Patient-Reported Health-Related Quality of Life in KEYNOTE-604: Pembrolizumab or Placebo Added to Etoposide and Platinum as First-Line Therapy for Extensive-Stage SCLC
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SUBMITTER: Kim H
PROVIDER: S-EPMC10637979 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Project description:PurposePembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.MethodsEligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS.ResultsOf the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.ConclusionPembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
| S-EPMC7474472 | biostudies-literature
Project description:BackgroundIn patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results.Patients and methodsIn KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score.ResultsNo clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (-2.5; 95% CI -5.2 to 0.1), EORTC QLQ-C30 physical functioning (-0.87; 95% CI -2.7 to 1.0), and FKSI-DRS (-0.7; 95% CI -1.2 to -0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%).ConclusionsAdjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy.Trial registrationClinicaltrials.gov Identifier: NCT03142334.
| S-EPMC10836324 | 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:Introduction To date, the efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy for patients with extensive-stage SCLC (ES-SCLC), with real-world evidence, stratified on the basis of age and performance status (PS), have not been fully investigated. The aim of this study was to evaluate the efficacy and safety of PD-L1 inhibitor plus platinum-etoposide chemotherapy in patients with ES-SCLC. Methods This multicenter prospective study evaluated patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy between September 2019 and October 2021. Results A total of 45 patients with ES-SCLC received the aforementioned treatment, including 18 elderly (≥75 y old) patients and six patients with a PS of 2. Multivariate analysis indicated that a PS of 2 was a significant independent prognostic factor for progression-free survival and overall survival (p = 0.008 and p = 0.001, respectively). Of patients with PS of 2 at the initial phase, those that achieved PS improvement during treatment had significantly longer progression-free survival and overall survival than those who did not (p = 0.02 and p = 0.02, respectively). The incidence of adverse events accompanied with treatment discontinuation was significantly higher in the elderly patients than in the non-elderly patients (p = 0.03). Conclusions This real-world prospective study found that PD-L1 inhibitor plus platinum-etoposide chemotherapy had limited efficacy in patients with ES-SCLC with a PS of 2, except for cases with improvement of PS during treatment. Owing to the emergence of adverse events and treatment discontinuation, this treatment should be administered with caution in elderly patients with ES-SCLC.
| S-EPMC9250020 | biostudies-literature
Project description:IntroductionIn the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases.MethodsPatients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of durvalumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophylactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020.ResultsAt baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radiotherapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophylactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%).ConclusionsThe OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.
| S-EPMC9204731 | biostudies-literature
Project description:BackgroundThe aim of the present study was to evaluate the cost-effectiveness of durvalumab plus platinum-etoposide versus platinum-etoposide as first-line treatments for small-cell lung cancer from the perspective of the US payer.MethodsThis study established a partition survival model for three health states, metastasis probability, and safety data based on the CASPIAN clinical trial. The health utility value was mainly derived from the published literature. Only direct medical costs were considered. Sensitivity analyses were conducted to assess the robustness of the incremental cost per quality-adjusted life year (QALY).ResultsDurvalumab plus platinum-etoposide increased QALY by 0.220 compared to that observed with platinum-etoposide only. The cost increased by $78,198.75 and the incremental cost per QALY increased by $355,448.86. One-way and probability sensitivity analyses indicated that the model parameters varied within a limited range and had no significant effect on the results.ConclusionsAlthough durvalumab plus platinum-etoposide can improve quality of life, it also substantially increases the cost of medical treatment. Under a willingness-to-pay threshold of $100,000, durvalumab does not have a cost-effective comparative advantage.
| S-EPMC7747765 | biostudies-literature
Project description:Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator's choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co-primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7-38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9-29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07-1.15). The median (95% CI) PFS was 16.5 (8.8-21.1) compared with 7.1 (4.7-21.4) months (HR, .62; 95% CI, .27-1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.
| S-EPMC8353942 | biostudies-literature
Project description:Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov).
| S-EPMC8411394 | biostudies-literature
Project description:BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%.MethodsECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTarget enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent.ConclusionsEpacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted.Trial registrationClinicalTrials.gov, NCT03374488. Registered 12/15/2017.
| S-EPMC11270759 | biostudies-literature
Project description:IntroductionIn recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy.MethodsWe prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses.ResultsThe responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12-0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13-0.85, p = 0.02).ConclusionsOur prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.
| S-EPMC10070895 | biostudies-literature