Cost-effectiveness of programmed cell death ligand 1 testing and tumor mutational burden testing of immune checkpoint inhibitors for advanced non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Li WQ
PROVIDER: S-EPMC7722558 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Cost-effectiveness of programmed cell death ligand 1 testing and tumor mutational burden testing of immune checkpoint inhibitors for advanced non-small cell lung cancer.
Li Wen-Qian WQ Li Ling-Yu LY Bai Ri-Lan RL Qian Lei L Chen Nai-Fei NF Cui Jiu-Wei JW
Chinese medical journal 20201101 21
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Project description:BACKGROUND:To achieve optimal outcomes, an individual approach is needed in the treatment and care of patients. The potential value of tumor mutational burden (TMB) status and/or programmed cell death ligand 1 (PD-L1) expression as biomarkers to predict which patients are most likely to respond to checkpoint inhibitors has been explored in many studies. The goal of this targeted literature review is to identify data available for TMB status and/or PD-L1 expression that predict response to checkpoint inhibitors and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies. METHODS:Targeted literature searches were performed using electronic medical databases (MEDLINE, Embase, and BIOSIS) and internet searches of specified sites. Bibliographies of key systematic literature reviews and meta-analyses also were reviewed for studies of interest. RESULTS:The review identified 27 studies of non-small cell lung cancer (NSCLC), 40 studies of melanoma, 10 studies of urothelial cancer, and 5 studies of renal cell cancer indications. Studies also were identified in other cancer types, e.g., colorectal, breast, gastric, and Merkel cell cancer and squamous-cell carcinoma of the head and neck. Twelve trials, including six in NSCLC and four in melanoma, evaluated TMB as a predictor of outcomes. A TMB of ≥10 mutations per megabase was shown to be an effective biomarker in the CheckMate 227 study. PD-L1 expression was included in the majority of identified studies and was found to predict response in in melanoma and in all types of NSCLC. Prediction of response was not a prespecified analysis in some studies; others had small sample sizes and wide confidence intervals. A clear predictive trend for PD-L1 expression was not identified in renal, breast, gastric, or Merkel cell cancer. CONCLUSION:Based on data contained in this review, assessment of TMB status and PD-L1 expression may help enhance the prediction of response to checkpoint inhibition in some tumors, such as NSCLC and melanoma. In this rapidly growing area of research, further exploratory biomarkers are being investigated including tumor-infiltrating lymphocytes, immune profiling (e.g., effector T cells or regulatory T cells), epigenetic signatures, T-cell receptor repertoire, proteomics, microbiome, and metabolomics.
| S-EPMC6990470 | biostudies-literature
Project description: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.
| S-EPMC5844278 | biostudies-literature
Project description:PurposeCheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).Patients and methodsTwo hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.ResultsOf treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.ConclusionNivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
| S-EPMC6494267 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) has the worst prognosis among all molecular types of breast cancer. Because of the strong immunogenicity of TNBC cells, programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, two kinds of immune checkpoint blockade agents, might help improve the prognosis of TNBC. However, how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial. This article summarizes published clinical studies in which PD-1/PD-L1 inhibitors were used in patients with advanced TNBC to explore how to maximize effectiveness of these medications.
| S-EPMC9086576 | biostudies-literature
Project description:PD-1/PD-L1 play key roles in tumor immune escape and the formation of the tumor microenvironment, and are closely related to the generation and development of tumors. Blocking the PD-1/PD-L1 pathway can reshape the tumor microenvironment or block the formation of the tumor microenvironment and enhance endogenous antitumor immune response. Clinical trials show that the treatment of non-small cell lung cancer (NSCLC) with PD-1/PD-L1 inhibitors has significant advantages. The review briefly describes these basic principles of the PD-1/PD-L1 pathway and action mechanism in the treatment of NSCLC. A summary of global PD-1/PD-L1 clinical trials and five PD-1/PD-L1 inhibitors approved by FDA, EMA and NMPA for advanced NSCLC were analyzed.
| S-EPMC9243588 | biostudies-literature
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.
| S-EPMC7280954 | biostudies-literature
Project description:IntroductionProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings.MethodsExtensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis.ResultsTen nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible.ConclusionsPD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.
| S-EPMC6458809 | biostudies-literature
Project description:BackgroundPembrolizumab monotherapy significantly extends progression-free and overall survival compared to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC), but also has a significant impact on medical costs.AimTo clarify the health economic evidence for selecting the first-line treatment for patients with stage IV advanced NSCLC with a programmed cell death ligand 1 tumor proportion score of 50% or greater in Japan, we assessed the cost-effectiveness of pembrolizumab monotherapy compared with that of platinum-based chemotherapy.MethodUsing a Markov model, the study simulated three health states for patients, based on clinical data and utility values from KEYNOTE-024. Transition probabilities were estimated exponentially. Direct medical costs were calculated according to the 2022 National Health Insurance Medical Fee Points and Drug Price Standards. The outcomes measured included life years, quality-adjusted life years, and incremental cost-effectiveness ratio, with sensitivity analysis performed to evaluate the effect of uncertainties.ResultsPembrolizumab led to an additional 1.58 life years and 1.23 quality-adjusted life years at an additional cost of 7,009,888 Japanese yen (48,448 U.S. dollars [USD]), resulting in incremental cost-effectiveness ratio of 4,436,638 Japanese yen (30,663 USD) per life year and 5,699,096 Japanese yen (39,388 USD) per quality-adjusted life year. Pembrolizumab was deemed cost-effective under a threshold of 7.5 million Japanese yen (51,835 USD) per quality-adjusted life year.ConclusionPembrolizumab monotherapy is a cost-effective option for the first-line treatment of advanced NSCLC with high programmed cell death ligand 1 expression in Japan, providing valuable health economic evidence for treatment selection.
| S-EPMC11919958 | biostudies-literature
Project description:PurposeTo investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).MethodsA phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.ResultsA total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).ConclusionDurvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.
| S-EPMC5569690 | biostudies-literature
Project description:Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.
| S-EPMC7900207 | biostudies-literature