Advances in immunotherapy (IT) and targeted therapy have transformed treatment for stage IV non-squamous non-small cell lung cancer (NS-NSCLC). However, real-world data comparing modern regimens to previous standards remains limited. Herein, we aim to determine whether survival outcomes have improved with contemporary therapies,

We conducted a retrospective analysis of de novo stage IV NS-NSCLC at diagnosis treated at the Cleveland Clinic, OH, from 1/2010 to 12/2022. Baseline variables, including age, sex, race, performance status, smoking history, PD-L1 testing, and molecular profiling, were collected along with treatment regimens. Treatment responses were assessed. Overall survival (OS) and progression-free survival (PFS) were estimated. Multivariable Cox regression (CPH) was used to adjust for confounding.

We identified 1,518 patients with NS-NSCLC, of which 97% had adenocarcinoma (N = 1,472). Median age was 65 (IQR 58–73); 51% were female, 82% white, and 42% current smokers. Treatments included conventional chemotherapy (CTX) (744, 49%), IT (186, 12%), CTX + IT (318, 21%), and targeted therapy (270, 18%). Common regimens were carboplatin + pemetrexed/paclitaxel (502, 80%) and bevacizumab + carboplatin + pemetrexed/paclitaxel (127, 20%) for CTX, pembrolizumab (167, 89%) for IT, and carboplatin + pemetrexed + pembrolizumab (153, 41%) for chemo-IT. Overall disease control rate was 58% with a median follow-up of 69.7 months. The 2- and 5-year OS were 30% and 12%, respectively. OS improved from 20% (2010–2012) to 38% (2019–2022) (P < 0.05). Modern regimens were associated with a 23% reduced hazard of death (HR 0.77, 95% CI 0.66–0.90, p < 0.001).

Modern regimens were associated with improved survival in stage IV NS-NSCLC, but long-term survival remains poor, underscoring the need for further research.