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Survival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors.

ABSTRACT: Importance:In science and medical research, extreme and dichotomous conclusions may be drawn based on whether the P value falls above or below the threshold. The fragility index (ie, the minimum number of changes from nonevents to events resulting in loss of statistical significance) captures the vulnerability of statistics in trials with binary outcomes. There are a growing number of clinical trials of immune checkpoint inhibitors (ICIs), as well as expanding eligibility for patients to receive them. The robustness of survival outcomes in randomized clinical trials (RCTs) should be evaluated using the fragility index extended to time-to-event data. Objective:To calculate the fragility of survival data in RCTs evaluating ICIs. Design, Setting, and Participants:In this cross-sectional study, data on phase 3 prospective RCTs investigating ICIs included in PubMed from inception until January 1, 2020, were extracted. Two- or three-group studies reporting results for overall survival were eligible for the survival-inferred fragility index (SIFI) calculation, which is the minimum number of reassignments of the best survivors from the interventional group to the control group resulting in loss of significance (defined as P?

SUBMITTER: Bomze D

PROVIDER: S-EPMC7584930 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Survival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors.

Bomze David D Asher Nethanel N Hasan Ali Omar O Flatz Lukas L Azoulay Daniel D Markel Gal G Meirson Tomer T

JAMA network open 20201001 10

<h4>Importance</h4>In science and medical research, extreme and dichotomous conclusions may be drawn based on whether the P value falls above or below the threshold. The fragility index (ie, the minimum number of changes from nonevents to events resulting in loss of statistical significance) captures the vulnerability of statistics in trials with binary outcomes. There are a growing number of clinical trials of immune checkpoint inhibitors (ICIs), as well as expanding eligibility for patients to ...[more]

PMID: 33095247

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Project description:Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

Project description:BackgroundThe outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AimTo evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials.MethodsWe searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials.ResultsFive phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.ConclusionAnti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.

Dataset Information

Survival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors.

Publications

Survival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors.

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