Introduction: Anti-PD-(L)1 immunotherapy with or without chemotherapy has shown superior overall survival as a first-line treatment for patients with advanced non-small-cell lung cancer (aNSCLC) and high tumor expression of PD-(L)1 (PD-L1 score ≥50%) compared to chemotherapy alone. However, evidence on the cross-comparative effectiveness of chemoimmunotherapy versus immunotherapy alone in patients with PD-L1 ≥50% and in those with PD-L1 ≥90% is limited due to lack of head-to-head efficacy trials making it difficult to decide who can be spared the additional side effects associated with combination therapy. We sought to compare survival in aNSCLC patients with PD-L1 score ≥50% receiving first-line pembrolizumab with or without chemotherapy.

Methods: Cohort study of aNSCLC patients with PD-L1 score ≥50% who initiated first-line treatment with pembrolizumab monotherapy or in combination with carboplatin-based chemotherapy between Oct 24th, 2016, and Oct 29th, 2021, using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Kaplan-Meier curves and Cox regression were used to estimate 6- and 12-month overall survival and hazard ratios, respectively, for all patients with PD-L1 score ≥50% and in the subgroup of patients with PD-L1 score ≥90%. Multiple imputation was used to impute missing covariates. Propensity score-based inverse probability of treatment weighting (IPW) was used to address confounding by age, race, sex, smoking history, PD-L1 score ≥90%, tumor histology, presence of KRAS/BRAF mutation, practice type, and ECOG performance status. Because of non-proportionality of hazards, we estimated hazard ratios over the first 6 months and after 6 months for the overall cohort, and over the first 12 months and after 12 months for a subgroup of persons with a PD-L1 score of ≥90%.

Results: The cohort included 3086 aNSCLC patients. 52% of whom were male, median age at therapy initiation was 71 years, 27% had a KRAS mutation and 93% had a history of smoking. Sixty-eight percent received pembrolizumab as monotherapy. PD-L1 score ≥90% was split evenly between the treatment groups (n=946 (45%) in immunotherapy alone group vs n=426 (43%) in the chemoimmunotherapy group). IPW adjusted survival was higher for chemoimmunotherapy compared to immunotherapy alone at 6 months (74% vs 68%). Similarly, chemoimmunotherapy was associated with lower mortality compared to immunotherapy alone in the first 6 months after therapy initiation [IPW-adjusted Hazard Ratio (aHR) 0.74, 95% CI 0.61-0.90]. In the subgroup of patients with a PD-L1 score ≥90%, chemoimmunotherapy was associated with no overall survival advantage during the entire follow-up period (aHR 0.99, 95% CI 0.87-1.22), but was associated with a survival benefit during the first 12 months compared to immunotherapy alone (12-month survival 62% vs 57%; aHR 0.74, 95% CI 0.57-0.97).

Conclusions: Chemoimmunotherapy was associated with no overall survival advantage over immunotherapy alone, although was associated with a survival benefit in the first 6 months. Among PD-L1 score ≥90% (subgroup), chemoimmunotherapy was not associated with an overall survival benefit, but associated with a survival benefit in the first 12 months. Providers should carefully weigh the short-term benefits of chemoimmunotherapy over immunotherapy versus their long-term equivalence.