Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

Huang

et al. 2021

Preprint

Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens.Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens. Results: We included 23 RCTs from 2016 to 2021 with a total of 14,378 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 74.88%), ICI-ICI-CT (50.60%), CT alone (74.79%), ICI-ICI (98.37%), and ICI monotherapy (99.37%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.38), ICI monotherapy (96.98%), ICI-CT (99.44%), and CT alone (99.98%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy. Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative Safety of Immune Checkpoint Inhibitors and Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Huang

et al. 2021

Preprint

“…2). Данная мысль находит подтверждение и в опубликованном метаанализе по оценке эффективности и безопасности различных доступных в лечении метастатического НМРЛ иммунных комбинаций [50]; именно в подгруппе с экспрессией PD-L1<1% комбинация ипилимумаб + ниволумаб и 2 курса ХТ показала лучший результат по ОВ среди 10 анализируемых лечебных опций. Если говорить о возможных перспективах использования двойного иммунного ингибирования, среди собранных в табл.…”

Section: дискуссияunclassified

Dual immunological blockade in the treatment of metastatic non-small cell lung cancer: reality and perspectives

et al. 2021

Nowadays immunotherapy is a crucial option in the treatment of non-small cell lung cancer. There are a lot of actual options of the first-line therapy for the patients with metastatic lung cancer, including dual immunological blockade of PD-1/PD-L1 and CTLA-4 pathways. This review is an attempt to clarify the place of dual immunological blockade now and in the future. The scientific rationale for dual immunotherapy is a possible synergy and overcome resistance to single-drug therapy. The review collected information from open sources, both current studies with dual immunological blockade, and already obtained results of the trials for nivolumab and ipilimumab, tremelimumab and durvalumab, and other combinations for the treatment of patients with metastatic non-small cell lung cancer. This approach is promising for the possible overcoming of resistance to monoimmunotherapy with anti-PD1/PD-L1 antibodies, especially in the population with low and negative PD-L1 status.

“…Today, advanced NSCLC patients can cherish the hope that they remain progression-free for several years after diagnosis upon treatment with immune checkpoint inhibitors (ICI) that target Programmed Death-1 (PD-1) or its ligand (PD-L1). Yet, this is only the case for 20-25% of patients ( 2 , 3 ). These sobering numbers suggest that additional immunomodulatory pathways need to be explored to harness at maximum the effects of radio(chemo)therapy and ICI, alone or in combination.…”

Section: Introductionmentioning

confidence: 99%

Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth

et al. 2021

The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.