Abstract 793: Association of serine/threonine kinase 11 mutations and response to programmed cell death 1 inhibitors in metastatic gastric cancer
Authors: Minsuk Kwon, Kyung Kim, Suhye Choi, Jung Yong Hong, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Kyoung-Mee Kim, Jeeyun Lee
Journal: Cancer Research (2020)

Abstract Background: Programmed cell death 1 (PD-1) inhibitors have shown therapeutic efficacy in metastatic gastric cancer (mGC). However, only a small portion the patients derive clinical benefits from PD-1 inhibitors, and no predictive biomarkers have been established in mGC. Inactivating mutations in serine/threonine kinase 11 (STK11), also known as liver kinase B1, are associated with immune suppression in the tumor microenvironment and poor response to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. Therefore, we hypothesized that STK11 inactivating mutations would be associated with inferior clinical response to PD-1 inhibitors in mGC. Methods: We analyzed 59 patients with mGC who had been treated with PD-1 inhibitors and whose tumors had been analyzed by targeted high-throughput sequencing. Clinicopathological characteristics, including Epstein-Barr virus positivity (EBV+), programmed death-ligand 1 (PD-L1) positivity, high microsatellite instability (MSI-H), response to PD-1 inhibitors, and survival were retrospectively evaluated. Result: STK11 mutations were identified in 30 (50.8%) patients, and were all missense mutations. Three patients (5.1%) had simultaneous STK11 gene amplification and mutation. STK11 mutations were not significantly associated with MSI-H, the number of tumor mutations, PD-L1+, EBV+, or the response to PD-1 inhibitors. Patients with STK11 mutations had prolonged overall survival (median: 19.0 vs 11.6 months, p=0.15), and progression-free survival (4.2 vs 1.9 months, p=0.06) when treated with PD-1 inhibitors, but these differences were not statistically significant. In addition, the distribution of STK11 mutations was not associated with the response to PD-1 inhibitor treatment. Patients with STK11 inactivating mutations without STK11 gene amplification had significantly prolonged progression-free survival compared to patients with intact wild type STK11 or STK11 gene amplification (4.8 vs 1.0 months, p=0.04). However, in multivariate Cox regression analysis with MSI-H, PD-L1+, EBV+, the number of mutations, and type of PD-1 inhibitor used (pembrolizumab vs nivolumab), only MSI-H and PD-L1+ were significantly associated with longer progression-free survival. Conclusions: In mGC, the presence of STK11 mutation was not predictive of the response to PD-1 inhibitors. Instead, patients with MSI-H or PD-L1+ tumors displayed superior clinical responses to PD-1 inhibitors. Citation Format: Minsuk Kwon, Kyung Kim, Suhye Choi, Jung Yong Hong, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Kyoung-Mee Kim, Jeeyun Lee. Association of serine/threonine kinase 11 mutations and response to programmed cell death 1 inhibitors in metastatic gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 793.