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• W3137201154 abstract "•ICIs have shifted the treatment paradigm to improve overall survival in advanced SCLC.•The magnitude of immune-chemotherapy strategy is still modest. The immunosuppressive phenotype of SCLC hamper ICI efficacy.•Efficacy of this new SoC in some subgroups of patients is challenging as well as new immunotherapeutic strategies. Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients. Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients. Small-cell lung cancer (SCLC) comprises about 15% of all new lung cancers and smoking is strongly associated with the risk of developing it. Although the incidence is higher in males, the incidence gap between males and females has narrowed over the past three decades.1Govindan R. Page N. Morgensztern D. et al.Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.J Clin Oncol. 2006; 24: 4539-4544Crossref PubMed Scopus (1328) Google Scholar Platinum-based chemotherapy is the standard of care for both limited disease (LD) and extensive disease (ED), with platinum plus etoposide combination the preferred regimen. The 1- and 2-year overall survival (OS) rates in LD-SCLC are 58% and 21%, respectively, whereas for ED-SCLC, they are 29.4% and 7% in ED-SCLC, respectively.2Amarasena I.U. Chatterjee S. Walters J.A.E. et al.Platinum versus non-platinum chemotherapy regimens for small cell lung cancer.Cochrane Database Syst Rev. 2015; 8: CD006849Google Scholar After over two decades without any breakthrough therapeutic strategies and no improvement in patient outcomes, the introduction of immune checkpoint inhibitors (ICIs), including inhibitors of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), is a welcome relief, shifting the therapeutic armamentarium and improving survival in ED-SCLC patients. Nonetheless, approvals differ between the American (Food and Drug Administration; FDA) and European (European Medicines Agency; EMA) health authorities (Figure 1). In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges and perspectives of immunotherapeutic strategies in these patients. Genomic profiling of SCLC has identified two defective tumor suppressor genes (p53 and RB1) that induce genomic instability, thus perpetuating the generation of tumor-associated antigens.3George J. Lim J.S. Jang S.J. et al.Comprehensive genomic profiles of small cell lung cancer.Nature. 2015; 524: 47-53Crossref PubMed Scopus (960) Google Scholar Long-term exposure to carcinogens from smoking induces smoking signatures (such as C:G > A : T transversions in up to one-third of patients3George J. Lim J.S. Jang S.J. et al.Comprehensive genomic profiles of small cell lung cancer.Nature. 2015; 524: 47-53Crossref PubMed Scopus (960) Google Scholar) and places SCLC among the tumor types with one of the highest mutational loads4Alexandrov L.B. Nik-Zainal S. Wedge D.C. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (5303) Google Scholar [median 8.6 non-synonymous mutations per megabase, (mut/Mb)]. Moreover, the presence of paraneoplastic syndromes exhibiting anti-Hu autoimmune responses suggests that SCLC may be an immunogenic tumor type. This premise is based on data obtained in non-small-cell lung cancer (NSCLC), where elevated tumor mutational burden (TMB) is associated with a higher likelihood of benefit with ICIs.5Rizvi H. Sanchez-Vega F. La K. et al.Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 633-641Crossref PubMed Scopus (637) Google Scholar Furthermore, in NSCLC, an association between an improved outcome with pembrolizumab and a genomic signature linked to smoking has been reported, characterized by high frequency of transversion, while the self-reported smoking history did not significantly predict the clinical outcome within the same population.6Rizvi N.A. Hellmann M.D. Snyder A. et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Crossref PubMed Scopus (4698) Google Scholar Likewise, for NSCLC, neoantigen intratumor heterogeneity impacts on tumor immunogenicity, and sensitivity to ICIs is enhanced in tumors enriched for clonal neoantigens, which are mainly induced by smoking.7McGranahan N. Furness A.J.S. Rosenthal R. et al.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469Crossref PubMed Scopus (1592) Google Scholar Chemotherapy may induce immunogenic cell death, which prompts the release of tumor antigens in the tumor microenvironment (TME), as well as damage-associated molecular patterns, and pro-inflammatory cytokines,8Rapoport B.L. Anderson R. Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.Int J Mol Sci. 2019; 20: 959Crossref Scopus (53) Google Scholar potentially increasing the immunogenicity of the tumor. In this context, cisplatin promotes tumor infiltration with antigen-presenting cells that express high levels of T-cell co-stimulatory ligands,9Beyranvand Nejad E. van der Sluis T.C. van Duikeren S. et al.Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells.Cancer Res. 2016; 76: 6017-6029Crossref PubMed Scopus (74) Google Scholar upregulates lytic activity of cytotoxic T cells and depletes immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) and Tregs.10de Biasi A.R. Villena-Vargas J. Adusumilli P.S. Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence.Clin Cancer Res. 2014; 20: 5384-5391Crossref PubMed Scopus (145) Google Scholar Based on this hypothetical chemotherapeutic booster of immune cell death, the combination of chemotherapy plus ICI has also been tested in SCLC. Based on a 2-year OS rate of ∼20% in SCLC patients reported in the CheckMate 032 trial11Ready N.E. Ott P.A. Hellmann M.D. et al.Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort.J Thorac Oncol. 2020; 15: 426-435Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and in the pooled analyses from phase Ib KEYNOTE 028 and phase II KEYNOTE 158 trials,12Chung H.C. Piha-Paul S.A. Lopez-Martin J. et al.Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies.J Thorac Oncol. 2020; 15: 618-627Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar the FDA (but not the EMA) initially approved both nivolumab (in 2018) and pembrolizumab (in 2019) as third-line treatments in ED-SCLC patients (Table 1; Figure 1). Indeed, in this setting in the randomized cohort of the CheckMate 032 trial, although nivolumab plus ipilimumab yielded a higher response rate (RR; the primary endpoint of the study), compared with nivolumab alone (22% versus 12%), this combination failed to show any OS advantage11Ready N.E. Ott P.A. Hellmann M.D. et al.Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort.J Thorac Oncol. 2020; 15: 426-435Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar (Table 1). In a pooled exploratory analysis from the CheckMate 032 trial, tumors with high-level tissue tumor mutational burden (tTMB) achieved greater efficacy with the nivolumab plus ipilimumab combination than with nivolumab alone; PD-L1 expression in tumor cells (measured by the 28-8 antibody) did not correlate with outcome for either treatment arm.13Hellmann M.D. Callahan M.K. Awad M.M. et al.Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer.Cancer Cell. 2018; 33: 853-861.e4Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar Conversely, in the KEYNOTE 158 trial, improved RR and longer OS were reported with pembrolizumab in SCLC tumors with PD-L1 ≥1% [assessed by the 22C3 antibody and measured using the combined positive score (CPS)], compared with tumors with PD-L1 <1% (33% versus 6% and 14.9 months versus 5.9 months, respectively).14Chung H.C. Lopez-Martin J.A. Kao S.C.-H. et al.Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158.J Clin Oncol. 2018; 36: 8506Crossref Google Scholar In the overall KEYNOTE 158 basket trial, pembrolizumab had better outcomes for all tumor types with high tTMB (≥10 mut/Mb, including 34 patients with SCLC),15Marabelle A. Fakih M. Lopez J. et al.Association of mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.Lancet Oncol. 2020; 21: 1353-1365Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar leading to FDA approval of pembrolizumab in previously treated tumors with high tTMB. It remained speculative whether the long-term survival tail with anti-PD-1 in the third-line setting was real or just a spurious effect related to the over-selection of patients with good prognostic factors enrolled in the phase I/II trials, in the absence of a control arm. In pretreated SCLC patients, other phase I/II trials with atezolizumab (IFCT1603 trial), durvalumab and durvalumab plus tremelimumab (BALTIC trial) have not reported clinically meaningful results. Likewise, the phase III CheckMate 331 trial16Spigel D.R. Vicente D. Ciuleanu T.E. et al.Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331.Ann Oncol. 2021; https://doi.org/10.1016/j.annonc.2021.01.071Abstract Full Text Full Text PDF Scopus (27) Google Scholar evaluating nivolumab versus topotecan or amrubicin in relapsed SCLC patients after platinum-based chemotherapy, did not achieve improvement in either OS, the primary endpoint [hazard ratio (HR) 0.86; 95% confidence interval (CI): 0.72-1.04, P = 0.11], in progression-free survival (PFS) (HR 1.41, 95% CI: 1.18-1.69) or RR (14% versus 17%). Although some patients obtained a delayed survival benefit with nivolumab (patients with baseline lactate dehydrogenase ≤ upper limit of normal and those without baseline liver metastases), this effect did not meet the predefined HR threshold of benefit. However, as phase III clinical trials did not meet their primary OS endpoints with nivolumab,16Spigel D.R. Vicente D. Ciuleanu T.E. et al.Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331.Ann Oncol. 2021; https://doi.org/10.1016/j.annonc.2021.01.071Abstract Full Text Full Text PDF Scopus (27) Google Scholar,17Owonikoko T.K. Park K. Govindan R. et al.Nivolumab and ipilimumab as maintenance therapy in extensive-disease small-cell lung cancer: CheckMate 451.J Clin Oncol. 2021; https://doi.org/10.1200/JCO.20.02212Crossref PubMed Scopus (19) Google Scholar the company has decided to withdraw the indication of nivolumab in the third-line setting in December 2020. Likewise, as pembrolizumab did not improve OS in first-line setting, its indication in third-line setting has been withdrawn in March 2021.Table 1Efficacy of nivolumab +/− ipilimumab or pembrolizumab in the third-line setting in SCLC patientsTrialNRR (%)Median PFS (months)Median OS (months)2-year OS (%)CheckMate 032 (randomized). Nivolumab11Ready N.E. Ott P.A. Hellmann M.D. et al.Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort.J Thorac Oncol. 2020; 15: 426-435Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar14711.61.45.718CheckMate 032 (randomized). Nivolumab + ipilimumab11Ready N.E. Ott P.A. Hellmann M.D. et al.Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort.J Thorac Oncol. 2020; 15: 426-435Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar9621.91.54.717Pooled analyses KEYNOTE 158 and 028. PembrolizumabaIn the KEYNOTE 158 pembrolizumab 200 mg Q3W was assessed in all comers' tumors, whereas in the KEYNOTE 028 trial pembrolizumab 10 mg/kg Q3W was assessed in PD-L1 ≥ 1% tumors.12Chung H.C. Piha-Paul S.A. Lopez-Martin J. et al.Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies.J Thorac Oncol. 2020; 15: 618-627Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar8319.32.07.721OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; RR, response rate.a In the KEYNOTE 158 pembrolizumab 200 mg Q3W was assessed in all comers' tumors, whereas in the KEYNOTE 028 trial pembrolizumab 10 mg/kg Q3W was assessed in PD-L1 ≥ 1% tumors. Open table in a new tab OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; RR, response rate. The use of ICIs as a maintenance strategy after induction chemotherapy has been explored in ED-SCLC. In a single-arm phase II trial, pembrolizumab displayed limited efficacy in 45 ED-SCLC patients (median PFS 1.4 months and median OS 9.6 months); however, an exploratory analysis reported that PD-L1 expression (≥1% in stromal cells, 22C3 antibody) correlated with better outcome in this setting.18Gadgeel S.M. Pennell N.A. Fidler M.J. et al.Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC).J Thorac Oncol. 2018; 13: 1393-1399Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Nonetheless, the three-arm phase III CheckMate 451 trial that investigated nivolumab with or without ipilimumab versus placebo did not meet the primary endpoint of OS, as nivolumab plus ipilimumab was not superior to placebo (HR 0.92; 95% CI: 0.75-1.12, P = 0.37). Nivolumab alone also did not improve the OS over placebo (HR 0.84, 95% CI: 0.96-1.02),17Owonikoko T.K. Park K. Govindan R. et al.Nivolumab and ipilimumab as maintenance therapy in extensive-disease small-cell lung cancer: CheckMate 451.J Clin Oncol. 2021; https://doi.org/10.1200/JCO.20.02212Crossref PubMed Scopus (19) Google Scholar not supporting ICI as a maintenance strategy in SCLC. Thus, despite a strong rationale for ICI efficacy in SCLC, chemotherapy-free ICI trials in this disease have not generated robust results. Finally, the question of whether onset of immune-related adverse events (irAEs) are a predictive biomarker has also been explored in SCLC. In a multicenter retrospective analysis, 73 out of 183 (40%) SCLC patients treated with ICI developed an irAE. These patients had a higher TMB than those who did not develop an irAE (14.2 versus 8.4 mut/Mb, P < 0.01) and obtained better outcome with ICI compared with those who did not develop irAEs (PFS: 3.8 versus 1.3 months, P < 0.0001; and OS: 13.8 versus 2.9 months, P < 0.0001, respectively).19Ricciuti B. Naqash A.R. Naidoo J. et al.Association between immune-related adverse events and clinical outcomes to programmed cell death protein 1/programmed death-ligand 1 blockade in SCLC.JTO Clin Res Rep. 2020; https://doi.org/10.1016/j.jtocrr.2020.100074Abstract Full Text Full Text PDF Scopus (3) Google Scholar Two small phase II trials reported promising results with the addition of ipilimumab to chemotherapy [carboplatin and paclitaxel20Reck M. Bondarenko I. Luft A. et al.Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.Ann Oncol. 2013; 24: 75-83Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar or carboplatin and etoposide21Arriola E. Wheater M. Galea I. et al.Outcome and biomarker analysis from a multicenter phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC.J Thorac Oncol. 2016; 11: 1511-1521Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar] in chemotherapy-naive ED-SCLC patients. However, this benefit was not confirmed in a phase III trial22Reck M. Luft A. Szczesna A. et al.Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer.J Clin Oncol. 2016; 34: 3740-3748Crossref PubMed Scopus (294) Google Scholar with ipilimumab (10 mg/kg) versus placebo added to platinum-etoposide from cycle 3 to 6, every 3 weeks, followed by ipilimumab or placebo as maintenance treatment every 12 weeks that failed to improve OS, the primary endpoint (11.0 versus 10.9 months; HR 0.94; 95% CI, 0.81-1.09; P = 0.377) and PFS (4.6 versus 4.4 months; HR 0.85; 95% CI, 0.75-0.97; P = 0.161).22Reck M. Luft A. Szczesna A. et al.Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer.J Clin Oncol. 2016; 34: 3740-3748Crossref PubMed Scopus (294) Google Scholar The immuno-chemotherapy strategy with anti-PD-L1 has been tested in three randomized phase III trials in the first-line setting (IMpower13323Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1068) Google Scholar,24Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (36) Google Scholar with atezolizumab, CASPIAN25Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar,26Goldman J.W. Dvorkin M. Chen Y. et al.Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2021; 22: 51-64Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar testing durvalumab with or without tremelimumab and KEYNOTE 60427Rudin C.M. Awad M.M. Navarro A. et al.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.J Clin Oncol. 2020; 38: 2369-2379Crossref PubMed Scopus (112) Google Scholar with pembrolizumab), as well as two randomized phase II trials (REACTION28Besse B. Menis J. Bironzo P. et al.REACTION: a phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer.Ann Oncol. 2020; 31: S1211-S1212Abstract Full Text Full Text PDF Google Scholar with pembrolizumab and ECOG-ACRIN516129Leal T. Wang Y. Dowlati A. et al.Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161.J Clin Oncol. 2020; 38: 9000Crossref Google Scholar with nivolumab). All of these trials23Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1068) Google Scholar, 24Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (36) Google Scholar, 25Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 26Goldman J.W. Dvorkin M. Chen Y. et al.Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2021; 22: 51-64Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 27Rudin C.M. Awad M.M. Navarro A. et al.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.J Clin Oncol. 2020; 38: 2369-2379Crossref PubMed Scopus (112) Google Scholar, 28Besse B. Menis J. Bironzo P. et al.REACTION: a phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer.Ann Oncol. 2020; 31: S1211-S1212Abstract Full Text Full Text PDF Google Scholar, 29Leal T. Wang Y. Dowlati A. et al.Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161.J Clin Oncol. 2020; 38: 9000Crossref Google Scholar have demonstrated that the addition of an anti-PD-L1 to standard platinum-etoposide chemotherapy improves survival compared with chemotherapy alone (Figure 2), improving median OS by approximately 2 months and reducing the risk of death by approximately 25% compared with chemotherapy alone, providing 1-year and 2-year OS rates of ∼50% and ∼20%, respectively.24Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (36) Google Scholar,26Goldman J.W. Dvorkin M. Chen Y. et al.Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2021; 22: 51-64Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar,27Rudin C.M. Awad M.M. Navarro A. et al.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.J Clin Oncol. 2020; 38: 2369-2379Crossref PubMed Scopus (112) Google Scholar In the phase III trials, crossover was not allowed, and only 5% to 10% of patients enrolled in the chemotherapy arm received a subsequent ICI treatment. Likewise, in phase III clinical trials, the survival benefit with the immuno-chemotherapy strategy was statistically significant only in IMpower13323Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1068) Google Scholar,24Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (36) Google Scholar and CASPIAN25Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar,26Goldman J.W. Dvorkin M. Chen Y. et al.Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2021; 22: 51-64Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar (durvalumab arm), but not in the KEYNOTE 604 trial27Rudin C.M. Awad M.M. Navarro A. et al.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.J Clin Oncol. 2020; 38: 2369-2379Crossref PubMed Scopus (112) Google Scholar (Figure 2) as this latter study did not reach the prespecified efficacy boundary for the co-primary OS endpoint (P value attained: 0.0164; however, the superiority boundary for OS was one-sided P = 0.0128), although it did meet the boundary for the PFS (P value attained: 0.0023, which was below of the superiority boundary for PFS, P = 0.0048). On the basis of these data, both the FDA and EMA have approved both atezolizumab and durvalumab in combination with a platinum-etoposide regimen as the new standard of care in the first-line setting. There are some differences between IMpower133 and the CASPIAN trial that are worth noting. The IMpower133 trial only allowed carboplatin, with a maximum of four cycles in both arms, and patients could have received prophylactic cranial irradiation (PCI), regardless of the treatment arm.23Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1068) Google Scholar In contrast, in the CASPIAN trial, cisplatin was allowed (∼25% of patients in both arms received cisplatin) and patients received four cycles in the durvalumab arm, whereas in the control arm, patients could receive up to six cycles (57% of the patients completed six cycles), and PCI was only allowed in the control arm.25Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar Maintenance treatment with ICI was allowed in both trials, with a median of seven doses of atezolizumab or durvalumab administered, including the induction treatment in IMpower133 and CASPIAN trial, respectively.23Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1068) Google Scholar,25Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar Likewise, it should be noted that although in the CASPIAN trial the addition of durvalumab improved the OS" @default.
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• W3137201154 title "Small cell lung cancer: a slightly less orphan disease after immunotherapy" @default.
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• W3137201154 doi "https://doi.org/10.1016/j.annonc.2021.02.025" @default.
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