Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

Roviello, Giandomenico; Varga, Andrea; Venturini, Sergio; Pistilli, Barbara; Curigliano, Giuseppe; Cristofanilli, Massimo; Rosellini, Pietro; Generali, Daniele

doi:10.1016/j.ejca.2017.09.018

Cited by 30 publications

(29 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through article searching, we found 19 articles in PubMed and one eligible meta-analysis by hand searching; among those 20 articles, five were not meta-analyses that evaluated the association of OS and other endpoints, three were meta-analyses but without association results for immunotherapies, and one was a meta-analysis for immunotherapies but it was conducted based on individuallevel analysis. Therefore, a total of 11 studies were eligible according to our inclusion/exclusion criteria (Figure 1) (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). In these studies, surrogate endpoints included PFS (20,21,(23)(24)(25)(26)(27)(28)(29)(30), three-month PFS (29), 6-month PFS (20,23,29), ORR (20)(21)(22)(23)(24)(25)27,28), disease control rate (DCR) (23,24), 1-year survival (26,28,30) and 2-year survival (30).…”

Section: Resultsmentioning

confidence: 99%

“…• 5 were not a meta-analysis evaluating the association of OS and other endpoints • 3 were meta-analyses but without association results for immunotherapies • 1 was a meta-analysis for immunotherapies but was conducted by individual-level analysis 11 of eligible meta-analyses For statistical method, even though correlation analysis and/or linear regression were used, our included metaanalyses performed them not in an exactly same way: most meta-analyses (82%; 9/11) were weighted by sample size (20)(21)(22)(23)(24)(25)(26)(27)30); among them, four meta-analyses performed the statistics on a logarithmic scale (21,22,26,30), and two conducted adjustment in linear regression model (23,26). For association results, six meta-analyses had evaluation criteria for considering validated endpoint surrogacy for OS, including R 2 ≥0.80 (21), R 2 ≥0.75 (24), R 2 ≥0.72 (23), R 2 ≥0.64 (28,30), and R 2 ≥0.60 (26).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Zhang

Liang

et al. 2019

Ann. Transl. Med

View full text Add to dashboard Cite

Few cancer drugs or their indications achieved survival benefit in subsequent trials during postmarket period after approval based on surrogate endpoints. This causes a concern of using surrogate endpoints instead of overall survival (OS) as the primary endpoint for trial design, implementation and regulation approval. We conducted a systematic review to summarize the findings from published metaanalyses which have evaluated endpoint surrogacy for OS in oncological randomized controlled trials (RCTs) with immunotherapies. After searching articles indexed in PubMed prior to 24 February 2019, we identified a total of 11 meta-analyses for advanced multiple tumors, non-small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, melanoma; most (91%; 10/11) focused on immune checkpoint inhibitors. Although the evaluation criteria adopted by these meta-analyses for validating endpoint surrogacy were not consistent (ranging from R 2 ≥0.60 to R 2 ≥0.80), the results were consistent. Few studies show an association between OS and progression-free survival (PFS)/objective response rate (ORR) that met the lowest evaluation criteria (R 2 ≥0.60), based on treatment effects (8%; 2/26 indications) or absolute results from experimental arm (0%; 0/11 indications). However, the association between OS and 1-year survival rate met the lowest criteria based on both the trial-level results (4/4 indications) and the arm-level results (5/5 indications). In lieu of this finding, we are supportive of an alternative endpoint, e.g., 1-year survival rate, rather than the more conventional choices PFS and ORR, as promising surrogate endpoint for OS in immunotherapy RCTs. We encourage further investigation on endpoint surrogacy based on the same or different settings, especially an assessment on survival rate at milestone time (e.g., 1-year), which has been demonstrated valuable for predicting OS in meta-analyses.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Zhang

Liang

et al. 2019

Ann. Transl. Med

View full text Add to dashboard Cite

show abstract

“…Finally, the use of ORR as a surrogate endpoint for OS in trials with ICI remains an unsolved question. A meta regression analysis of seventeen randomized trials testing ICI showed a weak but statistically significant correlation between the treatment effect on the ORR and the treatment effect on survival outcomes (i.e., OS and PFS) and suggested that the activity of ICI in terms of ORR explain ~50% of the effects detected in survival (29). Conversely, a systematic review of ten clinical trials evaluating PD-1/PD-L1 inhibitors in advanced NSCLC failed to show a significant correlation between response and survival (30).…”

Section: Objective Overall Response Ratementioning

confidence: 99%

Do immune checkpoint inhibitors need new studies methodology?

Ferrara¹,

Pilotto²,

Caccese³

et al. 2018

J. Thorac. Dis.

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICI) have widely reshaped the treatment paradigm of advanced cancer patients. Although multiple studies are currently evaluating these drugs as monotherapies or in combination, the choice of the most accurate statistical methods, endpoints and clinical trial designs to estimate the benefit of ICI remains an unsolved methodological issue. Considering the unconventional patterns of response or progression [i.e., pseudoprogression, hyperprogression (HPD)] observed with ICI, the application in clinical trials of novel response assessment tools (i.e., iRECIST) able to capture delayed benefit of immunotherapies and/or to quantify tumor dynamics and kinetics over time is an unmet clinical need. In addition, the proportional hazard model and the conventional measures of survival [i.e., median overall or progression free survival (PFS) and hazard ratios (HR)] might usually result inadequate in the estimation of the long-term benefit observed with ICI. For this reason, innovative methodologies such as milestone analysis, restricted mean survival time (RMST), parametric models (i.e., Weibull distribution, weighted log rank test), should be systematically investigated in clinical trials in order to adequately quantify the fraction of patients who are "cured", represented by the tails of the survival curves. Regarding predictive biomarkers, in particular PD-L1 expression, the integration and harmonization of the existing assays are urgently needed to provide clinicians with reliable diagnostic tests and to improve patient selection for immunotherapy. Finally, developing original and high-quality study designs, such as adaptive or basket biomarker enriched clinical trials, included in large collaborative platforms with multiple active sites and cross-sector collaboration, represents the successful strategy to optimally assess the benefit of ICI in the next future.

show abstract

“…However, since this meta-analysis analysed only three RCTs, it is not possible to conclude that ICIs do not work in pre-treated metastatic GC. In addition, it should be considered that endpoints, such as PFS and response rate (RR), are not optimal in patients treated with ICIs [18].…”

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis

Roviello

Corona

D’Angelo

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64–1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.

show abstract

Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

Abstract: The results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.

Cited by 30 publications

References 36 publications

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Do immune checkpoint inhibitors need new studies methodology?

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis

Contact Info

Product

Resources

About