Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis

Abstract

BackgroundImmune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.MethodsWe performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.ResultsSix trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57–0.67; P < .001), OS (HR, 0.68; 95% CI 0.53–0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29–1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).ConclusionsPD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0477-9) contains supplementary material, which is available to authorized users.

Rational application of the first‐line chemotherapy and immune checkpoint inhibitors in advanced nonsmall cell lung cancer: A meta‐analysis

“…The third question is whether additional ICIs to the first‐line chemotherapy is necessary for patients with low or negative expression for PD‐L1. Previous studies have shown that the synergistic activity and acceptable safety profile could be observed by the combination of checkpoint inhibitors and chemotherapy in the first‐line treatment of advanced NSCLC . With the inclusion of two recent studies, our study drew consistent conclusion that compared with standard chemotherapy, the combination of chemotherapy and ICIs, regardless of atezolizumab or pembrolizumab could acquire significant benefits in mOS, OSR1y, mPFS, PFSR6m, PFSR1y, and ORR for PD‐L1 unselected patients in spite of higher incidence of grade ≥ 3 TRAEs.…”

“…Previous studies have shown that the synergistic activity and acceptable safety profile could be observed by the combination of checkpoint inhibitors and chemotherapy in the first-line treatment of advanced NSCLC. 28,29 With the inclusion of two recent studies, our study drew consistent conclusion that compared with standard chemotherapy, the combination of chemotherapy and ICIs, regardless of atezolizumab or pembrolizumab could acquire significant benefits in mOS, OSR1y, mPFS, PFSR6m, PFSR1y, and ORR for PD-L1 unselected patients in spite of higher incidence of grade ≥ 3 TRAEs. When stratified by PD-L1 expression, patients with negative PD-L1 expression can further benefit from combination therapy in mOS, mPFS, and ORR, regardless of atezolizumab or pembrolizumab.…”

Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer

“…Fortunately, the development of immunotherapy challenged the management of treatment-related toxic effects. Like the prior study, ICI drugs were overall less toxic than chemotherapy especially in monotherapy, and combining an ICI with chemotherapy increased the rate of grade 3 or worse severity TRAEs [49,50]. Although combined therapy resulted in significantly longer overall survival and progression-free survival than chemotherapy, its cytotoxicity also improved, which should not be underestimated [51].…”

Optimizing Patient Outcomes with PD‐1/PD‐L1 Immune Checkpoint Inhibitors for the First‐Line Treatment of Advanced Non–Small Cell Lung Cancer

“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16] However, severe and dose-limiting AEs were significantly greater for chemoimmunotherapy versus chemotherapy, with risk ratios (RRs) of 1.14 (95% CI 1.04-1.26) and 1.29 (95% CI 1.01-1.60) for grade 3-5 AEs and treatment discontinuation, respectively. 33 The combination chemoimmunotherapy also had higher rates of any-grade irAEs (RR 2.37, 95% CI 1.98-2.84) and grade 3-5 irAEs (RR 3.71, 95% CI 2. 63-5.24).…”

“…Interim PFS and OS results are promising for squamous NSCLC, whereas the OS end point for nonsquamous NSCLC was not met (Table ). A meta‐analysis of six randomized trials in 3144 patients with aNSCLC supports the results of the individual trials, showing improved PFS (HR 0.63, 95% CI 0.58–0.68), OS (HR 0.68, 95% CI 0.53–0.87), and ORR (OR 1.56, 95% CI 1.29–1.89) for first‐line anti‐PD1/PD‐L1 agents (pembrolizumab, atezolizumab, or nivolumab) plus chemotherapy compared with chemotherapy . This meta‐analysis also found that combination chemotherapy plus PD‐1 inhibitor (e.g., pembrolizumab) may be more efficacious than chemotherapy plus PD‐L1 inhibitor (e.g., atezolizumab), with OS HRs of 0.56 (95% CI 0.47–0.67) and 0.85 (95% CI 0.68–1.07), respectively, compared with chemotherapy.…”