPTX recipients died within 30 days after the last administration. Subsequent CT was performed in 80 pts (71%) for CPT-11 and 97 pts (89%) for wPTX. Seventy-five pts (67%) in the CPT-11 group and 87 pts (80%) in the wPTX group received the crossover CT. Conclusions: The WJOG4007 trial, the first phase III study comparing second-line CT regimens for AGC, did not demonstrate the superiority of CPT-11 over wPTX. Thus, wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC.

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