Patients with metastatic non–small cell lung cancer (NSCLC) who received a combined therapy of tremelimumab, durvalumab, and chemotherapy experienced longer overall survival compared with those who received chemotherapy alone, regardless of STK11, KEAP1, or KRAS mutational status. These findings from the POSEIDON trial were presented by Peters et al at the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer 2022 in Vienna (Abstract OA15.04).
In previously reported results of the phase III POSEIDON trial, patients with EGFR/ALK wild-type metastatic NSCLC who were given first-line tremelimumab, durvalumab, and chemotherapy demonstrated statistically significant improvements in both progression-free survival and overall survival vs chemotherapy alone. In this study, Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois, Lausanne University, Switzerland and colleagues conducted an exploratory analyses of survival outcomes in POSEIDON according to KRAS, STK11, and KEAP1 mutational status.
Mutations in STK11 and KEAP1 correlate with poor prognosis and are associated with chemorefractory and immunologically “cold” tumors that are less responsive to therapy. KRAS-mutant NSCLC is heterogeneous and frequently comutated with STK11 and/or KEAP1. Based on these findings, researchers theorized that the triplet regimen of tremelimumab, durvalumab, and chemotherapy may improve clinical outcomes for hard-to-treat subgroups of patients with metastatic NSCLC.
Study Details
The investigators randomly assigned 1,013 patients (1:1:1) to first-line tremelimumab, durvalumab, and chemotherapy; durvalumab and chemotherapy; or chemotherapy alone, with stratification by tumor cell PD-L1 expression (≥ 50% vs < 50%), disease stage (IVA vs IVB), and histology (squamous vs nonsquamous). Patient tumors were molecularly characterized via sequencing of tumor tissue DNA and/or circulating tumor DNA samples. Progression-free survival and overall survival outcomes were analyzed in patients with or without functional mutations in KRAS, STK11, or KEAP1.
The mutation-evaluable nonsquamous NSCLC population included 612 patients (96% of the intent-to-treat nonsquamous population) whose tumors were molecularly characterized; 30%, 14% and 6% had KRAS, STK11, and KEAP1 mutations, respectively. Overall survival hazard ratios favored patients in the tremelimumab, durvalumab, and chemotherapy arm vs chemotherapy, irrespective of KRAS, STK11, or KEAP1 mutational status, consistent with results in the intent-to-treat population.
“Notably, landmark 24-month overall survival rates were higher with tremelimumab, durvalumab, and chemotherapy versus chemotherapy across all subgroups, including those with KRAS, STK11, and KEAP1 mutations, suggesting sustained benefit with the triplet regimen,” Dr. Peters reported.
“Our analysis supports using combined therapy of tremelimumab, durvalumab, and chemotherapy as a potential first-line treatment option for patients with metastatic NSCLC, including those with KRAS-, STK11-, or KEAP1-mutated tumors,” Dr. Peters reported.
