Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: A retrospective multicenter cohort study in Japan
Ryuya EdahiroMasaki KanazuHiroyuki KurebeMasahide MoriDaichi FujimotoYoshihiko TaniguchiHidekazu SuzukiKatsuya HiranoToshihide YokoyamaMitsunori MoritaYasushi FukudaJunji UchidaTakeshi MakioMotohiro Tamiya
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Background Pembrolizumab is currently approved as a first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with a programed death ligand-1 (PD-L1) expression ≥50%. However, the association between the efficacy of pembrolizumab and PD-L1 expression levels in patients with PD-L1 expression ≥50% has not been fully elucidated. Methods We retrospectively analyzed patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% who received pembrolizumab as a first-line therapy at 11 institutions in Japan between February 2017 and January 2018. Patients were divided into TPS 50–89% and TPS 90–100% (ultra-high PD-L1 expression) cohorts. Results In total, 149 patients were included: 99 (66.4%) and 50 (33.6%) patients were in the TPS 50–89% and TPS 90–100% cohorts, respectively. Baseline characteristics were similar between the TPS 90–100% and TPS 50–89% cohorts. The objective response rates (ORR) in the TPS 90–100% and TPS 50–89% cohorts were 58.0% and 46.5%, respectively (p = 0.23). Time to treatment failure (TTF) was longer in the TPS 90–100% cohort than in the TPS 50–89% cohort (hazard ratio [HR]: 0.67, 95% confidence interval (CI): 0.42–1.07; p = 0.09). Although TTF within 120 days after the initiation of pembrolizumab therapy was comparable between both cohorts (p = 0.54), TTF after 120 days was significantly longer in the TPS 90–100% cohort than in the TPS 50–89% cohort (HR: 0.22, 95% CI: 0.06–0.87; p = 0.031). Immune related adverse events of grade 3 or more occurred in 16.0% and 19.2% of patients in the TPS 90–100% and TPS 50–89% cohorts, respectively. Conclusions The patients with an ultra-high PD-L1 expression continued pembrolizumab therapy longer, driven by a reduced risk of treatment failure in the late phase. PD-L1 expression levels might be a predictive biomarker of a first-line immunotherapy benefit in the late phase among NSCLC patients with TPS ≥50%.Pembrolizumab is an approved first-line systemic therapy for unresectable metastatic melanoma. Despite the achievement of complete and durable responses in a small subgroup of patients, it is standard practice that pembrolizumab therapy continues beyond complete response. Nevertheless, the incidence of immune-related toxicities gradually increases with continuing pembrolizumab therapy. We report a case highlighting the occurrence of serious induced immune-related adverse events, which were attributed to pembrolizumab in a patient with metastatic melanoma who obtained a complete response (CR) after receiving pembrolizumab for a total of 6.5 months. Although mild pembrolizumab-related toxicity persists, the patient remains disease-free 5.5 months after discontinuation of pembrolizumab. Accordingly, we believe that cessation of pembrolizumab should be considered in patients who achieve a CR because of the ongoing risk of toxicity with extended pembrolizumab administration.
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Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown.To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers.Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse.From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.
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We conducted a meta-analysis to systematically review the efficacy and safety of pembrolizumab for advanced NSCLC. Databases were searched for randomized controlled trials (RCTs) treated with pembrolizumab till July 2021. Seven RCTs and 3988 patients were included. Our analysis suggests that pembrolizumab was more effective at improving PFS (HR, 0.59; 95% CI: 0.43-0.79; p = 0.0005), OS (HR, 0.65; 95% CI: 0.55-0.76; p ＜ 0.00001) and ORR (RR, 1.85; 95% CI: 1.64-2.09; p ＜ 0.00001) than chemotherapy. Patients with higher PD-L1 expression level were tend to have a better PFS, OS and ORR. Combination therapy of pembrolizumab was superior to pembrolizumab monotherapy in enhancing PFS. Pembrolizumab did not increase the frequency of commonly reported adverse events, but the immune-related adverse events (irAEs) occurred more frequently in the pembrolizumab group than those in the chemotherapy group. The pembrolizumab significantly improved the PFS, OS and ORR, simultaneously increasing the irAEs.
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Background and objectives Sedentary behavior is associated with increased mortality in the general population. Whether replacing sedentary behavior with low- or light-intensity activities confers a survival benefit in the general or CKD populations is unknown. Design, setting, participants, & measurements This observational analysis of the 2003–2004 National Health and Nutrition Examination Survey examined the associations of low- and light-intensity activities with mortality. On the basis of the number of counts/min recorded by an accelerometer, durations of sedentary (<100/min), low (100–499/min), light (500–2019/min), and moderate/vigorous (≥2020/min) activity were defined and normalized to 60 minutes. The mortality associations of 2 min/hr less sedentary duration in conjunction with 2 min/hr more (tradeoff) spent in one of the low, light, or moderate/vigorous activity durations while controlling for the other two activity durations were examined in multivariable Cox regression models in the entire cohort and in the CKD subgroup. Results Of the 3626 participants included, 383 had CKD. The mean sedentary duration was 34.4±7.9 min/hr in the entire cohort and 40.8±6.8 in the CKD subgroup. Tradeoff of sedentary duration with low activity duration was not associated with mortality in the entire cohort or the CKD subgroup. Tradeoff of sedentary duration with light activity duration was associated with a lower hazard of death in the entire cohort (hazard ratio, 0.67; 95% confidence interval, 0.48 to 0.93) and CKD subgroup (hazard ratio, 0.59; 95% confidence interval, 0.35 to 0.98). Tradeoff of sedentary duration with moderate/vigorous activity duration had a nonsignificant lower hazard in the entire cohort and CKD subgroup. Conclusions Patients with CKD are sedentary nearly two thirds of the time. Interventions that replace sedentary duration with an increase in light activity duration might confer a survival benefit.
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Background and objectives
Sedentary behavior is associated with increased mortality in the general population. Whether replacing sedentary behavior with low- or light-intensity activities confers a survival benefit in the general or CKD populations is unknown.Design, setting, participants, & measurements
This observational analysis of the 2003–2004 National Health and Nutrition Examination Survey examined the associations of low- and light-intensity activities with mortality. On the basis of the number of counts/min recorded by an accelerometer, durations of sedentary (<100/min), low (100–499/min), light (500–2019/min), and moderate/vigorous (≥2020/min) activity were defined and normalized to 60 minutes. The mortality associations of 2 min/hr less sedentary duration in conjunction with 2 min/hr more (tradeoff) spent in one of the low, light, or moderate/vigorous activity durations while controlling for the other two activity durations were examined in multivariable Cox regression models in the entire cohort and in the CKD subgroup.Results
Of the 3626 participants included, 383 had CKD. The mean sedentary duration was 34.4±7.9 min/hr in the entire cohort and 40.8±6.8 in the CKD subgroup. Tradeoff of sedentary duration with low activity duration was not associated with mortality in the entire cohort or the CKD subgroup. Tradeoff of sedentary duration with light activity duration was associated with a lower hazard of death in the entire cohort (hazard ratio, 0.67; 95% confidence interval, 0.48 to 0.93) and CKD subgroup (hazard ratio, 0.59; 95% confidence interval, 0.35 to 0.98). Tradeoff of sedentary duration with moderate/vigorous activity duration had a nonsignificant lower hazard in the entire cohort and CKD subgroup.Conclusions
Patients with CKD are sedentary nearly two thirds of the time. Interventions that replace sedentary duration with an increase in light activity duration might confer a survival benefit.Subgroup analysis
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Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and −189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.
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Pembrolizumab is an immune checkpoint inhibitor (programmed cell death 1) approved for use in non-small cell lung carcinoma (NSCLC). Pembrolizumab has shown remarkable results in regression of the size of tumors in NSCLC and has shown survival advantage. However, immune-related adverse effects are a serious negative outcome of therapy. The number of immune-related adverse effects with pembrolizumab has increased significantly over the recent past. We present a case of type 1 diabetes mellitus and autoimmune thyroiditis with pembrolizumab treatment for NSCLC.
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Pembrolizumab is a novel immune checkpoint inhibitor approved for use in non-small cell lung carcinoma. There have been a few cases that have associated adverse renal outcomes with pembrolizumab. We present a case of acute kidney injury in a patient on pembrolizumab who was noted to have acute tubulointerstitial nephritis on renal biopsy. Pembrolizumab was discontinued and the patient was started on long-term corticosteroids with a taper. Her renal function improved partially with treatment.
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Pembrolizumab is an approved first-line systemic therapy for unresectable metastatic melanoma. Despite the achievement of complete and durable responses in a small subgroup of patients, it is standard practice that pembrolizumab therapy continues beyond complete response. Nevertheless, the incidence of immune-related toxicities gradually increases with continuing pembrolizumab therapy. We report a case highlighting the occurrence of serious induced immune-related adverse events, which were attributed to pembrolizumab in a patient with metastatic melanoma who obtained a complete response (CR) after receiving pembrolizumab for a total of 6.5 months. Although mild pembrolizumab-related toxicity persists, the patient remains disease-free 5.5 months after discontinuation of pembrolizumab. Accordingly, we believe that cessation of pembrolizumab should be considered in patients who achieve a CR because of the ongoing risk of toxicity with extended pembrolizumab administration.
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The effects of immune checkpoint inhibitors have been reported to be linked with immune-related adverse events (irAEs). In patients with advanced non-small-cell lung cancer, who tested positive for programmed death-ligand 1 (PD-L1), pembrolizumab, an immune checkpoint inhibitor can be used as a treatment, and it was found to improve overall survival. However, there are only a few reports on the relationship between the therapeutic effects of pembrolizumab in patients with lung cancer and the irAEs of pembrolizumab. The purpose of this study was to determine the correlation between immune-related adverse events and the effects of pembrolizumab monotherapy in patients with non-small-cell lung cancer.From February 2017 to August 2019, we conducted a retrospective analysis of the effects of pembrolizumab treatment and immune-related adverse events in 94 patients with non-small-cell lung cancer treated with pembrolizumab only.In 63 cases, irAEs were observed. The most common irAE was rash. PD-L1 positivity ≥ 50% tended to cause irAEs. The median progression-free survival (PFS) rates with and without irAEs were 371 days (95% CI, 184-NR) and 67 days (95% CI, 51-87 days), respectively. In a multivariate analysis, irAEs and Eastern Cooperative Oncology Group performance status (PS) were the factors related to PFS.In patients with lung cancer, who were treated with pembrolizumab monotherapy, the development of irAEs was likely indicative of the positive effects of pembrolizumab. This novel finding appears to be useful for clinicians who work with pembrolizumab for lung cancer treatment.
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