Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving first-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving first-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 317 trials (78,644 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 28.2% (standard deviation (SD) = 12.4%), 5.1 months (SD = 2.1), and 10.4 months (SD = 2.5), respectively. ORR and PFS had weak (R = 0.351; 95% CI: 0.251-0.443) and (R = 0.397; 95% CI: 0.267-0.512) associations with OS, respectively. However, within phase III trials that did not allow crossover and reported balanced post-progression treatments, both ORR and PFS had stronger associations with OS (ORR and OS: R = 0.601, 95% CI: 0.399-0.747; PFS and OS: R = 0.695, 95% CI: 0.446-0.844). STE estimation indicated that trials that show statistically significant treatment effect size of ≥43% ORR or ≥3.2 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.