Impact of mutant STK11, KEAP1, and KRAS on firstline chemoimmunotherapy survival outcomes in metastatic non-small cell lung cancer (NSCLC): A meta-analysis of randomized and comparative studies.

Abstract

e20504 Background: Frontline chemoimmunotherapy has emerged as a revolutionary treatment modality for advanced lung cancer, significantly altering the therapeutic landscape. These therapies offer the potential for durable responses and improved survival outcomes. However, patients with specific genetic mutations present significant challenges to the efficacy of immunotherapy due to factors such as tumor microenvironment modulation, immune escape mechanisms, and intrinsic resistance related to specific genetic alterations. This meta-analysis explored the impact of STK11, KEAP1, and KRAS mutations on the survival outcome of first-line chemoimmunotherapy in metastatic NSCLC. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of the English language, diagnosis of metastatic NSCLC, randomized or comparative studies using chemoimmunotherapy versus chemotherapy, and studies that reported overall survival (OS). A meta-analysis using the fixed-effects and random-effects models was conducted. Results: Six randomized and one retrospective comparative studies with a total of 1596 patients were included. All studies reported the impact of STK11 and KEAP1 mutants on OS, but only six reported such impact of KRAS mutants. Three studies involved PD1 inhibitors (2 Pembrolizumab; 1 Nivolumab), 2 studies PDL1 inhibitors (1 Durvalumab, 1 Atezolizumab), and 2 studies CTLA4/PD1 or PDL1 inhibitors (1 Ipilimumab/Nivolumab, 1 Tremelimumab/Durvalumab). Chemoimmunotherapy maintained better OS when compared to chemotherapy alone despite the presence of mutations in STK11 (HR=0.80, 95%CI: 0.67-0.97; I 2 =0.00%), KEAP1 (HR=0.76, 95%CI: 0.59-0.98; I 2 =3.57%), and KRAS (HR=0.67, 95%CI: 0.55-0.82; I 2 =14.92%). Conclusions: This meta-analysis highlights the maintained survival benefit of first-line chemoimmunotherapy over chemotherapy alone in patients with metastatic NSCLC, even in the presence of deleterious mutations in STK11, KEAP1, and KRAS. These findings underscore the potential of chemoimmunotherapy to overcome some mutation-driven resistance in NSCLC, supporting its continued use as a first-line treatment strategy.