Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer

{Background Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced nonsmall cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression E 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression E1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of diMerent biomarkers for treatment selection and the eMectiveness of immunotherapy according to specific clinical characteristics. Objectives To determine the eMectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. Search methods We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. Selection criteria We included randomised controlled trials (RCTs) reporting on the eMicacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard firstline therapy (platinum-based chemotherapy +/- bevacizumab). All data come from `international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. Data collection and analysis Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed metaanalyses where appropriate using the random-eMects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the IU statistic to investigate heterogeneity. Main results Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both firstline single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 E 50 being considered the most clinically useful cut-oM level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 E 50. Single-agent ICI In the PD-L1 expression E 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PDL1 expression E 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50