Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status

In a cohort of patients with KRAS-mutant lung adenocarcinoma treated with anti-PD-(L)1, those with STK11 mutations had an overall response rate of 11.6% compared with 32.4% for patients with wild-type STK11.

“In a cohort of patients with KRAS-mutant lung adenocarcinoma treated with anti–PD-(L)1, those with STK11 mutations had an overall response rate (ORR) of 11.6% compared with 32.4% for patients with wild-type STK11.”

Clinical data identify STK11 loss-of-function alterations as a driver of immune evasion and resistance to immune checkpoint blockade in NSCLC tumors.

“This finding is consistent with clinical data that identified STK11 loss-of-function alterations as a driver of immune evasion and resistance to immune checkpoint blockade in NSCLC tumors (1, 6).”

In NSCLC, patients whose tumors have loss of STK11 have lower response rates to standard of care, including immune checkpoint antibodies such as anti-PD-1.

“In NSCLC, patients whose tumors have loss of STK11 have lower response rates to standard of care, including immune checkpoint antibodies such as anti–PD-1.”

STK11-mutant tumors are characterized by lower T-cell infiltration than tumors wild-type for STK11.

“STK11-mutant tumors are characterized by lower T-cell infiltration (1, 7, 8), higher levels of immune-suppressive neutrophils (8), and low levels of antigen presentation (9, 10) compared with those wild-type for STK11, contributing to their immune evasive phenotype.”

In the same cohort, overall survival for STK11-mutant patients was 6.2 months compared with 17.3 months in patients with wild-type STK11.

“Overall survival in the same cohort for STK11-mutant patients was 6.2 months compared with 17.3 months in patients with wild-type STK11 (1).”

Tumors with loss-of-function mutations in STK11 respond poorly to immune checkpoint blockade, leading to shorter progression-free survival and overall survival.

“Tumors with loss-of-function mutations in STK11 respond poorly to immune checkpoint blockade, leading to shorter progression-free survival and overall survival in these patients (1, 5, 6).”

Several studies have shown that loss of KEAP1 is also associated with immunotherapy resistance.

“Several studies have shown that loss of KEAP1 is also associated with immunotherapy resistance (1, 47).”

STK11/LKB1 mutations are associated with decreased responsiveness to immune checkpoint blockade and poor overall prognosis.

“Inactivating mutations or loss of STK11/LKB1, which define one of the major genomic sub-groups of KRAS-mutant lung cancers1,19,62, are of particular interest because they are associated with decreased responsiveness to immune checkpoint blockade9,63 and poor overall prognosis64.”

Several clinical reports have emphasized the role of KRAS comutation on the impact of STK11 loss on immune evasion.

“Several clinical reports have emphasized the role of KRAS comutation on the impact of STK11 loss on immune evasion (1, 6).”

STK11, TP53 or CDKN2A/CDKN2B co-mutations are frequent in KRAS-mutant tumours, and KRAS-STK11 or KRAS-KEAP1 co-mutation patterns are associated with treatment resistance in preclinical models and poor outcomes in NSCLC patients receiving immune-checkpoint inhibitors with or without chemotherapy.

“co-mutations in the tumour-suppressor genes STK11, TP53 or CDKN2A/CDKN2B are frequently found in KRAS-mutant tumours35. Patients in the KRAS–STK11 co-mutation group can be subdivided into KEAP1-wild-type or KEAP1-mutant subgroups, and KEAP1 can also be co-mutated with KRAS in the absence of STK11 mutations; each of these co-mutation patterns is associated with resistance to treatment in”

Clinical studies have shown that KRAS-mutant tumors with certain co-mutations, such as KEAP1 or STK11, are less responsive to certain therapeutic approaches, including anti-PD1 or KRASG12Ci.

“Clinical studies have also shown that KRAS-mutant tumors with certain co-mutations, such as KEAP1 or STK11, are less responsive to certain therapeutic approaches, including anti-PD1 (ref. 58) or KRASG12Ci (ref. 59).”

In a combined cohort of 536 patients with KRAS-mutant lung adenocarcinoma, both STK11 and KEAP1 mutations in the presence of a KRAS mutation were associated with poor response rates to anti-PD(L)1 inhibitors.

“In another recent combined cohort of 536 patients with KRAS-mutant lung adenocarcinoma, both STK11 and KEAP1 mutations in the presence of a KRAS mutation were associated with poor response rates to anti-PD(L)1 inhibitors [74].”