STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

Abstract

Background Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/ STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. Methods This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated firstline immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). Results Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/ STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. Conclusions This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or

Mechanisms of Resistance to KRASG12C Inhibitors

“…No genetic alteration, including KRAS -mutant allele frequency or STK11 mutation status, was able to predict the anti-tumour activity, although baseline gene/protein expression of members of the HER family of receptor tyrosine kinase did exhibit a trend with the degree of anti-tumour response. A small molecule screen found that HER, SHP2, mTOR and CDK4/CDK6 inhibitors increased the response rate to MRTX849 in KRAS G12C mutant xenografts [ 28 ] STK11 co-mutations in KRAS mutant NSCLC have been associated with poor response to therapy [ 32 , 33 , 34 ]; the fact that mutation in this gene did not correlate with drug resistance in cell lines offers some hope for this generally refractory group.…”

Comprehensive Molecular Characterizations of Chinese Patients With Different Subtypes of Lung Squamous Cell Carcinoma

“…A recent study reported a trend toward a reduced PFS in LUAD patients harboring STK11 mutations ( 20 ). Worse OS and PFS outcomes were also observed in NSCLC patients with STK11 mutations receiving immunotherapy or chemotherapy ( 30 ). Interestingly, Bange et al.…”

Understanding Lung Carcinogenesis from a Morphostatic Perspective: Prevention and Therapeutic Potential of Phytochemicals for Targeting Cancer Stem Cells

“…Serine/threonine kinase 11 ( STK11 ) is also one of the most frequently mutated genes in lung ADC [ 58 ]. Interestingly, mutations in this particular gene often co-occur with mutations of KRAS in NSCLCs [ 63 ]. Whether STK11 was presented as single or double mutations with KRAS , it was associated with worse overall survival (OS) and progression-free survival (PFS) in metastatic NSCLCs.…”