Evidence map›Paper›PMID 29470579›Full record

SynthesisJAMA oncology2018

Defining the Most Appropriate Primary End Point in Phase 2 Trials of Immune Checkpoint Inhibitors for Advanced Solid Cancers: A Systematic Review and Meta-analysis.

Georgia Ritchie, Harry Gasper, Johnathan Man, Sally Lord, Ian Marschner, Michael Friedlander, Chee Khoon Lee

Abstract readMeta-AnalysisSystematic Review
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in JAMA oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 14 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed, 14 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

67 citing papers in PubMed, 14 syntheses or guidelines pooled it.

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7 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors.

Georgia RitchieCancer Care Centre, St George Hospital, Sydney, Australia.
Harry GasperCancer Care Centre, St George Hospital, Sydney, Australia.
Johnathan ManCancer Care Centre, St George Hospital, Sydney, Australia.
Sally LordNational Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
Ian MarschnerNational Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
Michael FriedlanderSchool of Medicine, University of New South Wales, Sydney, Australia.
Chee Khoon LeeCancer Care Centre, St George Hospital, Sydney, Australia.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

importanceCheckpoint inhibitors have a unique mechanism of action that differs from chemotherapy or targeted therapies. The validity of objective response rate (ORR) as a surrogate for progression-free survival (PFS) and overall survival (OS) in checkpoint-inhibitor trials is uncertain.

objectiveTo determine the types of primary end points used in phase 2 checkpoint-inhibitor trials, and to assess the strength of associations for ORR with PFS and OS. DATA SOURCES: Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials). STUDY SELECTION: Advanced solid cancers in phase 2 and phase 3 trials. DATA EXTRACTION AND SYNTHESIS: Correlations between ORR odds ratios and hazard ratios (HRs) for PFS and OS were examined for randomized comparisons. Within checkpoint-inhibitor treatment arms, correlations for ORR with 6-month PFS and 12-month OS rates were examined. All analyses were weighted by trial size. Multivariable models to predict 6-month PFS and 12-month OS rates from ORR were developed and their performance validated in an independent sample of trials. MAIN OUTCOMES AND MEASURES: Correlation coefficient (r) of ORR with PFS and OS.

resultsOf 87 phase 2 trials identified, ORR was the most common (52 [60%]) primary end point. Twenty randomized clinical trials with 25 treatment comparisons were identified. Checkpoint-inhibitor therapy was associated with pooled ORR of 24% (95% CI, 18%-31%). For randomized comparisons, r between ORR odds ratio and PFS HR was 0.63 (95% CI, 0.35-0.89), ORR odds ratio and OS HR was 0.57 (95% CI, 0.23-0.89), and between PFS HR and OS HR was 0.42 (95% CI, 0.04-0.81). Within the checkpoint-inhibitor arms, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% CI, -0.06 to 0.95), 0.08 (95% CI, -0.17 to 0.70), and 0.74 (95% CI, 0.57-0.92), respectively. In validation, when 6-month PFS was used to predict 12-month OS, there was a good calibration between actual and predicted 12-month OS. When ORR was used to predict 6-month PFS and 12-month OS rates, respectively, the actual vs predicted rates calibrated poorly. CONCLUSIONS AND RELEVANCE: In checkpoint-inhibitor trials, ORR correlated poorly with OS. For future phase 2 studies, 6-month PFS rate is recommended as an end point.

Indexed as

Antineoplastic Agents, ImmunologicalBiomarkers, PharmacologicalBiomarkers, TumorCell Cycle CheckpointsClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDisease ProgressionHumansMolecular Targeted TherapyNeoplasmsPrognosisProtein Kinase InhibitorsRandomized Controlled Trials as TopicSurvival AnalysisTreatment OutcomeAntineoplastic Agents, ImmunologicalBiomarkers, PharmacologicalBiomarkers, TumorProtein Kinase Inhibitors

Identifiers

PMID29470579
PMCPMC5885200

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.