*Review* **PD-(L)1 Inhibitors in Combination with Chemotherapy as First-Line Treatment for Non-Small-Cell Lung Cancer: A Pairwise Meta-Analysis**

**Jorge García-González 1,\*,**†**, Juan Ruiz-Bañobre 1,\*,**†**, Francisco J. Afonso-Afonso 2, Margarita Amenedo-Gancedo 3, María del Carmen Areses-Manrique 4, Begoña Campos-Balea 5, Joaquín Casal-Rubio 6, Natalia Fernández-Núñez 5, José Luis Fírvida Pérez 4, Martín Lázaro-Quintela 6, Diego Pérez Parente 7, Leonardo Crama 7, Pedro Ruiz-Gracia 7, Lucía Santomé-Couto <sup>8</sup> and Luis León-Mateos 1,\***


Received: 10 June 2020; Accepted: 28 June 2020; Published: 3 July 2020

**Abstract:** The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. For this purpose, we performed a literature search of randomized controlled trials comparing PD-(L)1 inhibitors plus platinum-based chemotherapy versus chemotherapy alone in stage IV NSCLC patients. Seven clinical trials with 4562 patients were included. In the intention-to-treat wildtype population, PD-(L)1 inhibitor plus chemotherapy was significantly associated with improved progression-free survival (PFS) (Hazard ratio (HR) = 0.61, 95% confidence interval (CI): 0.57–0.65, *p* < 0.001) and overall survival (OS) (HR = 0.76, 95% CI: 0.67–0.86; *p* < 0.001) compared to chemotherapy. A significantly higher overall response rate (ORR) was also observed with the combined strategy (Odds ratio (OR) = 2.12, 95% CI: 1.70–2.63, *p* < 0.001). Furthermore, in all the analyzed subgroups, addition of PD-(L)1 inhibitors to chemotherapy significantly improved efficacy endpoints. Specifically, stratification according to PD-L1 expression revealed a benefit across all patients, regardless of their PFS status. In conclusion, PD-(L)1 blockade added to standard platinum-based chemotherapy significantly improved PFS, OS, and ORR in the up-front treatment of advanced NSCLC.

**Keywords:** non-small-cell lung cancer; immunotherapy; PD-1 inhibitors; PD-L1 inhibitors; chemotherapy; meta-analysis

#### **1. Introduction**

Lung cancer remains the leading cause of cancer-related death worldwide among men and the second among women [1]. Non-small-cell lung cancer (NSCLC), which is the most common type, accounts for 80% to 85% of all lung cancer diagnoses [2]. It is frequently diagnosed in the advanced stage, with 5-year survival rates ranging from 0% to 5% with chemotherapy, the only systemic therapeutic strategy available for decades [3]. In this regard, blockade of the programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis in particular has opened up a new horizon in the lung cancer therapeutic landscape, increasing overall survival (OS) not only in patients with advanced NSCLC but also in patients with stage III NSCLC and extensive-stage small-cell lung cancer [4–6].

Since 2015, three different PD-(L)1 inhibitors have been approved by the European Medicines Agency (EMA) and/or the U.S. Food and Drug Administration (FDA) for the treatment of metastatic NSCLC (mNSCLC) [7]: two anti-PD-1 antibodies (nivolumab and pembrolizumab) and one anti-PD-L1 antibody (atezolizumab), indicated for patients regardless of their PD-L1 expression status (nivolumab and atezolizumab) or for PD-L1-positive patients only (pembrolizumab). All of them have demonstrated an improvement in OS compared to docetaxel in second-line therapy [8–10]. In the first-line setting, results from the KEYNOTE 024 trial demonstrated that, compared with platinum-based chemotherapy, OS, progression-free survival (PFS), and overall response rate (ORR) were significantly improved in patients with PD-L1 expression on at least 50% of tumor cells and without oncogenic driver mutations [11,12]. Interestingly, an additional study assessing pembrolizumab efficacy versus chemotherapy using a PD-L1 tumor proportion score (TPS) of 1% or greater (KEYNOTE-042 [13]) demonstrated improved OS for the full cohort, which, despite being higher for higher PD-L1 expression, supported a potential extended role of pembrolizumab monotherapy as a standard first-line treatment for PD-L1-expressing advanced/metastatic NSCLC [14]. In contrast, nivolumab did not demonstrate statistically significant survival benefits in previously untreated PD-L1-positive mNSCLC (CheckMate-026 [15]).

Nevertheless, many patients with advanced NSCLC do not benefit from PD-(L)1 inhibitors, either in the first line or in the second or successive lines of treatment. The search for reliable predictive biomarkers of response to these drugs is therefore essential to improve patient outcomes.

The potential synergistic effects of combining chemotherapy and immunotherapy to improve the antitumor activity of anti-PD-(L)1 monotherapy were initially suggested in preclinical studies [16] (Apetoh, 2015 #16) and were further demonstrated in several clinical trials [4–6,17–25]. However, although promising outcomes have been reported, several questions remain unanswered, such as the potential real benefit for all patients at the expense of increased toxicity or the possible molecular factors that could predict the benefit of this combined therapeutic strategy.

The objective of this study was to evaluate the efficacy of the combined strategy by conducting a pairwise meta-analysis (MA) of the available information on PD-(L)1 inhibitors in combination with chemotherapy in the first-line treatment of patients with advanced NSCLC.
