Dataset Information

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

ABSTRACT:

Background

The advent of immuno-oncology (IO) represented a breakthrough in non-small cell lung cancer (NSCLC) therapy over the last few years. However, establishing the optimal therapeutic options among programmed death-ligand 1 (PD-L1) selected subgroups still addresses an unmet need in the clinical setting.

Methods

We performed a systematic review and finally included eleven first-line randomized controlled trials to compare efficacy and safety outcomes among first-line IO treatment strategies versus standard platinum-based chemotherapy (CT) according to PD-L1 expression level (<1%, 1-49%, ≥50%). Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), treatment-related adverse events (TRAEs), and discontinuation rates were obtained.

Results

Our results demonstrated that among the different IO-based strategies (single-agent IO, Combo-IO, IO + CT) the IO + CT approach resulted in a significant increase of the ORR, albeit with no relevant improvement of survival in patients with PD-L1 ≥50%. As regards patients with negative PD-L1 expression, no significant differences in terms of activity and efficacy profile have been detected between the IO + CT and the dual checkpoint blockade. Of note, in the PD-L1 1-49% subgroup, the use of anti-PD-1 agents in association with CT led to a statistically significant gain in OS. As concerns safety, the dual checkpoint blockade seemed to be better tolerated than IO + CT.

Conclusions

This meta-analysis suggested the current limited role of PD-1/CTLA-4 inhibitors combination in PD-L1-high and/or -low advanced NSCLC patients while emerging as a potentially effective and tolerable option in particular PD-L1 negative subgroups.

SUBMITTER: Passiglia F

PROVIDER: S-EPMC8350096 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

Passiglia Francesco F Galvano Antonio A Gristina Valerio V Barraco Nadia N Castiglia Marta M Perez Alessandro A La Mantia Maria M Russo Antonio A Bazan Viviana V

Translational lung cancer research 20210701 7

<h4>Background</h4>The advent of immuno-oncology (IO) represented a breakthrough in non-small cell lung cancer (NSCLC) therapy over the last few years. However, establishing the optimal therapeutic options among programmed death-ligand 1 (PD-L1) selected subgroups still addresses an unmet need in the clinical setting.<h4>Methods</h4>We performed a systematic review and finally included eleven first-line randomized controlled trials to compare efficacy and safety outcomes among first-line IO trea ...[more]

PMID: 34430351

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Project description:IntroductionThe combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC.MethodsA systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses.ResultsTotally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%.ConclusionCP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.

Project description:ObjectiveOur previous economic assessment found that nivolumab was not cost-effective for Chinese patients with advanced non-small cell lung cancer (NSCLC) and without EGFR mutations or ALK translocations, when compared with the standard second-line drug docetaxel. However, a greater survival benefit with nivolumab was observed for patients with 1% or greater tumor programmed death ligand 1 (PD-L1) expression. In view of this, we designed the present analysis to explore whether it is cost-effective to use the PD-L1 test to guide second-line nivolumab treatment in China.Material and methodsA Markov model was established to project the lifetime costs and quality-adjusted life-years (QALYs) of three second-line treatment strategies: nivolumab and docetaxel (strategies without a PD-L1 test) and PD-L1 test-based strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of our results. Additional price reduction and willingness-to-pay (WTP) threshold scenario analyses were performed to explore the impact of economic and health policies with Chinese characteristics on our results.ResultsThe PD-L1 test-based strategy costs approximately CNY 194,607 (USD 28,210) or more and yielded an additional 0.27 QALYs compared to the docetaxel strategy without a PD-L1 test, equating an incremental cost-effectiveness ratio (ICER) of CNY 731,089 (USD 105,978)/QALY. Deterministic sensitivity analyses showed that the price of nivolumab was the strongest source of variation in the ICERs. Probability sensitivity analysis showed that the probability for the PD-L1 test-based strategy being cost-effective increases with the increase of WTP thresholds.ConclusionFrom the perspective of the Chinese healthcare system, using a PD-L1 test to guide second-line nivolumab treatment was not cost-effective. The National Healthcare Security Administration negotiation on the price reduction of nivolumab was found to be the most effective action to improve its cost-effectiveness in China.

Project description:Background and aimThe objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model.MethodsA total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies.ResultsPatients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort.ConclusionsBased on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

Project description:BackgroundNumerous first-line immune checkpoint inhibitors (ICI) were developed for patients with advanced non-small cell lung cancer (NSCLC) lacking driver gene mutations. However, this group consists of a heterogeneous patient population, for whom the optimal therapeutic choice is yet to be confirmed.ObjectiveTo identify the best first-line immunotherapy regimen for overall advanced NSCLC patients and different subgroups.DesignSystematic review and Bayesian network meta-analysis (NMA).MethodsWe searched several databases to retrieve relevant literature. We performed Bayesian NMA for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (tr-AEs) with a grade equal or more than 3 (grade ⩾ 3 tr-AEs). Subgroup analysis was conducted according to programed death ligand 1 (PD-L1) levels, histologic type, central nervous system (CNS) metastases and tobacco use history.ResultsFor the PD-L1 non-selective patients, sintilimab plus chemotherapy (sinti-chemo) provided the best OS [hazard ratio (HR) = 0.59, 95% confidence interval (CI):0.42-0.83]. Nivolumab plus bevacizumab plus chemotherapy (nivo-bev-chemo) was comparable to atezolizumab plus bevacizumab plus chemotherapy (atezo-bev-chemo) in prolonging PFS (HR = 0.99, 95% CI: 0.51-1.91). Atezo-bev-chemo remarkably elevated the ORR than chemotherapy (OR = 3.13, 95% CI: 1.51-6.59). Subgroup analysis showed pembrolizumab plus chemotherapy (pembro-chemo) ranked first in OS in subgroups of PD-L1 < 1%, non-squamous, no CNS metastases, with or without smoking history, and ranked second in OS in subgroups of PD-L1 ⩾ 1% and PD-L1 1-49%. Cemiplimab and sugemalimab plus chemotherapy ranked first in OS and PFS for squamous subgroup, respectively. For patients with CNS metastases, nivolumab plus ipilimumab plus chemotherapy (nivo-ipili-chemo) and camrelizumab plus chemotherapy provided the best OS and PFS, respectively.ConclusionsSinti-chemo and nivo-bev-chemo were two effective first-line regimens ranked first in OS and PFS for overall patients, respectively. Pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1-49%, non-squamous, no CNS metastases, with or without smoking history. Addition of bevacizumab consistently provided with favorable PFS results in patients of all PD-L1 levels. Cemiplimab was the best option in squamous subgroup and nivo-ipili-chemo in CNS metastases subgroup due to their advantages in OS.

Dataset Information

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

Background

Methods

Results

Conclusions

Publications

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

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