Real World Outcomes of First-Line Pembrolizumab With or Without Chemotherapy in Patients With NonSmall Cell Lung Cancer.

Abstract

Introduction: Non-small cell lung cancer(NSCLC) remains the leading cause of cancer-related morbidity and mortality worldwide. Despite treatment advancements, prognosis for these patients remains poor. The use of immunotherapies such as pembrolizumab, an anti-PD-1 receptor antibody, in lung cancer treatment has dramatically improved outcomes for patients. Known associations with PDL-1 expression on tumour cells and efficacy of pembrolizumab treatment have been well described in other studies. This analysis aimed to evaluate survival outcomes and their predictors in patients with NSCLC who received either pembrolizumab monotherapy (monopembro) or combined pembrolizumab and chemotherapy (chemopembro). Method(s): This retrospective analysis included adult patients with NSCLC who received first-line pembrolizumab with or without chemotherapy between January 1, 2015 and March 31, 2024 at a major tertiary hospital network, identified through hospital prescribing records. Medical record data collection included biochemical and genetic testing results, severity of disease at diagnosis, and immunotherapy-related adverse events(irAE). Subgroup analyses were conducted for the mono-pembro and chemo-pembro cohorts. Kaplan-Meier methods were used to estimate survival as a function of time. Cox proportional hazards regression was used to analyse the primary outcomes of overall survival (OS) and progression-free survival (PFS). Variables of potential clinical significance and univariate analyses statistical significance were selected for inclusion in the multivariate analyses. Result(s): The mono-pembro cohort included 73 patients with 2-year survival of 42% and the chemo-pembro cohort included 132 patients with 2-year survival of 33%. Univariate analysis revealed ECOG, LDH and albumin were markers of prognosis across both subgroups. The presence of irAE was also found to improve OS and PFS in both mono-pembro (HR 0.40, p=0.002; HR 0.27, p=<0.001 respectively) and chemo-pembro (HR 0.45, p=0.001; HR 0.49, p=0.002 respectively) cohorts. The presence of KRAS non-G12C mutation was associated with worse PFS outcomes in the mono-pembro group (HR 2.30, 95% CI 1.07 - 4.97, p=0.03), but not in the chemopembro group (HR 0.98, p=0.96). Multivariate analysis demonstrated higher ECOG and NeutrophilLymphocyte ratio(NLR), and lower albumin were associated with worse OS and PFS in the mono-pembro group. Patients who smoked at higher volumes were associated with increased PFS (HR 0.54, p=0.008) whereas adenocarcinoma histopathology was related with poorer OS (HR 2.38, p=0.024). Statistically significant multivariate outcomes in the chemo-pembro group were ECOG and NLR, which both were associated with worse OS. Conclusion(s): Patient characteristics which carried a favourable prognosis included the presence of irAE, favourable biochemical markers(LDH, Albumin, NLR) and functional baseline(ECOG) at the time of initial treatment. Improved PFS was demonstrated with KRAS G12C mutation in the chemo-pembro group but not in the mono-pembro group, which also demonstrated reduced PFS with KRAS non-G12C mutation. This may suggest that pembrolizumab efficacy in NSCLC patients with KRAS mutations is inferior to traditional platinum-based chemotherapy. A proposed mechanism for the association between irAE and improved primary outcomes may be that they are both indicative of a stronger systemic immunological upregulation response to immunotherapy. Alternatively, the increased lysis of malignant cells in treatment response may result in higher rates of systemic adverse events.