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Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis.

ABSTRACT: PD-1/PD-L1 immune checkpoint blockade (ICB) has improved overall survival (OS) in solid tumor trials; however, parallel improvements in Response Evaluation Criteria in Solid Tumors (RECIST)-based surrogate end points, progression-free survival (PFS), and objective response rate (ORR), are not always observed. Here, we assess the surrogacy of PFS/ORR for OS with ICB therapy across advanced/metastatic tumors. In a trial-level analysis (N = 40 randomized trials), PFS, ORR, and OS treatment effects were correlated (Spearman's rho). In a patient-level analysis, data were extracted from available trials of durvalumab; the correlation of PFS and OS was evaluated (Bayesian normal-induced-copula-estimation model) and the ordinal association between objective response and OS hazard ratio (HR) were assessed with concordance index measures. High correlation was observed between PFS HR and OS HR in intention-to-treat (ITT; rho = 0.76) and PD-L1-enriched populations (0.74); modest (or limited) benefit in PFS was associated with meaningful improvement in OS. Moderate correlations were observed between ?ORR and OS HR: ITT, -0.63; PD-L1-enriched, -0.53. At the patient level, a positive association was observed between PFS and OS in non-small cell lung cancer (Kendall's Tau = 0.793; 95% confidence interval, 0.789-0.797), head and neck squamous cell carcinoma (0.794; 0.789-0.798), and bladder cancer (0.872; 0.869-0.875). Objective responders had significantly better OS (concordance index > 0.9) than nonresponders across these tumor types. Modest (or limited) improvement in RECIST-based end points did not rule out meaningful OS benefit, indicating they are imperfect surrogates and do not fully capture ICB clinical benefit. Therefore, caution is advised when basing early discontinuation of novel ICB agents on these end points.

SUBMITTER: Ye J

PROVIDER: S-EPMC7689755 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis.

Ye Jiabu J Ji Xiang X Dennis Phillip A PA Abdullah Hesham H Mukhopadhyay Pralay P

Clinical pharmacology and therapeutics 20200718 6

PD-1/PD-L1 immune checkpoint blockade (ICB) has improved overall survival (OS) in solid tumor trials; however, parallel improvements in Response Evaluation Criteria in Solid Tumors (RECIST)-based surrogate end points, progression-free survival (PFS), and objective response rate (ORR), are not always observed. Here, we assess the surrogacy of PFS/ORR for OS with ICB therapy across advanced/metastatic tumors. In a trial-level analysis (N = 40 randomized trials), PFS, ORR, and OS treatment effects ...[more]

PMID: 32564368

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Project description:Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Project description:ImportanceProgression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation.ObjectiveTo validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs).Data sourcesElectronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019.Study selectionEligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus.Data extraction and synthesisData were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Main outcomes and measuresValidation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected).ResultsData from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) - (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non-small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) - (0.02 × NSCLC) - (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups.Conclusions and relevanceThe findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results.

Dataset Information

Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis.

Publications

Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis.

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