MA19.09 Concurrent Mutations in STK11 and KEAP1 is Associated with Resistance to PD-(L)1 Blockade in Patients with NSCLC Despite High TMB

Abstract

cfRNA and PD-L1 with clinical response to therapy (chemotherapy, immunotherapy (IMMUNO) or targeted therapy) in stage IV NSCLC pts. Our group has been the first one to use cfRNA to detect PD-L1. Method: Blood was drawn from 31 pts under various treatments (tx) every 6-8 weeks, at the same time that CT scans were done. CfRNA was extracted from the resulting plasma and reverse transcribed with random hexamers to cDNA. Levels of cfRNA were quantitated by RT-qPCR and correlated with pts clinical response (CR/PR/SD/PD), as determined by CT scans. Result: A total of 31 lung cancer pts were enrolled in a 2-year clinical study. 25 of 31 pts completed already the first two cycles of tx and had CT scans done. Of these, 6/8 pts with progressive disease (PD) showed increased (INC) levels of cfRNA, 9/13 pts with stable disease (SD) showed either no change (NC) or decreased (DEC) cfRNA, and 4/4 pts with partial response (PR) had NC or DEC cfRNA, corresponding to 76% concordance between cfRNA and clinical responses. PD-L1 expression measured in plasma cfRNA matched the tissue expression in 7/10 pts. In the one pt where PD-L1 was (-) in blood and (+) in tissue there was PD on IMMUNO. Among 8 pts treated with IMMUNO: 3/3 pts with PD showed INC PD-L1 cfRNA expression, 3/3 pts with SD had NC in negative PD-L1 status, and 2 pts with PR showed DEC PD-L1 cfRNA, corresponding to 100% correlation between PD-L1 expression levels and pt response. Of the 31 pts, 32% (10/31) harbored KRAS mutations in cfDNA. Of those with KRAS+ status by tissue-based testing, 83% matched with cfDNA results. Among KRAS+ pts, 80% (8/10) showed PD-L1 cfRNA expression in same blood draws with KRAS+ cfDNA, suggesting correlation between these cfDNA and cfRNA analyses. Conclusion: Significant association was observed between clinical response and changes in plasma cfRNA levels in NSCLC pts (76%). There was concordance between tissue-and blood-based testing in both DNA (KRAS mutations, 83%) and RNA (PD-L1 expression, 70%). While on IMMUNO levels of PD-L1 expression could be used to monitor response to immunotherapy.

Choosing the best first-line therapy: NSCLC with no actionable oncogenic driver

“…These findings suggest that STK11 mutation is not only a poor predictive marker for response to chemoimmunotherapy compared with those without the mutation, but also that immunotherapy has no survival benefit added to chemotherapy in STK11 -mutated patients. KEAP1 , a gene that encodes for a protein that assists in transportation of NF-E2 related factor 2 to the cell nucleus, has been shown to be co-mutated often with STK11 , and it has been demonstrated in a small cohort study of 308 patients, those who had co-mutations in STK11/KEAP1 had less favorable OS and PFS compared with STK11 wt/ KEAP1 wt patients when treated with PD-L1 inhibitor despite high TMB in STK11/KEAP1 mutant patients [ 37 ]. Thus, while prior data suggest that STK11 and KEAP1 mutations might serve as emerging markers to select patients who may not receive benefit from immunotherapy, more recent data, suggest lack of correlation.…”

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

“…PD-L1 expression on tumor cells has been used to guide treatment selection, and more recently tumor mutational burden (TMB) has shown potential as a predictive biomarker for IO benefit [12][13][14][15]. Mutations in individual genes and co-mutation patterns have also been linked to patient response to standard chemotherapy and/or IO in advanced NSCLC [16][17][18][19][20][21][22][23][24].…”

Hyperprogression on immunotherapy with complete response to chemotherapy in a NSCLC patient with high PD-L1 and STK11

“…[ 19 ] STK11 and KEAP1 comutations occur in approximately 13% of all lung cancers with a higher median tumor mutational burden (9.4 vs 6.1) and are associated diminished outcomes in PFS and OS when treated with ICIs. [ 20 ] STK11-mutated patients represent a subgroup of NSCLC patients where new treatment strategies are needed. Continued evaluation of STK11 mutations and their role in HPD in NSCLC is reasonable.…”