Comparative effectiveness and safety of immunotherapy alone versus chemoimmunotherapy in advanced non-small cell lung cancer: a systematic review

The optimal first-line treatment strategy for advanced non-small cell lung cancer (NSCLC), particularly in patients with high Programmed Death-Ligand 1 (PD-L1) expression, remains debated. This systematic review compares the clinical outcomes and adverse events associated with immunotherapy (IMT) alone versus combination chemoimmunotherapy (ICT). A systematic search was conducted in PubMed, Scopus and Web of Science, originally to March 9, 2025, and re-run through July 23, 2026 following the 2020 PRISMA guidelines and a pre-registered protocol (PROSPERO ID: CRD4202510 19802). Retrospective cohort studies comparing chemoimmunotherapy with immunotherapy alone in adults with advanced or metastatic NSCLC were eligible; both single-agent PD-1/PD-L1 inhibitor regimens and dual PD-1/CTLA-4 checkpoint-inhibitor regimens were included and are explicitly distinguished throughout this revision. Outcomes assessed were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs), including immune-related adverse events (irAEs). Certainty of evidence was evaluated independently for each clinical outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Where two or more studies reported comparable adjusted hazard ratios for the same outcome, a random-effects meta-analysis was performed; remaining outcomes were synthesized narratively, with the reason for non-pooling reported for every study, and certainty of evidence graded using GRADE. Seven studies involving 4,354 patients were included. ICT was associated with numerically higher ORR and modest improvements in PFS in most, but not all, studies, particularly in patients with very high PD-L1 expression (≥ 75%-90%, threshold varying by study), good performance status, and younger age. Because ORR and PFS could not be quantitatively pooled across studies, these findings are reported as directional trends rather than statistically pooled effects. A limited random-effects meta-analysis of the two studies reporting comparable adjusted hazard ratios for OS showed no statistically significant difference between ICT and IMT (pooled HR 0.88, 95% CI 0.68–1.15; I² = 63%). ICT was associated with a higher incidence of grade ≥ 3 AEs and irAEs across studies, while treatment discontinuation was defined and reported inconsistently and is therefore presented narratively only. In exploratory, unadjusted subgroup comparisons vulnerable to confounding by indication, IMT alone appeared to yield comparable outcomes with better tolerability in patients with extensive metastatic disease, older age, or poor Eastern Cooperative Oncology Group (ECOG) status; these observations are hypothesis-generating only. One included study compared dual immune-checkpoint blockade (nivolumab plus ipilimumab) with or without chemotherapy, rather than single-agent PD-1 monotherapy plus or minus chemotherapy; this study is analyzed separately from the single-agent studies, and a sensitivity analysis excluding it did not change the overall direction of findings. ICT was associated with numerically higher response rates and a modest early survival trend in select subgroups, but the limited quantitative synthesis performed in this review did not demonstrate a statistically significant long-term OS advantage of ICT over IMT alone, and ICT carried a higher toxicity burden. Because all evidence is derived from retrospective, non-randomized studies and was judged low-to-very-low certainty by GRADE, subgroup observations (e.g., in elderly patients, poor performance status, or high disease burden) should be regarded as exploratory and hypothesis-generating rather than a basis for treatment recommendations. Treatment decisions should be individualized. Further prospective randomized trials are warranted to refine treatment algorithms.