Dataset Information

New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone.

ABSTRACT: The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors have revolutionized the field of oncology. The durability of the antitumor immune responses has raised the hope for long-term patient survival and potential cure; however, currently, only a minority of patients respond. Combination strategies to help increase antigen release and T-cell priming, promote T-cell activation and homing, and improve the tumor immune microenvironment, all guided by predictive biomarkers, can help overcome the tumor immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of patients. Great challenges remain because of the complex underlying biology, unpredictable toxicity, and accurate assessment of response. Carefully designed clinical trials guided by translational studies of paired biopsies will be key to develop reliable predictive biomarkers to choose which patients would most likely benefit from each strategy.

SUBMITTER: Hu-Lieskovan S

PROVIDER: S-EPMC5844278 | biostudies-literature | 2017 Jan/Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone.

Hu-Lieskovan Siwen S Ribas Antoni A

Cancer journal (Sudbury, Mass.) 20170101 1

The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors have revolutionized the field of oncology. The durability of the antitumor immune responses has raised the hope for long-term patient survival and potential cure; however, currently, only a minority of patients respond. Combination strategies to help increase antigen release and T-cell priming, promote T-cell activation and homing, and improve the tumor immune microenvironment, all guided by predicti ...[more]

PMID: 28114250

Similar Datasets

Project description:Introduction: Inhibitors of programmed cell death 1 (PD1) and its ligand (PDL1) have exhibited favorable long-term survival in many types of advanced-stage cancer and current approvals have to date been granted in certain tumour types irrespective of PD-L1 status. Methods: We extracted the following information: study sample size, trial period, cancer types, intervention of treatment, type of PD-L1 antibody, immunohistochemistry (IHC) scoring method, number and percentage of PD-L1 < 1% population, and median follow- up time. PD-L1 expression was defined as percentage of number of PD-L1-stained tumor cells (TPS), area of tumor infiltrated by PD-L1-stained immune cells (IPS), number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages; CPS). Different trials used distinct method to define low PD-L1 expression. The risk of bias of the included trials was assessed by using the Cochrane risk of bias tool for RCTs. Results: Here, a total of 34 trials were included to extract individual patient data (IPD) to evaluate the survival benefit of first line PD1/PDL1 inhibitors vs. standard-of-care (SOC) in patients with PDL1 < 1%. In term of anti-PD-1/PD-L1 monotherapy, OS (HR = 0.90, 0.81-1.01) and PFS (HR = 1.11, 0.97-1.27) between PD-1/PD-L1 inhibitor group and SOC group were comparable. In term of anti-PD-1/PD-L1 combination therapy, PD-1/PD-L1 inhibitor group exhibited longer OS (median 19.5 months vs. 16.3 months; HR = 0.83, 0.79-0.88, p < 0.001) and PFS than those of SOC group (median 8.11 months vs. 6.96 months; HR = 0.82, 0.77-0.87, p < 0.001).Subgroup analysis showed that survival benefit was mainly observed in non-small cell lung cancer (NSCLC) (HROS = 0.74; HRPFS = 0.69; p < 0.001), small-cell lung cancer (SCLC) (HROS = 0.58, p < 0.001; HRPFS = 0.55, p = 0.030), esophageal squamous cell carcinoma (ESCC) (HROS = 0.62, p = 0.005; HRPFS = 0.79, p < 0.001), melanoma (HROS = 0.53, p < 0.001) and nasopharyngeal carcinoma (NPC) (HRPFS = 0.35, p = 0.013). Conclusion: Anti-PD-1/PD-L1 combinational therapy rather than monotherapy exhibit survival benefit in the low PD-L1 population in the first-line setting, and the survival benefit was mainly observed in specific tumor types.

Project description:BackgroundThe prognostic value of programmed cell death-ligand 1 (PD-L1) in gynecological cancers has been explored previously, but the conclusion remains controversial due to limited evidence. This study aimed to conduct an updated meta-analysis to re-investigate the predictive significance of PD-L1 expression.MethodsPubMed, EMBASE and Cochrane Library databases were searched. The associations between PD-L1 expression status and prognosis [overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), cancer-specific survival (CSS) or disease-free survival (DFS)], clinical parameters [FIGO stage, lymph node metastasis (LNM), tumor size, infiltration depth, lymphovascular space invasion (LVSI) or grade] and response to anti-PD-1/PD-L1 treatment [objective response rate (ORR)] were analyzed by hazard ratios (HR) or relative risks (RR).ResultsFifty-five studies were enrolled. Overall, high PD-L1 expression was not significantly associated with OS, PFS, RFS, CSS and DFS of gynecological cancers. However, subgroup analysis of studies with reported HR (HR = 1.27) and a cut-off value of 5% (HR = 2.10) suggested that high PD-L1 expression was correlated with a shorter OS of gynecological cancer patients. Further sub-subgroup analysis revealed that high PD-L1 expressed on tumor-infiltrating immune cells (TICs) predicted a favorable OS for ovarian (HR = 0.72), but a poor OS for cervical cancer (HR = 3.44). PD-L1 overexpression was also correlated with a lower OS rate in non-Asian endometrial cancer (HR = 1.60). High level of PD-L1 was only clinically correlated with a shorter PFS in Asian endometrial cancer (HR = 1.59). Furthermore, PD-L1-positivity was correlated with LNM (for overall, ovarian and endometrial cancer expressed on tumor cells), advanced FIGO stage (for overall, ovarian cancer expressed on tumor cells, endometrial cancer expressed on tumor cells and TICs), LVSI (for overall and endometrial cancer expressed on tumor cells and TICs), and increasing infiltration depth/high grade (only for endometrial cancer expressed on TICs). Patients with PD-L1-positivity may obtain more benefit from anti-PD-1/PD-L1 treatment than the negative group, showing a higher ORR (RR = 1.98), longer OS (HR = 0.34) and PFS (HR = 0.61).ConclusionOur findings suggest high PD-L1 expression may be a suitable biomarker for predicting the clinical outcomes in patients with gynecological cancers.

Project description:ImportanceInitial approval for immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC) was limited to patients with high levels of programmed cell death ligand 1 (PD-L1) expression. However, in the period after approval, it is not known how new evidence supporting efficacy of these treatments in patients with low or negative PD-L1 expression was incorporated into real-world practice.ObjectiveTo evaluate the association between PD-L1 testing and first-line ICI use.Design, setting, and participantsThis retrospective cohort study (January 1, 2011, to December 31, 2018) used a deidentified nationwide electronic health record-derived database reflecting real-world care at more than 280 US community and academic cancer clinics (approximately 800 sites of care). Patients included those with advanced NSCLC without other identifiable variations diagnosed in the period after the US Food and Drug Administration's initial first-line approval of ICIs for patients with high PD-L1 expression (≥50%).ExposureFirst-line ICI treatment.Main outcomes and measuresPatterns of PD-L1 testing and first-line ICI treatment among all patients and patients stratified by tumor histologic type (squamous vs nonsquamous).ResultsA total of 45 631 patients (mean [SD] age, 68.4 [9.6] years; 21 614 [47.4%] female) with advanced NSCLC were included in the study. PD-L1 testing increased from 468 (7.2%) in 2015 to 4202 (73.2%) in 2018. Within a subset of 7785 patients receiving first-line treatment in the period after first-line approval of pembrolizumab, those who received PD-L1 testing had a greater odds of receiving an ICI (odds ratio, 2.11; 95% CI, 1.89-2.36). Among patients with high PD-L1 expression (≥50%), 1541 (83.5%) received first-line ICI treatment; 776 patients (40.3%) with low PD-L1 expression (1%-49%) and 348 (32.3%) with negative PD-L1 expression (0%) also received ICIs. In addition, 755 untested patients (32.8%) were treated with a first-line ICI. The proportion of patients who received ICIs without PD-L1 testing increased during the study period (59 [17%] in quarter 4 of 2016 to 141 [53.8%] in quarter 4 of 2018).Conclusions and relevanceIn this study, use of first-line ICI treatment increased among patients with advanced NSCLC with negative, low, or untested PD-L1 expression status in 2016 through 2018. These findings suggest that national practice was rapidly responsive to new clinical evidence rather than adhering to regulatory guidance in place at the time.

Dataset Information

New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone.

Publications

New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets