Immunotherapy beyond progression combined with platinum-based chemotherapy after primary resistance to first-line immunotherapy in patients with advanced NSCLC and PD-L1 ≥50%

Background: Primary resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in patients with advanced non-small-cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) expression ≥50%. The benefit of continuing ICIs beyond progression in combination with chemotherapy is unclear. Patients and methods: This multicenter retrospective study included patients with advanced NSCLC and PD-L1 ≥50% treated with first-line ICI monotherapy at five European centers. Primary resistance was defined as progressive disease as best response or stable disease lasting <6 months. Outcomes of second-line platinum-based chemotherapy alone or combined with ICI were compared. The primary endpoint was progression-free survival 2, defined as time from first-line ICI initiation to second-line progression or death. Results: Among 293 eligible patients, 119 (38%) showed primary resistance. Compared with those who did not develop primary resistance, patients with primary resistance more often had multisite progression (74% versus 42%) and less often oligoprogression (13% versus 54%) (P < 0.001). Second-line platinum-based chemotherapy was administered to 43.7% (52/119) of patients with primary resistance, 34.6% (18/52) of whom received ICI beyond progression. Baseline characteristics were comparable across treatment groups. Patients who received ICI beyond progression, compared with those who received only chemotherapy, had significantly longer median progression-free survival 2 (12.3 versus 7.0 months, P < 0.001) and OS (21.8 versus 10.1 months, P = 0.007), with similar overall response rate (66.7% versus 39.3%, P = 0.13). No relevant safety signals emerged. Conclusion: In patients with NSCLC and PD-L1 ≥50% showing primary resistance to first-line ICI, continuing immunotherapy beyond progression combined with chemotherapy may improve survival outcomes. These findings should be considered hypothesis-generating and warrant prospective confirmation.