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A pooled meta-analysis of PD-1/L1 inhibitors incorporation therapy for advanced non-small cell lung cancer.

ABSTRACT: Objective: Immune checkpoint inhibitors, especially the programmed cell death receptor-1/ligand 1 (PD-1/L1) inhibitors, displayed promising efficacy in non-small cell lung cancer (NSCLC) patients. Incorporation of anti-PD-1/L1 antibodies into other therapeutic regimens (including CTLA-4 inhibitors, chemotherapy, EGFR-TKIs and IDO inhibitors) is currently in active clinical research. This meta-analysis summarized recent developments in four combination regimens of PD-1/L1 inhibitors. Methods: We searched PubMed, the Cochrane Library and the Embase database up to July 2018, on the combination therapy of PD-1/L1 inhibitors in NSCLC patients. Results: Seventeen trials were finally included in the current meta-analysis. The combined objective response rate s (ORR) for PD-1/L1 inhibitors in combination with CTLA-4 inhibitors, chemotherapy, EGFR-TKIs, and IDO inhibitors were 32% (19%-44%), 49% (46%-53%), 55% (28%-83%) and 35% (20%-50%) respectively. The combined ORR for first line PD-1/L1 inhibitors combination with CTLA-4 inhibitors, chemotherapy, and EGFR-TKIs were 35% (17%-53%), 51% (46%-56%) and 43% (-7%-93%) respectively, and the combined ORR in the second or more line setting were 36% (8%-65%), 17% (-13%-46%), 39% (19%-59%) and 35% (20%-50%) respectively. The pooled 6-month progression-free survival rate (6m PFSr) and 1-year overall survival rate (1y OSr) for combination therapy of PD-1/L1 inhibitors with CTLA-4 inhibitors or chemotherapy were 35% or 65% (6m PFSr) and 31% or 70% (1y OSr) respectively. Anti-PD-1/L1 drugs combined with anti-CTLA-4 drugs exhibited a more potent efficacy on PD-L1 positive patients (OR=0.33, 95%CI: 0.12-0.88). This trend was not observed in patients receiving combination therapy of PD-1/L1 inhibitors with chemotherapy (OR=0.96, 95%CI: 0.51-1.78). Conclusion: The included four combination regimens were potential treatment strategies and well tolerated for NSCLC patients. Further, the therapy lines and PD-L1 expression status were correlated with treatment efficacy.

SUBMITTER: Wan N

PROVIDER: S-EPMC6604807 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A pooled meta-analysis of PD-1/L1 inhibitors incorporation therapy for advanced non-small cell lung cancer.

Wan Ning N Ji Bo B Li Jian J Jiang Jie J Yang Chen C Zhang Tiantian T Huang Wenjie W

OncoTargets and therapy 20190627

<b>Objective:</b> Immune checkpoint inhibitors, especially the programmed cell death receptor-1/ligand 1 (PD-1/L1) inhibitors, displayed promising efficacy in non-small cell lung cancer (NSCLC) patients. Incorporation of anti-PD-1/L1 antibodies into other therapeutic regimens (including CTLA-4 inhibitors, chemotherapy, EGFR-TKIs and IDO inhibitors) is currently in active clinical research. This meta-analysis summarized recent developments in four combination regimens of PD-1/L1 inhibitors. <b>Me ...[more]

PMID: 31303759

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Project description:Immune checkpoint inhibitors (ICIs) are recommended as first-line treatment for late-stage non-small cell lung cancer (NSCLC), either as monotherapy or in combination with chemotherapy. However, efficacy and safety comparisons between ICIs as monotherapy and ICIs with chemotherapy are lacking. We searched PubMed, Embase, and Cochrane Library for randomized controlled trials published before February 29th, 2020, with the search terms "immunotherapy" and "chemotherapy". 10 eligible trials were identified with a total of 5,956 patients. Of these patients, 3,204 received immune therapy and 2,752 received chemotherapy. PD-1 inhibitors with chemotherapy improved OS (HR 0.84, 0.77-0.92), PFS (HR 0.80, 0.75-0.85), and objective response rate (ORR) (odds ratio (OR) 2.55, 1.20-5.28) compared to PD-1 inhibitors as monotherapy. In contrast, PD-L1 inhibitors plus chemotherapy showed no significant differences in OS, PFS, or ORR compared with PD-L1 inhibitors as monotherapy. When patients were stratified according to PD-L1 expression level, patients with high PD-L1 expression (≥ 50%) receiving PD-1 inhibitors plus chemotherapy had improved PFS, but not other outcomes, compared to PD-1 inhibitors as monotherapy. In these patients, PD-L1 inhibitors plus chemotherapy showed no significant difference in survival compared with PD-L1 inhibitors. In the low PD-L1 expression group (1%-49%), PD-1 inhibitors plus chemotherapy improved OS and PFS, but no advantage was observed in PD-L1 inhibitors plus chemotherapy in OS, PFS, or ORR compared with PD-L1 inhibitor monotherapy. When comparing PD-1/PD-L1 inhibitors plus chemotherapy with PD-1/PD-L1 inhibitors monotherapy, no significant differences were observed in the rate of immune-related adverse events (AEs). In summary, for treating patients with late-stage NSCLC, PD-1 inhibitors plus chemotherapy have improved efficacy compared with PD-1 inhibitor monotherapy, but PD-L1 inhibitors plus chemotherapy have similar efficacy as PD-L1 monotherapy. Survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy were particularly significant in patients with low PD-L1 expression levels.Systematic review registrationPROSPERO, identifier CRD42020166678 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166678).

Project description:BackgroundThe present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.MethodsIn this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.ResultsSeventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 vs. 2.1 months; P=0.004), while no significant difference was found in OS (14.0 vs. 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 vs. 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).ConclusionsIn the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.

Project description:Importance:Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown. Objectives:To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants:In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions:The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures:The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results:Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance:Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Project description:BackgroundDue to the increasing number of trials with immune checkpoint inhibitors (ICIs) in the first-line therapy of non-small cell lung cancer (NSCLC) patients, we performed a systematic review and meta-analyses to investigate the difference between anti PD-1 and PD-L1 antibodies, used alone or in combination with chemotherapy, through adjusted indirect analysis to minimize the potential bias regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3-5 adverse events (AEs).MethodsA systematic review of studies reporting clinical outcomes and toxicity associated with first-line therapy employing anti-PD1 or anti-PD-L1 antibodies alone, or in combination with chemotherapy, to treat metastatic, treatment-naïve NSCLC patients was performed. Primary outcomes were OS, PFS, ORR and grade 3-5 AEs. We used a random-effects model to generate pooled estimates for proportions. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies with the random effects model.ResultsA total of 13 eligible studies met our eligibility criteria, including 7673 patients. In the ICI-chemotherapy combination subgroup, we observed that anti-PD1 therapy was associated with better OS (p = 0.022) and PFS (p = 0.029) compared with anti-PD-L1 therapy. In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 for OS and PFS. With regard to ORR and toxicity, in the ICI-chemotherapy combination subgroup, we observed a trend of better ORR (p = 0.12) with the use of anti-PD1 therapy and less frequent grade 3-5 AEs compared to the use of anti-PD-L1 therapy (p = 0.0302). In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 regarding ORR and toxicity.ConclusionsOur study suggests that PD-1 drug plus chemotherapy is superior to anti-PD-L1 plus chemotherapy for NSCLC; nevertheless, as monotherapy, both strategies appear to be similar.

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A pooled meta-analysis of PD-1/L1 inhibitors incorporation therapy for advanced non-small cell lung cancer.

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A pooled meta-analysis of PD-1/L1 inhibitors incorporation therapy for advanced non-small cell lung cancer.

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