Combination of the EP and Anti-PD-1 Pathway or Anti-CTLA-4 for the Phase III Trial of Small-Cell Lung Cancer: A Meta-Analysis

Abstract

The morbidity and mortality of lung cancer remain one of the highest among multiple cancers, respectively. Small-Cell Lung Cancer (SCLC) accounts for around 10%–15% of all lung cancers. Approximately two-thirds of the diagnosed SCLCs are in extensive stage (ES). Decades later, we still rely on the same traditional regimen with etoposide and platinum (EP) as the mainstay of treatment with poor prognosis. This meta-analysis aims to assess the effect of adding Immune Checkpoint Inhibitors (CPIs) such as (ipilimumab, atezolizumab, pembrolizumab, and durvalumab) to the traditional EP regimen for small-cell lung cancer extensive stage (ES-SCLC). We searched through PubMed looking for studies that compare between EP and CPIs, with EP alone, and only Phase III randomized controlled trials were considered eligible for this study. A total of 3645 papers were the results of the initial search, and only 4 studies met our criteria. Each investigator extracted the data independently using the PRISMA MODEL (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Each author used a prespecified sheet. The primary endpoint was to calculate OS (overall survival) and PFS (progression-free survival) hazard ratios for both arms. We found that adding EP plus CPIs increased both OS (HR, 95% CI 0.80 [0.70, 0.93], P = 0.0001, I2 = 49%) and PFS (HR95% CI 0.81 [0.74, 0.88], P < 0.00001, I2 = 0%). On the other hand, ORR (overall response rate) was not affected by the addition of CPIs to EP compared to EP alone, and the same was true for adverse events. To conclude, CTLA-4 alone is not encouraging, but PD-1/PD-L1 adds survival benefits. A combined treatment regimen shows to be more effective, improving overall survival rate Durvalumab and atezolizumab showed improvement for OS, but pembrolizumab and ipilimumab did not show a significant increase of OS over EP; however, pembrolizumab showed significant prolongation of the disease-free period.

Impact of liver metastases status on survival outcomes of first-line immunotherapy in extensive stage small cell lung cancer: a systematic review and meta-analysis

“…SCLC, with its high tumor mutational burden, is notably responsive to immunotherapy [17,18]. Multiple trials have substantiated the survival benefits of blocking the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) axis, either in conjunction with chemotherapy or as maintenance therapy, for ES-SCLC patients [19][20][21]. However, several studies indicated that immunotherapy did not improve OS and PFS of ES-SCLC patients with liver metastases [22][23][24].…”

Tumor mutation burden in the prognosis and response of lung cancer patients to immune-checkpoint inhibition therapies

“…Past studies showed that treatment with anti-CTLA-4 mab alone did not have a significant effect on the prognosis of lung cancer, which is why most recent investigations focus on combining CTLA-4 inhibition therapy with either other ICIs, or traditional regimens (e.g., etoposide and platinum chemotherapies) in SCLC and NSCLC [ 63 ]. A preclinical mouse trial, conducted by Bates et al., for example, indicates anti-CTLA-4 as a possible adjunct to bempegaldesleukin (a CD122-preferential IL-2 pathway agonist), as a secondary treatment after surgical resection or hypo-fractionated radiation therapy of primary Lewis Lung Carcinoma (LLC), a specific type of NSCLC.…”