Dataset Information

The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

ABSTRACT: Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled, real-world, retrospective cohort of patients with solid tumors treated with ICI. Of the total pooled cohort (N = 578), 47.2%, 38.2% and 14.5% of patients were stratified into good, intermediate and poor LIPI group, respectively. Median OS were 22.8 (95% CI 17.4-29.5), 7.8 (95% CI 6.6-9.6), and 2.5 months (95% CI 1.4-3.4) (p < 0.0001). Median PFS were 9.9 (95% CI 7.2-11.5), 3.6 (95% CI 2.7-4.3), and 1.4 months (95% CI 1.2-2.2) (p < 0.0001). ORR was also associated with LIPI group (p < 0.001). Intermediate and poor LIPI were independently prognostic of OS compared to good LIPI, with hazard ratios (HR) of 1.8 (95% CI 1.4-2.3, p < 0.001) and 3.6 (95% CI 2.5-5.1, p < 0.001), respectively. These data are the first to suggest that in a real-world setting, the prognostic value of LIPI may be tumor agnostic.

SUBMITTER: Meyers DE

PROVIDER: S-EPMC6896022 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

Meyers Daniel E DE Stukalin Igor I Vallerand Isabelle A IA Lewinson Ryan T RT Suo Aleksi A Dean Michelle M North Scott S Pabani Aliyah A Cheng Tina T Heng Daniel Y C DYC Bebb D Gwyn DG Morris Don G DG

Cancers 20191102 11

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free surviv ...[more]

PMID: 31684111

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Project description:Background: A large proportion of patients eventually experience disease progression despite treatment with immune checkpoint inhibitors (ICIs), but subsequent treatment options are limited for this population. Retreatment with the same or different types of ICIs is a possible strategy, but the clinical efficacy and safety data are limited. This systematic review aims to evaluate the efficacy and safety of ICIs retreatment in patients with solid tumors after disease progression to previous ICIs.Methods: We searched MEDLINE, EMBASE, the Cochrane Library, and major meeting libraries for prospective studies. The primary outcomes included the objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), and the incidence of grade ?3 immune-related adverse events (irAEs).Results: We identified 22 prospective studies including 1865 patients. For disease progression after CTLA-4 inhibitors, three studies evaluated anti-CTLA-4 retreatment. The ORR was 12-23%, the DCR was 48.4-67.7%, and the mOS was 12?months. The incidence of grade ?3 irAEs was 5.9-25%. Four studies evaluated anti-programmed cell death protein 1 (PD-1) retreatment. The ORR was 22-36%, the DCR was 40-64%, and the mOS was 13.4-20.6?months. The incidence of grade ?3 irAEs was <10%. For disease progression after PD-(L)1 inhibitors, 13 studies evaluated anti-PD-(L)1 retreatment. The ORR was 5-53%, the DCR was 38-83%, and the mOS was 13.9?months. The incidence of grade ?3 irAEs was 0-15% for patients retreated with single anti-PD-(L)1 agent, but was higher (0-64%) for those retreated with ICIs combined with other agents. Two studies evaluated anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) retreatment. The ORR was 0-22.4%, the DCR was 50-72%, and the mOS was 4-21?months. The incidence of grade ?3 irAEs was 26-61%.Conclusion: Retreatment with ICIs is feasible for cancer patients considering its encouraging efficacy and tolerable safety. Further prospective trials are needed to explore more promising strategies and identify suitable populations for retreatment.

Project description:Importance:As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear. Objective:To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients. Design, Setting, and Participants:This cohort study used multidimensional genomic data of 10?195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non-small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation-associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019. Main Outcomes and Measures:Genomic factors associated with ICI response, overall survival, and clinical response. Results:Of the 10?195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10?195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P?<?.001) and neoantigen load (median [IQR], 179 [74-394.5] neoantigens vs 48 [24-89] neoantigens; difference, 131 antigens; 95% CI, 116.5-145 neoantigens; P?<?.001) than those without mutations. The tumor immune microenvironment with dual-positive CD8A and PD-L1 was overrepresented in MUC16-mutated tumors compared with wild-type ones (43.8% vs 32.4%; odds ratio, 1.63; 95% CI, 1.46-1.80; P?<?.001). Of the 40 immune-related genes, 37 (92.5%) exhibited differential expression between 2 states. MUC16 mutation was associated with improved overall survival in both the NSCLC (hazard ratio, 0.34; 95% CI, 0.12-0.99; P?=?.04) and melanoma (hazard ratio, 0.57; 95% CI, 0.36-0.90; P?=?.02) cohorts. The improvement persisted after adjusting for age, sex, and dominant mutational signatures in the melanoma cohort (hazard ratio, 0.57; 95% CI, 0.33-0.96; P?=?.04). MUC16 mutation was associated with greater response rates in the NSCLC cohort (odds ratio, 4.03; 95% CI, 1.06-16.43; P?=?.03) and the melanoma cohort (odds ratio, 3.38; 95% CI, 1.07-14.25; P?=?.03). Gene set enrichment analysis revealed that gene sets regarding cell proliferation and immune response were enriched in MUC16-mutated tumors (false discovery rate, <.001). Conclusions and Relevance:MUC16 mutation appears to be associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors. It may hold promise as a marker for guiding immunotherapeutic responsiveness.

Project description:ImportanceIn 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.ObjectiveTo calculate the fragility of survival data in RCTs evaluating ICIs.Design, setting, and participantsIn 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 < .05 by log-rank test). For nonsignificant results, a negative SIFI was calculated by reversing the direction of reassignment (from the control group to the interventional group).Main outcomes and measuresSurvival-inferred fragility index.ResultsA total of 45 phase 3 prospective RCTs (4 of which had 3 groups, for a total of 49 groups) were identified, of which 6 (13%) investigated anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents, 25 (56%) investigated anti-programmed cell death 1 (PD-1) agents, 12 (27%) investigated anti-programmed cell death 1 ligand 1 agents, and 3 (7%) investigated the combination of anti-CTLA-4 and anti-PD-1 agents. The median SIFI was 5 (interquartile range, -4 to 12) for the intention-to-treat analysis; for these trials, the SIFI was 1% or less of the total sample size in 17 of 49 populations (35%). In 25 of the 49 intention-to-treat populations (51%), the SIFI was less than the number of censored patients in the intervention group shortly after randomization (defined as <5% of the follow-up time).Conclusions and relevanceThis study suggests that many phase 3 RCTs evaluating ICI therapies have a low SIFI for overall survival, resulting in uncertainty regarding their potential clinical benefit. Although not a definitive solution for the problems arising from dichotomization, SIFI provides an additional means of assessing and communicating the strength of statistical conclusions.

Dataset Information

The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

Publications

The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

Similar Datasets

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