Pooled HR For Overall Survival Research Articles

Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapies.

Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS. A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis. Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses. OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies.

The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials.

We conducted a meta-analysis to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy or immunotherapy combined with chemotherapy and further estimated the value of PD-L1 expression in predicting the response from anti-PD-1/PD-L1 treatments as monotherapy or in combination with chemotherapy. Clinical trial data were searched from electronic databases, which evaluated PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC) and correlated with PD-L1 expression levels. Fifteen randomized-controlled trials involving 10,074 patients were identified. Comparing anti-PD-1/PD-L1 monotherapy to chemotherapy, the pooled HR for overall survival (OS) was 0.77 (95% CI: 0.69-0.85, P<0.00001). Subgroup analyses revealed that patients had longer OS at ≥1%, ≥5%, ≥10% and ≥50% PD-L1 expression levels. Patients with higher PD-L1 expression may get increased benefit from PD-1/PD-L1 inhibitors. Moreover, patients with PD-L1 ≥50% had an objective response rate (ORR) improvement from anti-PD-1/PD-L1 therapy (RR =1.87, 95% CI: 1.27-2.75, P=0.001), but no ORR benefits were observed in patients with PD-L1 expression <1% (RR =0.82, 95% CI: 0.56-1.22, P=0.33) or 1-49% (RR =0.80, 95% CI: 0.64-0.98, P=0.03). OS was significantly better in patients receiving second-or-third line treatments (P<0.00001) with PD-L1 ≥1%. The efficacy of PD-1 inhibitors was similar to that of PD-L1 inhibitors, with no significant difference (P=0.63, I2=0%). Furthermore, immunotherapy combined with chemotherapy had better OS (HR =0.64, 95% CI: 0.48-0.84, P=0.001) than chemotherapy alone. Subgroup analyses showed that patients benefited from the combined chemo-IO treatment in the first-line setting regardless of PD-L1 expression level. PD-L1 expression may be a valuable predictor of the efficacy of anti-PD-1/PD-L1 monotherapy in certain NSCLC patients. However, the combination of chemotherapy plus immunotherapy significantly improved survival regardless of the PD-L1 expression level in the first-line treatment of NSCLC.

Association of obesity with breast cancer outcome in relation to cancer subtypes.

11557 Background: Obesity at breast cancer (BC) diagnosis is associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. Here we report on the association of obesity at BC diagnosis with disease-free (DFS) and overall survival (OS) in the following subtypes: (i) hormone receptor (ER/PgR) +ve, HER2-ve, (ii) HER2+ve, any ER/PgR and (iii) triple negative (TN). Methods: We searched MEDLINE, EMBASE and COCHRANE databases to December 31, 2018 and meeting presentations (past 5 years) using predefined search terms. Study eligibility, data abstraction were performed independently by two authors; those reporting hazard ratios (HR) for obesity and DFS/OS in BC subtypes were included. Using Review Manager pooled HRs were computed and weighted using generic inverse variance in fixed and random effects models (results were similar, random effects are presented). Results: Of 10,702 titles, 26 studies (108,793 patients) were included. Pooled HR for DFS for obese vs non-obese were (i) ER/PgR+ve HER2-ve 1.21 (95% Confidence interval, CI; 1.12-1.31, p &lt; 0.00001), (ii) HER2+ve, any ER/PgR 1.16 (95%CI, 1.06-1.26; p = 0.0006) and (iii) TN, 1.13 (95%CI; 1.05-1.22 p = 0.002). Pooled HRs for OS were (i) ER/PgR+ve, HER2-ve 1.45 (95%CI; 1.30-1.62 p &lt; 0.00001), (ii) HER2+ve any ER/PgR 1.21 (95%CI; 1.10-1.34 p = 0.0001) and (iii) TN 1.13 (95%CI, 1.04-1.23, p = 0.003).PooledHR for OS (but not DFS) were somewhat higher in observational vs interventional studies in (i) ER/PgR+ve, HER2-ve 1.57 vs 1.36, HER2+ve any ER/PgR (ii) 1.37 vs 1.09 but not (iii) TN 1.12 vs 1.22 (p = 0.21, 0.03 and 0.48, respectively). Conclusions: Obesity was associated with a worse outcome in all BC subtypes. Higher HR for OS in observational studies in (i) ER/PgR+ve, HER2- and (ii) HER2+ve any ER/PgR BC may reflect selection of healthier patients for intervention trials.

Correlation between patients’ age and cancer immunotherapy efficacy

ABSTRACTBackground: Although immunosenescence-induced difference on overall immune function and immune cell subsets between younger and older populations has been well characterized, the potential effect of patients’ age on the efficacy of immune checkpoint inhibitors (ICIs) remains little known. We performed a meta-analysis to investigate whether age differences play a role in cancer immunotherapy efficacy based on a large amount of clinical data.Methods: We conducted a systematic search of PubMed, Embase and MEDLINE for relevant randomized controlled trials. The primary outcome was overall survival (OS) and progression-free survival (PFS) was secondary outcome. The interaction test was used to assess the heterogeneity of HR between younger and older groups.Results: In total, 19 clinical randomized trials involving 11157 patients were included. The pooled HR for OS was 0.73 (95% CI 0.69–0.78) and 0.63 (95% CI 0.52–0.73) for PFS in younger patients receiving ICIs treatments, when compared with younger patients treated with controls. For older patients treated with ICIs, the pooled HR for OS compared with controls was 0.64 (95% CI 0.59–0.69) and 0.66 (95% CI 0.58–0.74) for PFS. The difference on OS efficacy between younger and older patients treated with ICIs was significant (Pheterogeneity = 0.025).Conclusions: Immune checkpoint inhibitors significantly improved OS and PFS in both younger and older patients compared with controls, but the magnitude of benefit was clinically age-dependent. Patients ≥65 y can benefit more from immunotherapy than younger patients. Future research should take age difference into consideration in trials and focus on tolerance and toxicity of ICIs in older patients.

Efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in patients with advanced melanoma

BackgroundAlthough immune checkpoint inhibitor monotherapy has demonstrated significant efficacy in advanced melanoma, no study has systematically evaluated the efficacy and safety of the combination regimens. In this study, we conduct a comprehensive meta-analysis to explore the efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in advanced melanoma. MethodsWe performed a systematic search of Medline, PubMed, Embase and Web of Science for relevant clinical trials. The primary objective was to explore the efficacy and safety of combination regimens compared to monotherapy. The secondary objective was to compare the difference in efficacy between CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy. ResultsA total of 12 trials involving 3308 patients were included for our meta-analysis. For combination regimens compared to monotherapy, the pooled HR for overall survival (OS) was 0.67 (95%CI 0.53–0.81) and for progression-free survival (PFS) was 0.56 (95%CI 0.41–0.71). For CTLA-4 inhibitors plus PD-1 inhibitors, the combined one-year OS rate (OSR1y), six-month PFS rate (PFSR6m) and disease control rate (DCR) were 64.0% (95%CI: 49.6%–78.4%), 56.4% (95%CI: 50.1%–62.7%) and 69.9% (95%CI: 65.1%–74.7%), respectively. For CTLA-4 inhibitors plus chemotherapy, the combined OSR1y, PFSR6m and DCR were 35.2% (95%CI: 25.4%–45.0%), 54.6% (95%CI: 42.7%–66.60%) and 33.5% (95%CI: 28.0%–38.9%), respectively. ConclusionsCombination regimens significantly improved OS and PFS of advanced melanoma patients compared to monotherapy. An acceptable safety profile was observed in both CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy. A comparison of these two combination regimens showed that patients who received CTLA-4 inhibitors plus PD-1 inhibitors had a better therapeutic effect compared to those receiving CTLA-4 inhibitors plus chemotherapy. Further randomized clinical trials are urgently required to validate our results.

Anti-PD-1/anti-PD-L1 immunotherapy versus docetaxel for previously treated advanced non-small cell lung cancer: a systematic review and meta-analysis of randomised clinical trials

BackgroundTo compare the efficacy and toxicity of anti-programmed cell death receptor 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) versus docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC).Materials and methodsPhase III randomised clinical trials (RCTs) were identified after systematic review of databases and conference proceedings. A random-effect model was used to determine the pooled HR for overall survival (OS), progression-free survival (PFS) and duration of response. The pooled OR for overall response and treatment-related side effects were calculated using the inverse-variance method. Heterogeneity was measured using the τ2 and I2 statistics.ResultsAfter the systematic review, we included four phase III RCTs (n=2737) in this meta-analysis. The use of anti-PD-1/anti-PD-L1 agents (atezolizumab, nivolumab and pembrolizumab) was associated with better OS in comparison with docetaxel alone (HR: 0.69; 95% CI 0.63 to 0.75; p<0.00001). Similarly, the PFS and duration of response was significantly longer for patients receiving immunotherapy (HR: 0.85; 95% CI 0.75 to 0.96; p=0.007 and HR:0.32; 95% CI 0.24 to 0.43; p<0.00001, respectively) versus single agent chemotherapy. The overall response rate was also higher for patients who received any anti-PD-1/anti-PD-L1 therapy in comparison with docetaxel (OR: 1.77; 95% CI 1.26 to 2.50; p=0.001). Regarding treatment-related side effects grade 3 or higher, patients who received immunotherapy experienced less events than patients allocated to docetaxel (OR: 0.19; 95% CI 0.12 to 0.30; p<0.00001)ConclusionThe use of anti-PD-1/anti-PD-L1 therapy in patients with progressive advanced NSCLC is significantly better than the use of docetaxel in terms of OS, PFS, duration of response and overall response rate.

P09.27 Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. Methods: the authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results: sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

328PD - Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. The authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

S01 - Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)

Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. Methods: the authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results: sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.

Association of promoter methylation of RUNX3 gene with the development of esophageal cancer: a meta analysis.

BackgroundRunt-related transcription factor 3 (RUNX3) is a member of the runt-domain family of transcription factors. Emerging evidence indicates that RUNX3 is a tumor suppressor gene in several types of human cancers including esophageal cancer. However, the association between RUNX3 promoter methylation and esophageal cancer remains unclear. Here we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 promoter methylation on the incidence of esophageal cancer.MethodsA detailed literature search was made on Medline, Pubmed and Web of Science for related research publications written in English and/or Chinese. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, the odds ratios (OR) were calculated and summarized respectively.ResultsFinal analysis of 558 patients from 9 eligible studies was performed. The result showed that RUNX3 methylation was significantly higher in esophageal cancer than in normal squamous mucosa from the proximal resection margin or esophageal benign lesions (OR = 2.85, CI = 2.01–4.05, P<0.00001). The prevalence of lymph node involvement, tumor size (T1–T2 vs T3–T4) and histological grade was significantly greater in RUNX3-negative cases (RUNX3 unmethylated groups) than in RUNX3-positive cases (OR = 0.25, CI = 0.14–0.43, P<0.00001). RUNX3 methylation was significantly higher in esophageal adenocarcinoma (EAC) than Barrett’s esophagus (OR = 0.35, CI = 0.20–0.59, P<0.0001). In addition, the pooled HR for overall survival (OS) showed that decreased RUNX3 expression was associated with worse survival in esophageal cancer (HR = 4.31, 95% CI = 2.57–7.37, P<0.00001).ConclusionsThe results of this meta-analysis suggest that RUNX3 methylation is associated with an increased risk, progression as well as worse survival in esophageal cancer. RUNX3 methylation, which induces the inactivation of RUNX3 gene, plays an important role in esophageal carcinogenesis.