Impact of Age on the Efficacy of Immune Checkpoint Inhibitor-Based Combination Therapy for Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Tian, Xuan; Wu, Zhiqiang; Han, Weidong

doi:10.3389/fonc.2020.01671

Cited by 40 publications

(26 citation statements)

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“…In previous studies which investigated the relationship between age and the efficacy of immunotherapy, the cut-off age was mostly 65 years old. They found no statistical difference between the ICI group and non-ICI group in patients <65 years old and ≥65 years old (40,41). However, it remains unclear whether elderly NSCLC patients aged ≥75 years will also benefit from immunotherapy.…”

Section: Discussionmentioning

confidence: 97%

The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Wang

Xie

et al. 2021

Front. Oncol.

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BackgroundThis meta-analysis aimed to investigate the efficacy of immune checkpoint inhibitor (ICI)-based therapy in non-small cell lung cancer (NSCLC) patients with different clinical and molecular characteristics such as age, sex, histological type, performance status (PS), smoking status, driver mutations, metastatic site, region and number of prior systemic regimens.MethodsA systematic literature search was conducted in PubMed, Embase, and the Cochrane library databases to identify qualified randomized controlled trials (RCTs). The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS).ResultsA total of 19 RCTs were included in this meta-analysis. ICI-based therapy significantly improved OS compared with non-ICI therapy in patients aged <65 years (HR, 0.74; P<0.00001), 65-74 years (HR, 0.73; P<0.00001), receiving first-line (HR, 0.75; P<0.00001) or second-line (HR, 0.72; P<0.00001) treatment, current or previous smokers (HR, 0.76; P<0.00001), and EGFR wild-type patients (HR, 0.76; P<0.00001), but not in patients aged ≥75 years (HR, 0.91; P=0.50), receiving third-line treatment (HR, 0.93; P=0.55), never smokers (HR, 0.84; P=0.10), or EGFR mutant patients (HR, 0.99; P=0.92). No statistical OS improvement was observed in KRAS mutant (HR, 0.68; P=0.05) or KRAS wild-type (HR, 0.95; P=0.65) patients. Immunotherapy improved OS in NSCLC patients, regardless of sex (male or female), histological type (squamous or non-squamous NSCLC), PS (0 or 1), metastatic site (brain or liver metastases), and region (East Asia or America/Europe) (all P<0.05). Subgroup analysis showed that the survival benefit of ICIs in patients with brain metastases was observed in first-line combination therapy (P<0.05), but not in second or more line monotherapy (P>0.05). Programmed death-1 (PD-1) inhibitors significantly prolonged OS in patients with liver metastases compared with non-ICI therapy (P=0.0007), but PD-L1 inhibitors did not (P=0.35). Similar results were observed in the combined analysis of PFS.ConclusionsAge, smoking status, EGFR mutation status, and number of prior systemic regimens predicted the efficacy of immunotherapy. While sex, histological type, PS 0 or 1, KRAS mutation status and region were not associated with the efficacy of ICIs. Patients with liver metastases benefited from anti-PD-1-based therapy, and those with brain metastases benefited from first-line ICI-based combination therapy.Systematic Review Registrationhttp://www.crd.york.ac.uk/prospero, identifier CRD42020206062.

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Section: Discussionmentioning

confidence: 97%

The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Wang

Xie

et al. 2021

Front. Oncol.

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“…22 Some studies suggest that older patients might have a tendency to respond better to aPD1 therapy, however, this is still debated. 23,24,25,26 To address potential trial bias and the non-randomized set-up, patients in MM1636 were matched on age, PS, Gender, M-stage, LDH-level, PD-L1 status and BRAF-status with a historical control group from the Danish Metastatic Melanoma Database, DAMMED, who were treated contemporarily (2015-2019) with aPD1 monotherapy as standard of care. We found a significantly higher ORR and CRR in MM1636 compared to matched patients, who had an ORR of 43% and a CRR of 13%, comparable to patients treated in CheckMate067.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy and immunity of a novel immune-modulatory peptide vaccine against IDO/PD-L1 (IO102/IO103) in combination with nivolumab in patients with metastatic melanoma

Kjeldsen¹,

Lorentzen²,

Martinenaite³

et al. 2021

Preprint

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Anti-PD-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, >50% of the patients progress due to resistance. Improved combination therapies enhancing aPD1 efficacy without leading to increased toxicity are needed. In this non-randomized phase I/II study (ClinicalTrials.gov: NCT03047928), we treated 30 aPD1 naive MM patients with a novel immune-modulatory vaccine (IO102/IO103) activating indoleamine 2,3-dioxygenase (IDO) and programmed death ligand-1 (PD-L1) specific T-cells combined with nivolumab. The vaccine has a dual mechanism of action, targeting both immunosuppressive cells and tumour cells expressing IDO/PD-L1. The vaccine was administered every two weeks for the first 6 injections and every fourth week thereafter, for up to 15 vaccines. Nivolumab was administered every two weeks (3mg/kg) for a maximum of 2 years. The primary endpoint was safety and feasibility; the systemic toxicity profile was comparable to nivolumab monotherapy, except for local and transient reactions at the vaccination site. Secondary endpoints were clinical efficacy and immunogenicity. An ORR of 80% (CI: 62.7-90.5%) was reached, with the majority of 43% (CI: 27.4-60.8%) achieving a complete response. After a median follow-up of 22.9 months, the median PFS was 26 months (CI: 15.4-69). Vaccine-specific responses were detected in vitro in blood from >93% of the patients on vaccination, suggesting the induction of memory response up to 6 months after the last vaccine. Vaccine reactive T-cells comprised both CD4+ and CD8+ T-cells. Paired biopsies from five patients with matched longitudinal PBMCs showed T-cell influx at the tumour site of peripherally expanded T-cells in responding patients and general enrichment of IDO and PD-L1 clones after treatment. These unprecedented clinical efficacy data support further validation in a larger randomized trial, to confirm the clinical potential of this first-in-class immunomodulating vaccine.

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“…Importantly, the authors noted that analyses of the ≥75 year patients were limited by the relatively small number of patients in this age cohort (~3%), and relatively fewer studies using age of 75 years as a cutoff for subgroup analyses (41). Several other meta-analyses have also demonstrated no statistically significant difference in treatment efficacy of ICIbased therapy between younger and older patients using the age cut-off of 65 years (7,8,42,43), with potentially less benefit among patients 75 years and older (6,(44)(45)(46)(47).…”

Section: Efficacymentioning

confidence: 99%

Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy

2021

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The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs. While generally better tolerated than traditional cytotoxic chemotherapy, ICIs are associated with unique toxicities, termed immune-related adverse events (irAEs), which can be severe or even lethal. As a disease of aging, older individuals make up a large proportion of patients diagnosed with cancer, yet this population is often underrepresented in clinical trials. Because ICIs indirectly target malignant cells through T cell activation, it has been hypothesized that age-related changes to the immune system may impact the efficacy and toxicity of these drugs. In this review, we discuss differences in the clinical efficacy and toxicity of ICIs in patients at the extremes of age.

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Impact of Age on the Efficacy of Immune Checkpoint Inhibitor-Based Combination Therapy for Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Cited by 40 publications

References 52 publications

The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Clinical efficacy and immunity of a novel immune-modulatory peptide vaccine against IDO/PD-L1 (IO102/IO103) in combination with nivolumab in patients with metastatic melanoma

Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy

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