Durvalumab: A Review in Extensive-Stage SCLC.
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ABSTRACT:
SUBMITTER: Al-Salama ZT
PROVIDER: S-EPMC8648650 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionSystemic treatment with chemotherapy is warranted for patients with extensive-stage SCLC (ES-SCLC). The objective of this study was to determine whether racial and other healthcare disparities exist in receipt of chemotherapy for ES-SCLC.MethodsUtilizing the National Cancer Database, 148,961 patients diagnosed to have stage IV SCLC from 2004 to 2016 were identified. Adjusted ORs with 95% confidence intervals (95% CIs) were computed for receipt of chemotherapy using multivariate logistic regression modeling. Cox regression modeling was used to perform overall survival analysis, and adjusted hazard ratios were calculated.ResultsA total of 82,592 patients were included, among which chemotherapy was not administered to 6557 (7.9%). Higher education, recent year of diagnosis, and treatment at more than one facility were associated with increased odds of receiving chemotherapy. Factors associated with a decreased likelihood of receiving chemotherapy were increasing age, race, nonprivate insurance, and comorbidities. On multivariate analysis, black patients had lower odds of receiving chemotherapy compared with white patients (adjusted OR, 0.85; 95% CI: 0.77-0.93, p = 0.0004). Furthermore, black patients had better survival compared with white patients (adjusted hazard ratio, 0.91; 95% CI: 0.89-0.94, p = 0.91). The 1-year survival (median survival) for black and white patients was 31.7% (8.3 mo) and 28.6% (8 mo), respectively.ConclusionsBlack patients with ES-SCLC were less likely to receive chemotherapy, as were elderly, uninsured, and those with nonprivate insurance. Further studies are required to address underlying reasons for lack of chemotherapy receipt in black patients with ES-SCLC and guide appropriate interventions to mitigate disparities.
| S-EPMC8474393 | biostudies-literature
Project description:IntroductionDespite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients.MethodsA total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing.ResultsAmong patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load.ConclusionsExpression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC.Clinical trial registrationUMIN000041056.
| S-EPMC9356091 | biostudies-literature
Project description:IntroductionThe real-world data evaluating treatment outcomes of atezolizumab plus carboplatin-etoposide chemotherapy (atezolizumab) for extensive-stage SCLC (ESCLC) are lacking. Our objective was to evaluate real-world outcomes of ESCLC treated with atezolizumab.MethodsA retrospective analysis of provincial patients with ESCLC who started first-line (1L) systemic treatment was conducted. We primarily evaluated the progression-free survival (PFS) and overall survival (OS) outcomes in association with atezolizumab compared with platinum-etoposide chemotherapy (chemotherapy) while adjusting for relevant demographic and clinical factors. Adverse events (AEs) during 1L were evaluated.ResultsA total of 67 patients were identified. Of the 34 patients who received atezolizumab, 24% had Eastern Cooperative Oncology Group performance status greater than or equal to 2, approximately 50% were more than or equal to 65 years, 21% received cisplatin-etoposide chemotherapy before atezolizumab, and 12% had thoracic radiation (tRT).Within the atezolizumab versus chemotherapy group, the median PFS equals to 6.0 versus 4.3 months (p = 0.03) whereas OS = 12.8 versus 7.1 months (p = 0.01). Relative to chemotherapy, the hazard ratio (95% confidence interval) for PFS was 0.53 (0.28-1.02) and OS was 0.42 (0.20-0.88) with atezolizumab. tRT compared with no tRT receipt correlated with reduced death risk (hazard ratio [95% confidence interval] = 0.33 [0.13-0.88]).AE-related treatment withdrawal with atezolizumab was 32% and 15% with chemotherapy (p = 0.02). Within the tRT subgroup, 25% versus 20% in atezolizumab versus chemotherapy group, respectively, discontinued 1L owing to AE.ConclusionsThis is the first real-world study revealing comparable survival with that in the IMpower133 trial. Treatment discontinuation from AEs was higher with atezolizumab among Canadian patients with ESCLC. Our data suggest safe use of tRT and chemoimmunotherapy, but its efficacy for ESCLC warrants further study.
| S-EPMC8628038 | biostudies-literature
Project description:BackgroundImmunotherapy has made significant advances in the treatment of extensive-stage small-cell lung cancer (ES-SCLC), but data in combination with radiotherapy are scarce. This study aims to assess the safety and efficacy of chemoimmunotherapy combined with thoracic radiotherapy in patients with ES-SCLC.MethodsThis single-center retrospective study analyzed patients with ES-SCLC who received standard platinum-etoposide chemotherapy combined with atezolizumab or durvalumab immunotherapy as induction treatment, followed by consolidative thoracic radiotherapy (CTRT) before disease progression in the first-line setting. Adverse events during radiotherapy with or without maintenance immunotherapy and survival outcomes were assessed.ResultsBetween December 2019 and November 2021, 36 patients with ES-SCLC were identified to have received such treatment modality at one hospital. The number of metastatic sites at diagnosis was 1-4. The biological effective dose of CTRT ranged from 52 to 113 Gy. Only two patients (6%) developed grade 3 toxic effect of thrombocytopenia, but none experienced grade 4 or 5 toxicity. Four patients developed immune-related pneumonitis during the induction treatment period but successfully completed later CTRT. The rate of radiation-related pneumonitis was 8% with grades 1-2 and well tolerated. The median progression-free survival (PFS) was 12.8 months, but the median overall survival (OS) was not determined. The estimated 1-year OS was 80.2% and 1-year PFS was 53.4%.ConclusionsImmunotherapy combined with CTRT for ES-SCLC is safe and has ample survival benefit.
| S-EPMC10080806 | biostudies-literature
Project description:BackgroundIn the phase 3 CASPIAN study (NCT03043872), first-line durvalumab plus etoposide and cisplatin or carboplatin (EP) significantly improved OS versus EP alone in patients with extensive-stage (ES)-SCLC (HR 0.73 [95% CI 0.59-0.91; p = 0.0047]). Here we report results for a preplanned subgroup analysis of patients recruited in Japan.MethodsTreatment-naïve patients with ES-SCLC received either 4 cycles of durvalumab 1500 mg plus EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression or up to 6 cycles of EP q3w. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability.ResultsIn the Japan subgroup, 18 patients were randomized to durvalumab plus EP and 16 patients to EP. At the interim analysis with a median follow-up of 12.5 months in the subgroup, OS numerically favored durvalumab plus EP versus EP (HR 0.77 [95% CI 0.26‒2.26]; median not reached vs 15.2 months). PFS was similar for durvalumab plus EP versus EP (HR 0.90 [95% CI 0.43‒1.89]). Confirmed ORR was 89% with durvalumab plus EP versus 69% with EP. Adverse events (AEs) of CTCAE grade 3 or 4 were reported in 78% versus 94% of patients in the durvalumab plus EP versus EP arms. There were no AEs leading to treatment discontinuation or death in the Japan subgroup.ConclusionFirst-line durvalumab plus EP was effective and well tolerated in Japanese patients with ES-SCLC. Despite the small size of the Japan subgroup, results were generally consistent with the global study population.
| S-EPMC8134304 | biostudies-literature
Project description:The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting. A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan-Meier method. Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months. Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.
| S-EPMC11293570 | 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:BackgroundOnly few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial.MethodsPre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR).ResultsIn ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07).ConclusionsAdipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.
| S-EPMC10576666 | biostudies-literature
Project description:PurposeDespite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade.MethodsA single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells in direct contact with tumor).ResultsA total of 20 patients were enrolled. Their median age was 64 years, and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, two were observed to have partial or complete responses (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four patients (21.1% [95% confidence interval: 6.1%-45.6%]) with confirmed responses or prolonged stable disease (≥8 months). The most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leukopenia (50%). Nine of 14 tumors (64%) exhibited an excluded phenotype; 21% and 14% of tumors exhibited the inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no during-treatment increase in T-cell infiltration or programmed death ligand 1 expression on tumor-infiltrating immune cells was observed.ConclusionsThe study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.
| S-EPMC6660419 | biostudies-literature
Project description:Background and objectivesDurvalumab and atezolizumab are approved as first-line therapy in extensive-stage small-cell lung cancer. Although cost-effectiveness analyses compared these immunotherapy drugs with standard chemotherapy-alone regimens, no head-to-head cost-effectiveness comparisons for these treatments exist. The aim of the present analysis is to determine the cost-effectiveness of durvalumab and atezolizumab as first-line therapy for extensive-stage small-cell lung cancer from the US payers' perspective.MethodsThis study is based on two placebo-controlled, phase 3 clinical trials: CASPIAN and IMpower133. A Markov model was developed to simulate the three health states: progression-free survival, progressed disease, and death in patients with extensive-stage small-cell lung cancer. Transition probabilities were estimated from the clinical trial survival curves and extended with life-time modelling. Health utilities and direct costs of adverse event treatment were included. Main outcome was the incremental cost-effectiveness ratio (ICER) using quality-adjusted life-years saved (QALYS). Sensitivity analysis was performed to assess the impact of variables on the ICER.ResultsDurvalumab group has a cost of $187,503 with an effectiveness of 1.08 while atezolizumab has a cost of $160,219 and an effectiveness of 0.932. Durvalumab is not cost-effective compared to atezolizumab with an ICER of $165,182 QALYS, which is over the willingness-to-pay threshold of $150,000. The model was most sensitive to durvalumab cost and the cost of treating durvalumab adverse effects.ConclusionsWith the ICER of durvalumab treatment group being very close to $150,000, setting a higher willingness-to-pay threshold or decreasing the drug cost through contract pricing can increase the cost-effectiveness of durvalumab compared to atezolizumab.
| S-EPMC9188525 | biostudies-literature