First-line immunotherapy-based regimens for metastatic non-small cell lung cancer: A network meta-analysis of landmark trials.

[INTRODUCTION] First-line immunotherapy, alone or with chemotherapy, has revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC). However, with multiple approved regimens, the optimal therapeutic choice is undefined due to a lack of direct comparative trials. This network meta-analysis was conducted to establish a hierarchy of efficacy for five landmark immunotherapy-based regimens to inform clinical and policy decisions.

[MATERIALS AND METHODS] A network meta-analysis of five pivotal phase III trials (KEYNOTE-024, KEYNOTE-189, KEYNOTE-407, CheckMate 9LA, IMpower 110), all recently reimbursed in our country, was performed. We synthesized overall survival (OS) data for the total population and across subgroups defined by histology (squamous vs. non-squamous) and PD-L1 expression (<1%, 1-49%, ≥50%), with chemotherapy as the common comparator.

[RESULT] Pembrolizumab-based therapies ranked consistently high. In nonsquamous NSCLC, pembrolizumab-chemotherapy was highest-ranked and significantly superior to the nivolumab-based combination (HR: 0.76, 95% CI: 0.58-0.99). In squamous disease, the combination of nivolumab, ipilimumab, and chemotherapy emerged as the highest-ranked regimen (SUCRA: 78.3%). By PD-L1 status, pembrolizumab monotherapy was topranked for ≥50% expression (SUCRA: 82.8%), while pembrolizumabchemotherapy was superior for the 1-49% subgroup (SUCRA: 87.5%). For PD-L1 negative (<1%) patients, a subgroup with substantial heterogeneity, no regimen showed a statistically significant OS benefit over chemotherapy.

[CONCLUSIONS] Our analysis indicates pembrolizumab-based regimens, as monotherapy or with chemotherapy, offer the most robust and highestranking survival advantage across most key NSCLC subgroups. These findings provide a critical, evidence-based framework to guide individualized first-line treatment selection.