Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).

Abstract

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p < 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

“…Furthermore, the KRAS p.G12C mutation was observed in the presence of high STK11 mutation levels in this study, as has recently been reported by others in a single treatment center [39]. STK11 mutations have been observed at a high rate in NSCLC and even higher in KRAS mutated NSCLC; the KRAS p.G12C/STK11 co-mutation pattern has been associated with lower overall survival and resistance to immune checkpoint inhibitors [38,[40][41][42][43][44]. KEAP1 mutations were prevalent in the G12C cohort, as well as the other cohorts in this study; although others have reported even higher levels of KEAP1 co-mutation [39].…”

KRAS G12 isoforms exert influence over up-front treatments: A retrospective, multicenter, Italian analysis of the impact of first-line immune checkpoint inhibitors in an NSCLC real-life population

“…In the BATTLE-1 trial, patients were exposed to several TKIs; however, this evidence suggested a modulation of the pathways when mutations are exposed to similar treatments. Similar to our data, the mPFS of C and V isoforms exposed to ICI was 4 months, but the authors highlighted a worsening PFS in those who have STK11/LKB1 comutations ( 63 ); unfortunately, this information is not available in our dataset. The disadvantageous weight of the V isoform has been extensively described ( 47 , 64 – 66 ), and contrary to what has been reported in the literature ( 63 , 67 ), our series was released from the high expression of PD-L1.…”

Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors

“…Furthermore, with the improvement of precision detection technology, the accurate analysis of negative mutation sites helps to identify the possibly effective ones. For example, the analysis of study data of second-line PD-1/L1 inhibitor therapy found that the mPFS of patients with KRAS G12C or G12V was significantly better than that of patients with KRAS mutations at other sites [52].…”