Immune-checkpoint inhibitors plus chemotherapy versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer

We performed a meta-analysis to comprehensively investigate the efficacy and safety of immune-checkpoint inhibitors (ICIs) plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary outcome was overall survival (OS). The secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and ≥grade 3 adverse events (AEs). A total of six studies involving 2905 patients were identified, including 469 patients receiving program death ligand 1 (PD-L1) inhibitor plus chemotherapy, 308 receiving PD-1 inhibitors plus chemotherapy, 563 receiving CTLA-4 inhibitors plus chemotherapy, 268 receiving PD-L1/CTLA-4 inhibitors plus chemotherapy, and 1297 receiving chemotherapy alone. 10.8% (283/2615) patients had baseline brain metastases (BMs). Notably, ICIs plus chemotherapy was associated with significantly improved OS (HR, 0.82; 95% CI, 0.75 to 0.89). Subgroup analyses revealed that PD-1 inhibitors (HR, 0.77; 95% CI, 0.64 to 0.92) and PD-L1 inhibitors (HR, 0.73; 95% CI, 0.63 to 0.85) plus chemotherapy yielded a statistically significant improvement in OS while CTLA-4 inhibitors did not (HR, 0.92; 95% CI, 0.81 to 1.06). In patients with baseline BMs, ICIs plus chemotherapy showed no survival benefits over chemotherapy alone (HR, 1.23; 95% CI, 0.92 to 1.64). ICIs plus chemotherapy also significantly prolonged PFS (HR, 0.81; 95% CI, 0.75 to 0.87) while the pooled ORRs were comparable between ICIs plus chemotherapy and chemotherapy alone (RR, 1.04; 95% CI, 0.99 to 1.10). Patients treated with CTLA-4 inhibitors (relative risk (RR), 1.12; 95% CI, 0.99 to 1.28) experienced more≥grade 3 AEs than those treated with PD-1/PD-L1 inhibitors (RR, 1.03; 95% CI, 0.96 to 1.11). The addition of PD-1/PD-L1 inhibitors to chemotherapy resulted in significant improvements in both PFS and OS for patients with treatment-naïve ES-SCLC, not at the cost of increased AEs.

[1]  C. Rudin,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. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  N. Reinmuth,et al.  Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study. , 2020, Journal of Clinical Oncology.

[3]  S. Ramalingam,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. , 2020 .

[4]  Y. Kluger,et al.  Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. , 2020, The Lancet. Oncology.

[5]  S. Novello,et al.  Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  L. Horn,et al.  Immunotherapeutic approaches for small-cell lung cancer , 2020, Nature Reviews Clinical Oncology.

[7]  J. Lee,et al.  Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients With Cancer: A Systematic Review and Meta-analysis. , 2019, JAMA oncology.

[8]  D. Planchard,et al.  Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic Small-Cell Lung Cancer: Results From the KEYNOTE-028 and KEYNOTE-158 Studies. , 2019, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[9]  Young Hak Kim,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 , 2019, The Lancet.

[10]  D. de Ruysscher,et al.  Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors. , 2019, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[11]  N. Reinmuth,et al.  Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. , 2019, The Lancet. Oncology.

[12]  A. Mansfield,et al.  First‐Line Atezolizumab plus Chemotherapy in Extensive‐Stage Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[13]  A. Tafreshi,et al.  Pembrolizumab plus Chemotherapy for Squamous Non–Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[14]  J. Szustakowski,et al.  Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. , 2018, Cancer cell.

[15]  R. Govindan,et al.  Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Michael Thomas,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. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  D. Jäger,et al.  Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. , 2016, The Lancet. Oncology.

[18]  F. Koinis,et al.  Small cell lung cancer (SCLC): no treatment advances in recent years. , 2016, Translational lung cancer research.

[19]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[20]  L. Bracci,et al.  Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer , 2013, Cell Death and Differentiation.

[21]  T. Lynch,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. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.