Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Riano I
PROVIDER: S-EPMC8293071 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immunotherapy with immune checkpoint inhibitors has opened a new arena in cancer therapeutics. Pembrolizumab is a highly selective anti-programmed cell death protein 1 (PD-1) antibody that has shown efficacy, leading to survival benefit and durable responses, in some patients with non-small cell lung cancer (NSCLC). It has been approved by the US Food and Drug Administration for the treatment of patients with metastatic NSCLC, whose tumors express PD-1 ligand 1 (PD-L1), with disease progression on or after platinum-containing chemotherapy. Here, we briefly discuss the PD-1/PD-L1 pathway and pembrolizumab before delving into the clinical trials that have led to its just-mentioned approval in NSCLC and ongoing clinical trials. Finally, we discuss the use of biomarkers, primarily PD-L1, in the context of pembrolizumab and NSCLC.
| S-EPMC5045223 | biostudies-literature
Project description:Background The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). Taken into account the clinical benefits of pembrolizumab and its high cost, this study aimed to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the US payer perspective. Methods A Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examine the robustness of our model. Results Adding pembrolizumab to standard first-line EP resulted in the better effectiveness than EP chemotherapy alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio (ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerted no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide range of willingness to pay were modest. Conclusion From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compared with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary to improve its cost-effectiveness.
| S-EPMC8592441 | biostudies-literature
Project description:Small cell lung cancer (SCLC) remains a poorly understood disease with aggressive features, high relapse rates, and significant morbidity as well as mortality, yet persistently limited treatment options. For three decades, the treatment algorithm of SCLC has been stagnant despite multiple attempts to find alternative therapeutic options that could improve responses and increase survival rates. On the other hand, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable. In extensive stage SCLC, immunotherapy significantly altered the course of disease and is now part of the treatment algorithm in the first-line setting. Nevertheless, the important questions that arise are how best to implement immunotherapy, who would benefit the most, and finally, how to enhance responses.
| S-EPMC8534845 | biostudies-literature
Project description:BackgroundThe clinical trial of Keynote-604 showed that pembrolizumab plus chemotherapy could generate clinical benefits for extensive-stage small-cell lung cancer (ES-SCLC). We aim to assess the efficacy and cost of pembrolizumab combined with chemotherapy in the first-line treatment setting of ES-SCLC from the United States (US) payers' perspective.MethodsA synthetical Markov model was used to evaluate cost and effectiveness of pembrolizumab plus platinum-etoposide(EP) versus EP in first-line therapy for ES-SCLC from the data of Keynote-604. Lifetime costs life-years(LYs), quality adjusted LYs(QALYs) and incremental cost-effectiveness ratios(ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed. Furthermore, we performed subgroup analysis.ResultsPembrolizumab plus EP resulted in additional 0.18 QALYs(0.32 LYs) and corresponding incremental costs $113,625, resulting an ICER of $647,509 per QALY versus EP. The price of pembrolizumab had a significant impact on ICER. Probabilistic sensitivity analysis indicated that pembrolizumab combined chemotherapy may become a cost-effective option with a probability of 0%. Besides, subgroup analysis suggested that all subgroups were not cost-effective.ConclusionFrom the perspective of the US payer, pembrolizumab plus EP is not a cost-effective option for first-line treatment patients with ES-SCLC at a WTP threshold of $150,000 per QALY.
| S-EPMC8642846 | biostudies-literature
Project description:BackgroundGenomic studies in small-cell lung cancer (SCLC) lag far behind those carried out in nonsmall-cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of 'every-day' SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.Patients and methodsA total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of tumor specimens.ResultsIn all, 39 patients had ES-SCLC; 15 patients had either primary refractory/resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low-frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (P = 0.038) in predicting response to first-line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 with wild-type. Patients with mutant RB1 had both better OS (11.7 versus 9.1 months P = 0.04) and PFS (11.2 versus 8.6 months, P = 0.06) compared with patients with wild-type RB1. Interestingly, ?25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.ConclusionsWe found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.
| S-EPMC4803453 | biostudies-literature
Project description:Extensive stage small cell lung cancer (ES-SCLC) represents approximately half of all diagnosed small cell lung cancer worldwide. It is notorious for a high risk of local recurrence although it's sensitive to chemotherapy. Nearly 90% of intrathoracic failures happen in the first year after diagnosis. The cornerstone of treatment for ES-SCLC is etoposide-platinum based chemotherapy. Consolidative radiotherapy to thorax has diminished the incidence of local relapse, therefore it should be offered to patients with excellent response to induction first-line chemotherapy. This review centers on the clinical evidence for the use of thoracic radiotherapy (TRT) and current modalities of TRT delivery, then tries to determine a feasible way to conduct TRT in a selective group of cases.
| S-EPMC5400661 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ⩾ 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ⩾ 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives.
| S-EPMC5933587 | biostudies-literature
Project description:BackgroundIn recent years, immune checkpoint inhibitors (ICIs) including atezolizumab, durvalumab, pembrolizumab, and nivolumab have reported their efficacy and safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). However, given the diverse efficacy and inconsistent safety among the ICIs, with the absence of head-to-head researches designed to evaluate the efficacy among them, it might bring with confusion on selection in clinical practice.ObjectivesThe present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs, including atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC.DesignSeveral databases were retrieved with established criteria until June 20, 2020, with the main MeSH Terms and their similarities. Hazard ratios of overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) of disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were compared indirectly with network meta-analysis.Data sourcesMedline, Cochrane library, and Embase.Eligibility criteriaProspective, randomized, controlled clinical studies, which reported PFS, OS, and AEs.Data extraction and synthesisClinical characteristics were extracted by the 2 authors independently. Comparisons of HRs were calculated for PFS and OS by random effect model. ORR, DCR, and AEs were presented with ORs. Based on surface under the cumulative ranking curve, and forest plots, efficacy and safety of the treatments were ranked, with predicted histogram described.ResultsIn total, there were 4 studies including 1547 patients who met the eligibility criteria and enrolled. For indirect comparisons, no significant difference on PFS was observed between atezolizumab and durvalumab (HR 0.96, 95% CI, 0.72-1.29), or between atezolizumab and pembrolizumab (HR 1.05, 95% CI, 0.78-1.43), or between atezolizumab and nivolumab (HR 1.18, 95% CI, 0.79-1.79), or between durvalumab and pembrolizumab (HR 1.10, 95% CI, 0.84-1.43). or between durvalumab and nivolumab (HR 1.23, 95% CI, 0.83-1.82), or between pembrolizumab and nivolumab (HR 1.12, 95% CI, 0.76-1.66), nor significant difference on OS observed between atezolizumab and durvalumab (HR 0.93, 95% CI, 0.67-1.30), or between atezolizumab and pembrolizumab (HR 0.88, 95% CI, 0.62-1.24), or between atezolizumab and nivolumab (HR 1.04, 95% CI, 0.66-1.66), or between durvalumab and pembrolizumab (HR 0.94, 95% CI, 0.70-1.25), or between durvalumab and nivolumab (HR 1.12, 95% CI, 0.73-1.71), or between pembrolizumab and nivolumab (HR 1.19, 95% CI, 0.77-1.84). However, durvalumab was shown statistical superiority on ORR when compared with atezolizumab (HR 0.79, 95% CI, 0.64-0.98), also with significantly higher risk on immune-related AEs when compared with atezolizumab (OR 0.22, 95% CI, 0.10-0.50), and pembrolizumab (OR 3.12, 95% CI, 1.27-7.64).ConclusionsResults of the study revealed that there was no statistical difference on PFS or OS among agents of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. However, durvalumab was shown superiority on ORR when compared with atezolizumab, also with significantly higher risk on immune-related AEs.
| S-EPMC8051984 | biostudies-literature
Project description:IntroductionThe combination of a PD-L1 inhibitor plus carboplatin/cisplatin and etoposide (EC/EP) has become a new standard first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). Combining concurrent palliative hypofractionated radiotherapy of the thorax (HFRT) and immunochemotherapy may have a synergistic effect. In this study, we explored an optimal model of combination radiotherapy with immunochemotherapy as first-line treatment of ES-SCLC.Patients and methodsIn this multicenter single-arm phase 2 trial, patients with ES-SCLC received atezolizumab with EC/EP for two cycles (induction phase), then, those who did not progress received concurrent palliative HFRT and two cycles of atezolizumab with EC/EP (combination phase). Afterward they received atezolizumab every 3 weeks for a maximum of 2 years after study enrolment (maintenance phase). Prophylactic cranial irradiation (PCI) was recommended. The primary endpoints were safety and tolerance; the second endpoints were progression-free survival (PFS).ResultsForty patients were enrolled, and all had completed palliative HFRT and four cycles of immunochemotherapy. There were seven grade 3 adverse events (3 decreased neutrophil count, 1 anemia, 2 pneumonitis, 1 esoenteritis), two grade 4 adverse events (2 decreased white cell count) and no grade 5 toxicities. The pneumonitis rate was 12.5% (three grade 2 and two grade 3 events). At the median follow-up of 14.2 months (range, 6.8-28.7), the median PFS was 8.6 months (95%CI, 6.1-11.1).ConclusionThe addition of concurrent hypofractionated thoracic radiotherapy to first-line immunochemotherapy for ES-SCLC was well tolerated and showed promising clinical efficacy. Additional randomized trials are needed to validate benefits.Clinical trial registrationhttps://clinicaltrials.gov/ (NCT04636762).
| S-EPMC10282832 | biostudies-literature
Project description:The prevalence of small cell lung cancer (SCLC) has declined in the U.S. as the prevalence of tobacco use has declined. However, a significant number of people in the U.S. are current or former smokers and are at risk of developing SCLC. Routine histological or cytological evaluation can reliably make the diagnosis of SCLC, and immunohistochemistry stains (thyroid transcription factor-1, chromogranin, synaptophysin, and CD56) can be used if there is uncertainty about the diagnosis. Rarely do patients present with SCLC amendable to surgical resection, and evaluation requires a meticulous workup for extra-thoracic metastases and invasive staging of the mediastinum. Resected patients require adjuvant chemotherapy and/or thoracic radiation therapy (TRT), and prophylactic cranial radiation (PCI) should be considered depending on the stage. For limited-stage disease, concurrent platinum-etoposide and TRT followed by PCI is the standard. Thoracic radiation therapy should be started early in treatment, and can be given twice daily to 45 Gy or once daily to 60-70 Gy. For extensive-stage disease, platinum-etoposide remains the standard first-line therapy, and the standard second-line therapy is topotecan. Preliminary studies have demonstrated the activity of immunotherapy, and the response rate is approximately 10-30% with some durable responses observed. Rovalpituzumab tesirine, an antibody drug conjugate, has shown promising activity in patients with high delta-like protein 3 tumor expression (approximately 70% of patients with SCLC). The emergence of these and other promising agents has rekindled interest in drug development in SCLC. Several ongoing trials are investigating novel agents in the first-line, maintenance, and second-line settings.Implications for practiceThis review will provide an update on the standard therapies for surgically resected limited-stage small cell lung cancer and extensive-stage small cell lung cancer that have been investigated in recent clinical trials.
| S-EPMC5728020 | biostudies-literature