Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study

Rudin, Charles M.; Awad, Mark M.; Navarro, Alejandro; Gottfried, Maya; Peters, Solange; Csőszi, Tibor; Cheema, Parneet K.; Rodríguez-Abreu, Delvys; Wollner, Mirjana; Yang, James Chih‐Hsin; Mazières, Julien; Orlandi, F; Luft, Alexander; Gümüş, Mahmut; Kato, Terufumi; Kalemkerian, Gregory P.; Luo, Yang; Ebiana, Victoria; Pietanza, M. Catherine; Kim, Hye Ryun; Investigators, Keynote

doi:10.1200/jco.20.00793

Cited by 522 publications

(536 citation statements)

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“…The literature search identified a total of 142 records, which, after vetting, resulted in a total of six phase III trials reporting efficacy outcomes on the use of ICIs for the treatment of ES‐SCLC (the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses diagram is shown in Fig. 1) [37, 39, 40, 43, 44, 48].…”

Section: Resultsmentioning

confidence: 99%

“…Four phase III trials assessed ICIs plus chemotherapy as first‐line therapy for ES‐SCLC (Table 1) [37, 40, 43, 48]. CA184 156 randomized patients to receive chemotherapy (etoposide 100 mg/m 2 and cisplatin 75 mg/m 2 or carboplatin area under the curve 5) every 3 weeks for four cycles plus either ipilimumab 10 mg/kg ( n = 478) or placebo ( n = 476) during cycles 3 and 4 followed by ipilimumab or placebo alone for cycles 5 and 6 then maintenance ipilimumab or placebo every 12 weeks for up to 3 years.…”

Section: Resultsmentioning

confidence: 99%

“…The co‐primary endpoints were OS and PFS. With a median follow‐up of 21.6 months, median OS was numerically improved among patients in the pembrolizumab versus placebo arms, although this did not achieve statistical significance according to prespecified criteria (10.8 vs. 9.7 months; HR, 0.80; 95% CI, 0.64─0.98; p = .016; Table 1) [48]. A significant improvement in median PFS was seen among patients receiving pembrolizumab (4.5 vs. 4.3 months; HR, 0.75; 95% CI, 0.61─0.91; p = .0023), and ORRs (70.6% vs. 61.8%), and median DoRs (4.2 vs. 3.7 months) were higher for the pembrolizumab versus placebo groups.…”

Section: Resultsmentioning

confidence: 99%

“…Studies assessing ipilimumab or tremelimumab used with chemotherapy or in combination with a PD‐1/PD‐L1 inhibitor either as first‐line therapy or as first‐line maintenance therapy did not show improved survival [39, 43, 52], nor did the use of nivolumab alone as first‐line maintenance (not formally tested as per protocol) [44]. However, three studies combining PD‐1/PD‐L1 inhibitors with chemotherapy first‐line, IMpower 133, CASPIAN, and KEYNOTE‐604, showed more promise [37, 40, 48]. The three trials were similar in design, and all combined an ICI with chemotherapy and specified survival as a primary endpoint (Table 3).…”

Section: Discussionmentioning

confidence: 99%

“…Initial efficacy signals from phase I/II trials in recurrent SCLC including CheckMate 032, KEYNOTE‐028, and KEYNOTE‐158 [41, 42, 45], led to the approval of nivolumab and pembrolizumab in this setting [46, 47]. The first phase III trial of ICIs for the treatment of ES‐SCLC was reported in 2016 [43], followed by more recent reports from other phase III studies [37, 39, 40, 44, 48]. These new data require a comprehensive analysis of the efficacy and safety of ICIs in this setting with a thorough discussion of clinical implications.…”

Section: Introductionmentioning

confidence: 99%

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Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

et al. 2020

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Background Small cell lung cancer (SCLC) represents approximately 15% of lung cancers, and approximately 70% are diagnosed as extensive‐stage SCLC (ES‐SCLC). Although ES‐SCLC is highly responsive to chemotherapy, patients typically progress rapidly, and there is an urgent need for new therapies. Immune checkpoint inhibitors (ICIs) have recently been investigated in SCLC, and this review provides guidance on the use of these agents in ES‐SCLC based on phase III evidence. Methods Published and presented literature on phase III data addressing use of ICIs in ES‐SCLC was identified using the key search terms “small cell lung cancer” AND “checkpoint inhibitors” (OR respective aliases). Directed searches of eligible studies were periodically performed to ensure capture of the most recent data. Results Six phase III trials were identified, with four assessing the benefits of ICIs plus chemotherapy first‐line, one evaluating ICIs as first‐line therapy maintenance, and one assessing ICI monotherapy after progression on platinum‐based chemotherapy. The addition of ipilimumab or tremelimumab to first‐line treatment or as first‐line maintenance did not improve survival. Two out of three studies combining PD‐1/PD‐L1 inhibitors with first‐line platinum‐based chemotherapy demonstrated significant long‐lasting survival benefits and improved quality of life with no unexpected safety concerns. PD‐1/PD‐L1 inhibitors as first‐line maintenance or in later lines of therapy did not improve survival. Biomarker research is ongoing as well as research into the role of ICIs in combination with radiation therapy in limited‐stage SCLC. Conclusion The addition of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy for ES‐SCLC prolongs survival and improves quality of life. Implications for Practice Platinum‐based chemotherapy has been standard of care for extensive‐stage small cell lung cancer (ES‐SCLC) for more than a decade. Six recent phase III trials investigating immune checkpoint inhibitors (ICIs) have clarified the role of these agents in this setting. Although ICIs were assessed first‐line, as first‐line maintenance, and in later lines of therapy, the additions of atezolizumab or durvalumab to first‐line platinum‐based chemotherapy were the only interventions that significantly improved overall survival and increased quality of life. These combinations should therefore be considered standard therapy for first‐line ES‐SCLC. Biomarker research and investigations into the role of ICIs for limited‐stage disease are ongoing.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

et al. 2020

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Serplulimab With Chemotherapy in Extensive-Stage SCLC

Riely

2022

JAMA

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There is a need to synthesize the available data from the various recently completed clinical trials, and an individual patient data network meta-analysis would assist clinicians to determine which noninvasive respiratory support strategy, if any, is most effective. Furthermore, it is increasingly recognized that the definition of AHRF is broad and captures many different groups of patients. While COVID-19 represents a single disease process, there is increasing evidence that genotypes 13,14 and phenotypes 15 exist and can affect outcome. There is a clear need to incorporate these phenotypes in AHRF and COVID-19-induced AHRF into future trial designs, to determine which subgroups of patients are most likely to derive benefit (or harm) from these therapies.The available evidence suggests that the initial choice of supplemental oxygen therapy for patients with COVID-19-related AHRF does not influence mortality. This will provide some reassurance for clinicians in times of reduced availability of certain noninvasive respiratory support strategies during surges in COVID-19 hospitalizations. Particular attention should be given to the potential for complications with each approach, as well as patient preference and tolerance of the selected therapy.

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Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

Cheng

Liang

et al. 2022

JAMA

207

120

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ImportanceProgrammed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC.ObjectiveTo evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC.Design, Setting, and ParticipantsThis international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021.InterventionsPatients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks.Main Outcomes and MeasuresThe primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P &lt; .012). There were 13 secondary outcomes, including progression-free survival and adverse events.ResultsAmong the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P &lt; .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group.Conclusions and RelevanceAmong patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT04063163

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Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study

Cited by 522 publications

References 18 publications

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

Serplulimab With Chemotherapy in Extensive-Stage SCLC

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

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