Immune Checkpoint Inhibitors and Radiotherapy in NSCLC Patients: Not Just a Fluke.
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ABSTRACT:
SUBMITTER: Belluomini L
PROVIDER: S-EPMC7360008 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer is the leading cause of cancer-related mortality worldwide. Cytotoxic chemotherapy and tyrosine kinase inhibitors provide palliation and prolong survival, however, the median survival for patients with metastatic disease remains poor and more effective therapies are needed. Immune checkpoint inhibitors have shown promising results in phase I trials and are being evaluated in ongoing clinical trials in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients. These include agents targeting the programmed cell death-1 receptor and its ligand (PD-1/PD-L1; notably nivolumab, pembrolizumab, MPDL3280A, and MEDI-4736) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; ipilimumab and tremelimumab); these agents induce antitumor responses by inhibiting critical negative T cell regulators. In particular, the anti-PD-1/PD-L1 therapies administered as single agent therapy in chemotherapy refractory patients have produced objective response rates ranging from 15 %-25 %, the majority of which were rapid and ongoing 1 year after starting therapy. Furthermore, the toxicity profile for these agents differs from that of cytotoxic chemotherapy but generally is much better tolerated. Promising biomarkers, particularly tumor expression of PD-L1 and tumor infiltrating lymphocytes, may aid in treatment selection and stratification. Ongoing evaluation is needed to define the most appropriate timing and patient population that will benefit from therapy with an immune checkpoint inhibitors and the role of combining these agents with existing therapies including systemic therapy and radiation.
| S-EPMC4216599 | biostudies-literature
Project description:Immune checkpoint inhibition has been proven to be highly efficacious in NSCLC and associated with durable responses in a limited number of patients. Chemotherapy and targeted therapies, which have also expanded rapidly in this field lead to high response rates and improved survival although inevitably resistance occurs and hence treatment failure. There is increasing evidence showing that chemotherapy and targeted therapy interplay with the immune system including exerting effects on tumor cells and the host immune cells. Naturally combining both of these treatment modalities to induce cytotoxic effects on tumor cells to release tumor antigens and priming of the immune system should in turn lead to enhanced anticancer activity. This review will explore some of the preclinical rationale and clinical trial data we have to date on combining various systemic therapies with immunotherapies.
| S-EPMC6310331 | biostudies-literature
Project description:BackgroundWe indirectly compared the effects of immune checkpoint inhibitors alone (ICI) and ICI-combined chemotherapy (chemo-ICI) in patients with non-small cell lung cancer who had high programmed death-ligand 1 (PD-L1) expression (defined as tumour proportion score ≥50% or TC3/IC3) through network meta-analyses.MethodsThrough literature searches, we shortlisted 22 randomised controlled trials encompassing 4289 patients, with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) set as the primary outcomes. The dichotomous data for ORR and hazard ratios (HRs) and their 95% confidence intervals (CIs) for OS and PFS were extracted.ResultsWe found that chemo-ICI had significantly improved ORR (OR 1.7, 95% CI 1.1-2.5) and PFS (HR 0.59, 95% CI: 0.48-0.74) relative to ICI. Although no significant difference in OS was observed, the analyses revealed that the chemo-ICI patients tended to undergo fewer progression events than ICI patients (HR 0.82, 95% CI 0.6-1.1). In subgroup analysis, the non-squamous, PD-1 inhibitor and first-line treatment cohorts exhibited significant differences in ORR and PFS, but not in OS. However, in the squamous, PD-L1 inhibitor, and previously treated cohorts, PFS, OS and ORR were not different between chemo-ICI and ICI patients.ConclusionsIn conclusion, for non-squamous NSCLC patients, accepting PD-1 as the first-line treatment may be a relatively better option.
| S-EPMC9427994 | biostudies-literature
Project description:PurposeImmune checkpoint inhibitors (ICIs) dramatically changed the prognosis of patients with NSCLC. Unfortunately, a reliable predictive biomarker is still missing. Commonly used biomarkers, such as PD-L1, MSI, or TMB, are not quite accurate in predicting ICI efficacy.MethodsIn this prospective observational cohort study, we investigated the predictive role of erythrocytes, thrombocytes, innate and adaptive immune cells, complement proteins (C3, C4), and cytokines from peripheral blood of 224 patients with stage III/IV NSCLC treated with ICI alone (pembrolizumab, nivolumab, and atezolizumab) or in combination (nivolumab + ipilimumab) with chemotherapy. These values were analyzed for associations with the response to the treatment and survival endpoints.ResultsHigher baseline Tregs, MPV, hemoglobin, and lower monocyte levels were associated with favorable PFS and OS. Moreover, increased baseline basophils and lower levels of C3 predicted significantly improved PFS. The levels of the baseline immature granulocytes, C3, and monocytes were significantly associated with the occurrence of partial regression at the first restaging. Multiple studied parameters (n = 9) were related to PFS benefit at the time of first restaging as compared to baseline values. In addition, PFS nonbenefit group showed a decrease in lymphocyte count after three months of therapy. The OS benefit was associated with higher levels of lymphocytes, erythrocytes, hemoglobin, MCV, and MPV, and a lower value of NLR after three months of treatment.ConclusionOur work suggests that parameters from peripheral venous blood may be potential biomarkers in NSCLC patients on ICI. The baseline values of Tregs, C3, monocytes, and MPV are especially recommended for further investigation.
| S-EPMC10881622 | biostudies-literature
Project description:ImportanceImmune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined.ObjectiveTo examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.Design, setting, and participantsThis retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line.ExposureDeveloping an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs).Main outcomes and measuresThe primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS.ResultsAmong the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001).Conclusions and relevanceIn this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.
| S-EPMC10797458 | biostudies-literature
Project description:IntroductionProgrammed cell death 1 (PD-1) inhibitors have become standard treatment for patients with advanced NSCLC. However, few studies have focused on the impact of cancer cachexia on the efficacy of PD-1 or programmed death-ligand 1 (PD-L1) inhibitors among patients with NSCLC.MethodsWe retrospectively reviewed medical records of patients with advanced NSCLC who received PD-1 or PD-L1 inhibitor monotherapy from May 2016 to December 2018. We defined cancer cachexia as unintentional weight loss greater than 5% over 6 months and high PD-L1 as greater than 50% expression on tumor cells. We evaluated the objective response rates (ORRs) and progression-free survival (PFS).ResultsAmong 108 patients, 52 had cancer cachexia. Patients with cachexia had a lower ORR (15% versus 57%, p < 0.001) and shorter PFS (2.3 mo versus 12.0 mo, p < 0.001) than those without cachexia. Patients with low PD-L1 expression had a lower ORR (14% versus 53%, p < 0.001) and shorter PFS (2.8 mo versus 10.8 mo, p = 0.002) than those with high PD-L1 expression. Multivariate analysis revealed cancer cachexia and low PD-L1 expression as independent negative predictors of PFS. Among patients with cachexia, there was no significant difference in the ORR (p = 0.514) or PFS (p = 0.992) on the basis of PD-L1 expression.ConclusionsOur findings indicate that cancer cachexia might be a negative predictor of the efficacy of PD-1 or PD-L1 inhibitors and reduce the impact of PD-L1 expression on the effect of PD-1 or PD-L1 inhibitors in patients with advanced NSCLC. Further clinical and basic studies are needed.
| S-EPMC8474252 | biostudies-literature
Project description:Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations.
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Project description:Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.
| S-EPMC6097415 | biostudies-literature
Project description:The treatment landscape has changed since the immune checkpoint inhibitors were approved in the treatment of non-small cell lung cancer (NSCLC). Although the promising clinical benefit from programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitors was observed in the second or subsequent line treatment of patients who progressed on chemotherapy, it has a long way for single PD-1/PD-L1 inhibitor to move forward to the frontline without a predictive biomarker. Tumor response is far from satisfactory without selection and primary or acquired resistance to PD-1/PD-L1 inhibitors hampered their utility. Therefore, it is crucial to determine a strategy that can optimize the application of immune checkpoint inhibitors and increase the numbers of the responders. Multiple combination approaches based on PD-1/PD-L1 inhibitors are designed and aimed to boost anti-tumor response and benefit a broader population. In this review, we will integrate the updated clinical data to highlight the four most promising combination strategies in advance NSCLC: combination of checkpoint inhibition with chemotherapy, anti-angiogenesis, immunotherapy and radiotherapy. We further discuss the issues needed to be addressed and perspectives in the context of "combination era".
| S-EPMC5994489 | biostudies-literature
Project description:In the present study, the influence of purely palliative radiotherapy (pRT) on the outcomes of patients with advanced cancer undergoing immune checkpoint blockade was evaluated. Patients were stratified into three groups: Patients who had received pRT within 6 months prior to the initiation of immunotherapy (previous pRT); patients who received pRT during immunotherapy (concurrent pRT); and patients who did not receive RT prior to or during immunotherapy (no RT group), and these groups were compared. The median overall survival (mOS), median progression free survival (mPFS) and median time-to-treatment failure (mTTF) for the previous pRT group were significantly shorter compared with the no RT group (mOS, 3.6 vs. 12.1 months, respectively, P=0.0095; mPFS 1.8 vs. 5.4 months, respectively, P=0.0016; mTTF 1.8 vs. 5.7 months, respectively, P=0.0035). The concurrent pRT group had a longer mTTF compared with the previous pRT group and similar outcomes to the no RT group. In the previous pRT group, 26.9% of the patients experienced immune-related adverse events compared with 40.1% of patients in the no RT group. Despite the use of pRT during immunotherapy being considered safe, the results of the present study suggest that pRT has a negative effect on immune balance.
| S-EPMC6951237 | biostudies-literature