Abstract A175: A comparative meta-analysis of survival outcomes in Non-Small Cell Lung Cancer: Influence of tumor mutational burden and KEAP1, KRAS, STK11 mutations on the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone
Authors: Elfaituri Muhammed Khaled , Khaled Ala 
Published: December 2023

Background: The management of non-small cell lung cancer (NSCLC) has been revolutionized by the identification of critical genetic markers such as Tumor Mutational Burden (TMB), KEAP1, KRAS, PD-L1 expression levels, and STK11 mutations, which have shown the potential to impact patient survival outcomes. This study aimed to assess the impact of these markers on the survival of NSCLC patients treated with immunotherapy combined with chemotherapy versus chemotherapy alone.

Methods: A comprehensive search of PubMed, Embase, and Cochrane Library databases until March 2023 included randomized controlled trials (RCTs) assessing Progression-Free Survival (PFS) and Overall Survival (OS) in NSCLC patients treated with either combined immunotherapy and chemotherapy or chemotherapy alone and considering specific genetic and cellular factors. Using R software (version 4.0.3) with metafor and meta packages, data were analyzed through a random-effects model, using hazard ratios (HRs) for PFS and OS and relative risks (RRs) for response rate and major adverse events.

Results: Our analysis included 17 studies, totaling 9520 patients; 5247 patients received combined immunotherapy and chemotherapy, while 4273 patients were treated with chemotherapy alone. For OS, patients with high TMB demonstrated a significant improvement, with a HR of 0.72 (95% Confidence Interval (CI) 0.56-0.91, P&lt;0.01, I^2=0%). Similarly, patients with KRAS mutations showed a significant increase in OS, with a HR of 0.67 (95% CI 0.53-0.85, P&lt;0.01, I^2=14%). Patients expressing PD-L1 in more than 1% and more than 50% also revealed significant improvement in OS, with HRs of 0.71 (95% CI 0.64-0.78, P&lt;0.01, I^2=0%) and 0.67 (95% CI 0.57-0.79, P&lt;0.01, I^2=0%) respectively. Furthermore, patients without STK11 mutations exhibited a significant improvement in OS with a HR of 0.77 (95% CI 0.62-0.96, P=0.02, I^2=38%). Turning to PFS, patients with low TMB showed significant improvement with a HR of 0.66 (95% CI 0.55-0.81, P&lt;0.01, I^2=35%). This was also the case for patients with high TMB, with a HR of 0.43 (95% CI 0.33-0.57, P&lt;0.01, I^2=47%), and for patients with KRAS mutations (HR=0.54, 95% CI 0.36-0.82, P&lt;0.01, I^2=63%). Patients with PD-L1 expression levels of less than 1%, more than 1%, and more than 50% also demonstrated significant improvements in PFS, with HRs of 0.64 (95% CI 0.56-0.72, P&lt;0.01, I^2=62%), 0.51 (95% CI 0.44-0.59, P&lt;0.01, I^2=66%), and 0.42 (95% CI 0.37-0.48, P&lt;0.01, I^2=0%) respectively. The response rate demonstrated a significant increase in the combined treatment group (RR=1.54, 95% CI 1.38-1.72, P&lt;0.01, I^2=65%), while the major adverse events showed no significant difference between treatment groups (RR=0.98, 95% CI 0.87-1.13, P=0.87, I^2=89%).

Conclusions: High TMB, KRAS mutations, and elevated PD-L1 expression in NSCLC patients may be associated with better outcomes with combined therapy. However, the roles of KEAP1 and STK11 mutations in survival require further study. These findings highlight these genetic markers' prognostic and therapeutic implications in NSCLC.

Citation Format: Muhammed Khaled Elfaituri, Ala Khaled. A comparative meta-analysis of survival outcomes in Non-Small Cell Lung Cancer: Influence of tumor mutational burden and KEAP1, KRAS, STK11 mutations on the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A175.