Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer

Introduction

Immune checkpoint inhibitors (ICIs) have become an established therapeutic option for patients with advanced non-small cell lung cancer (NSCLC). In patients with wild-type status of oncogenic driver genes, programmed death 1/programmed death ligand 1 (PD-1/PD-L1) axis inhibitors can be administered, either as monotherapy or in combination with chemotherapy. The primary objective of immunotherapy is to restore the antitumor immune response, which is typically suppressed by tumors. However, despite the significant efficacy of ICIs, their success is not universal, and not all patients, even those exhibiting high PD-L1 expression, obtain benefit from this treatment (1). The resistance to ICIs can be categorized into primary (intrinsic) resistance and acquired (secondary) resistance (2). Primary resistance in NSCLC patients occurs when the tumor microenvironment (TME) or the patient’s immune system is not conducive to an effective immune response (2). These challenging cases often present with non-driver or non-actionable mutations, characterized as tumor-intrinsic genetic abnormalities that influence the TME, thereby affecting disease progression, therapeutic outcomes, and patient survival. Acquired resistance develops during treatment and may arise through various adaptive mechanisms that allow tumors to evade immune detection and destruction (2). Among the various defense mechanisms activated by cancer cells during disease progression, particular attention is currently focused on abnormalities in the Kelch-like ECH-associated protein 1 (KEAP1), serine/threonine kinase 11 (STK11), and Kirsten rat sarcoma viral oncogene homolog (KRAS) genes (3-5). Furthermore, the analysis of genetic abnormalities in these genes at the time of diagnosis may provide predictive information regarding the success of frontline immunotherapy. Understanding the impact of these gene mutations on the functionality of cancer cells and the TME is crucial for improving the efficacy of ICIs (6).

The aim of this manuscript is to summaries data related to the effectiveness of immunotherapy alone and in combination with chemotherapy and immunotherapy in different cohorts of patients depending on the presence of genetic abnormalities in the genes discussed above.

KEAP1, STK11 and KRAS: key mechanism in tumour promotion and suppression

The KEAP1 gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis (3,7,8). Cell response to reactive oxygen species (ROS) oxidative stress is controlled by multiple cellular regulatory factors and could be divided into the following steps (3,7,8). First, the cellular protein that acts as an ROS sensor detects the presence of danger signals and transduces them into the gene expression machinery. The next step is to activate the expression of a set of stress-responsive genes involved in cellular protection (7). At the molecular level, nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of the antioxidant response. Controls the expression of genes that encode antioxidant proteins and enzymes, such as glutathione S-transferase (GST), NAD(P)H dehydrogenase 1, and heme oxygenase, which help neutralize ROS and reduce oxidative stress (4,7). KEAP1 acts as a negative regulator of NRF2. Under normal conditions, KEAP1 binds to NRF2 and promotes its ubiquitination and subsequent degradation by the proteasome, preventing excessive accumulation of NRF2 in cells. When cells experience oxidative stress, modifications in KEAP1 lead to the release of NRF2. Free NRF2 is translocated to the nucleus, where it binds to antioxidant response elements (ARE) in DNA, initiating the transcription of various cytoprotective genes involved in detoxification, antioxidant defense, and repair processes (4,7). Loss of function in the KEAP1 gene can lead to uncontrolled activation of NRF2, which, while initially protective, can paradoxically contribute to cancer progression. Hyperactivation of NRF2 in cancer cells can contribute to chemoresistance (very efficient and rapid removal of free oxygen radical induced by chemotherapy) and tumour progression. Elevated NRF2 activity supports cancer cell survival by providing enhanced antioxidant capacities, allowing them to thrive under the high oxidative stress conditions characteristic of the tumour microenvironment (4,7,8).

The KEAP1 gene is altered in 3.43% of all cancers with lung adenocarcinoma, squamous-cell lung carcinoma, colon adenocarcinoma, and breast invasive ductal carcinoma having the highest prevalence of alterations (9-11). The most common abnormalities in KEAP1 are point mutations [2.74%, e.g., substitution c.1085G>A (p.Arg362Gln) and c.959G>T (p.Arg320Leu)], KEAP1 amplification (0.29%) and homozygous or heterozygous loss of KEAP1 (0.09%) (9-11). According to the data from the American Association for Cancer Research (AACR) Project GENIE Consortium, KEAP1 is altered in 11% of NSCLC patients. The mutations are mostly located in an NRF2-binding region (11). The impact of KEAP1 mutations on the TME is profound and highly significant, influencing various immune and metabolic pathways. Firstly, these mutations are associated with a higher tumour mutations burden (TMB), resulting in a greater number of neoantigens and, consequently, greater immunogenicity of KEAP1-mutated cancer cells (12). Secondly, the highest percentage of cancer cells expressed PD-L1 was found in cancer tissue with abnormalities of KEAP1. These two are significant factors indicating the increased possibilities of the benefits of ICIs. Lastly, the KEAP1-NRF2 activation pathway can lead to the expression of anti-inflammatory cytokines and suppression of pro-inflammatory signaling. Furthermore, KEAP1-NRF2 signaling influences cell metabolism, promoting a shift toward anabolic processes, including increased glucose uptake and utilisation, enhancing the energy supply for tumour growth. In summary, these conditions create a TME that could potentially enhance the effectiveness of ICIs (12-14).

The status of KEAP1 and NRF2 is increasingly recognized as an essential factor in the prognosis of cancer and the outcome of therapy (12-14). Assessing KEAP1 mutations can help predict the aggressiveness of certain cancers and their likely response to treatment with ICIs. However, the results of clinical trials involving ICIs in patients with KEAP1 gene mutations need to be clarified and confirmed in a large group of patients, including those with other abnormalities.

The STK11 gene, also known as liver kinase B1 (LKB1), encodes a serine/threonine kinase (STK11). This protein is involved in the regulation of cell growth, polarity, motility, differentiation and cell metabolism (9,15,16). STK11 gene is altered in 3.04% of all cancers, mainly observed in lung adenocarcinoma, breast invasive ductal carcinoma, NSCLC, and colon adenocarcinoma. The most common alterations in STK11 are various point mutations (1.76%), homozygous or heterozygous loss of STK11 (0.31%), as well as STK11 amplification (0.11%) (9-11).

STK11 germline inactivating mutations cause Peutz-Jeghers syndrome, but somatic inactivation by point mutation and frequent deletion in the short arm of chromosome 19 (19p13) occurs in approximately 30% of NSCLC (10,11,17). Inactivating STK11 mutations are more common in male and smoker tumours and in poorly differentiated adenocarcinomas. STK11 inactivation appears to be particularly prevalent in NSCLC, but it is rare in small cell lung cancer (SCLC). It makes STK11 the third most frequently mutated gene in lung adenocarcinoma after p53 and RAS (9-11).

STK11 is an important regulator of cell metabolism and energy sensing and is a tumour suppressor kinase. Its functions involve activation of AMP kinase (AMPK) and AMPK-related family members (5,15,16). Therefore, loss of STK11 increases the use and synthesis of serine S-adenosyl methionine (SAM), a substrate for multiple epigenetic silencing enzymes, including DNA methyltransferase 1 (DNMT1), that can affect the expression of genes that affect immune recognition [including the DNA sensor such as the stimulator of interferon genes (STING)-related protein] and guard uncontrolled tumour growth (14-16,18). Therefore, STK11 mutations will affect the progression and development of cancer cells and inhibit the immune system in the tumour microenvironment.

Firstly, STK11 mutations are often associated with an immunologically “cold” tumour microenvironment (14-16). This means that tumours with STK11 mutations could be characterized by low or no PD-L1 expression, low T cell infiltration densities, high levels of granulocyte colony-stimulating factor and interleukin-8 (IL-8) family cytokines, high density of neutrophil-like cells, and production of myeloid cell-recruiting chemokines such as interleukin-6 (IL-6). This lack of immune cell infiltration can make tumours less responsive to immunotherapies, such as checkpoint inhibitors, which rely on the presence of immune cells to attack cancer. There is often an increased presence of regulatory T cells (Tregs), which suppress the immune response and support tumour growth (14-16).

Secondly, the STK11 protein is a crucial regulator of cellular energy homeostasis through the AMPK pathway (14-16,18,19). Mutations can disrupt normal metabolic processes, leading to altered glucose and lipid metabolism within the tumour microenvironment. Changes in metabolic products and cytokine secretion also inhibit the recruitment and activity of cytotoxic T cells that support the formation of ‘cold’ TME. Furthermore, metabolic irregularities result in hypoxic TME, further promoting angiogenesis and tumour progression. Cancer-associated fibroblasts (CAFs) in tumours with STK11 mutations are often more activated, contributing to extracellular matrix remodeling and promoting a more invasive tumour phenotype (16,18,19). Based on observational genomic studies in the real world, it could be summarized that STK11 mutations had a negative prognostic value in patients with metastatic NSCLCs, and treatment of these patients involves a multifaceted approach due to the complexity of the tumour microenvironment and the associated therapeutic resistance (6,14,20).

Considering the effectiveness of immunotherapy, it seems extremely important to indicate KRAS gene abnormalities. STK11 mutations, as well as KEAP1, often correlate with KRAS activation and result in the promotion of cell growth (6,21). KRAS is a crucial gene in cell biology, playing a significant role in several fundamental cellular processes (22). It encodes a protein that is part of the RAS family of GTPases, which acts as molecular switches within cells (6,14,21,22). The primary functions of KRAS in cell biology included: (I) regulation of signal transduction from cell surface receptors to the nucleus, promoting gene expression involved in cell growth, differentiation, and survival; (II) by activating the MAPK/ERK pathway, KRAS promotes cell proliferation crucial for normal cell growth and tissue development; (III) KRAS also interacts with the phosphoinositide 3-kinase (PI3K)/AKT pathway, which is involved in promoting cell survival and inhibiting apoptosis (21,22). Furthermore, KRAS is involved in cytoskeletal organization, migration, and cell metabolism. Genetic abnormalities in the KRAS gene are involved in oncogenic transformation. Mutations in KRAS gene are among the most common oncogenic alterations in human cancers. These mutations typically lock KRAS in its active GTP-bound state, leading to uncontrolled cell proliferation and survival, contributing to tumorigenesis and triggering cell proliferation (6,14,21,22). KRAS is the most frequent mutated oncogene in human cancer, with a prevalence of 25–30% in all human cancer cases. KRAS mutations are detected in 30–40% of patients with lung adenocarcinoma, while only 4–5% of patients with squamous-cell carcinoma. KRAS substitutions occur mainly in one of five hotspots in codons 12, 13, 61, 117, and 146, where the substitution of p.Gly12Cys (glycine-to-cysteine) accounts for 50% of all mutations in codon 12 (9-11). In historical observational studies, the risk of death in patients with advanced NSCLC was more significant in the presence of KRAS gene mutations. In the era before immunotherapy and molecularly targeted therapies, patients with KRAS gene mutations compared to patients without these mutations had a mortality risk of 1.47 compared to patients without these alterations (21).

The third most common mutation in KRAS gene is the substitution of p.Gly12Asp in codon 12 (23,24). Substitution p.Gly12Asp is observed approximately in 15% of patients with KRAS mutation (23,24). Moreover, STK11 and KEAP1 mutations co-occurred with p.Gly12Asp mutation the least common of all other mutations in the KRAS gene; 14.2% and <5% of patients with p.Gly12Asp substitution have also mutations in STK11 or KEAP1 genes (9-11). The presence of p.Gly12Asp mutation in tumor cells causes a state of immunosuppression in the tumor environment (25). The expressions of PD-L1, PD-1, TIGIT, TIM-3, and LAG-3 were up regulated on immune cells in lung cancer mouse model with p.Gly12Asp substitution (25). At the same time, infiltration of Treg lymphocytes increased. MRTX1133 is a novel non-covalent KRAS inhibitor, which showed significant preclinical antitumor activity in tumor cells with p.Gly12Asp substitution, especially pancreatic ductal adenocarcinoma (26). Treatment with MRTX1133 strongly inhibited tumor progression, reduced the percentage of Tregs and downregulated the expression of PD-1 on CD4- and CD8-positive T cells infiltrating lung cancers. MRTX1133 is being tested in clinical trials in patients with solid tumors with the p.Gly12Asp mutation in the KRAS gene (25,26).

Activation of the immune system is observed more frequently in patients with NSCLC with KRAS mutations because they are more common in smokers. Almost 90–95% of the KRAS gene mutations occur in current smokers or patients with a smoking history, predominantly women; 90% of patients with KRAS mutations have high or moderate tumour infiltration by CD8 positive T cells compared to 70% of patients without KRAS mutations. A higher tumour mutation burden (TMB) was detected as well as higher expression of PD-L1 in tumour cells (TC) in patients with KRAS mutation than in patients with KRAS wild type. This could inhibit the natural antitumor immune response in the tumour microenvironment (21,22).

Furthermore, KRAS mutations, unlike other oncogene mutations, often coexist with other abnormalities. Approximately 25% of patients mutated in KRAS also have a STK11 gene mutation, and another 25% of patients have a KEAP1 gene mutation.

It is speculated that the co-occurrence of STK11 or KEAP1 abnormalities with the KRAS mutation changes the composition of the tumour microenvironment as compared when presented alone (Table 1) (6,14). Interestingly, STK11 alterations occur more frequently in tumours with low expression of PD-L1. The coexistence of mutations in the KRAS gene and mutations in tumour suppressor genes (especially in the STK11 gene) may have an adverse effect on the course of the disease and the activity of the immune system (20,27,28). These could have a huge impact on the effectiveness of treatment in these patients. Data from the literature had shown that the presence of dual STK11 and KRAS mutations has been associated with a trend towards poorer survival outcomes in NSCLC in response to immunotherapy and chemotherapy (6,14).

Here, we analyze the effectiveness of immunotherapy alone and in combination with chemotherapy and immunotherapy in different cohorts of patients depending on the presence of genetic abnormalities in the genes discussed above.

First clinical data on effectiveness of immunotherapy in STK11-, KEAP1- and KRAS-mutated NSCLC patients

The first studies on immunotherapy effectiveness in patients with NSCLC with mutations of the STK11, KEAP1 and KRAS genes concern the second line of treatment.

Skoulidis et al. examined 174 patients from the Stand Up to Cancer (SU2C) dataset (from three cancer centres) (29). The patients were diagnosed with lung adenocarcinoma and mutations in the KRAS gene. Most patients received monotherapy with the PD-1 inhibitor in second-line treatment (146 patients were treated with nivolumab and 19 with pembrolizumab). Coexistence of mutations in the KRAS and STK11 genes was found in 31% of the patients, 32% had the coexistence of mutations in the KRAS and TP53 genes, and 37% had only a mutation in the KRAS gene. Patients with commutations in the KRAS and STK11 genes were mainly resistant to anti-PD-1 antibodies with an overall response rate (ORR) of 7.4%. In contrast, the remaining patients were more sensitive to PD-1 inhibitors with ORR of 35.7% in the group with commutations of the KRAS and TP53 genes, as well as 28.6% in the group with only KRAS mutations. The risk of progression was significantly higher in the group with mutations in the KRAS and STK11 genes compared to patients with mutations in the KRAS and TP53 genes [hazard ratio (HR) =1.77] and with only mutations in the KRAS gene (HR =1.98). On the contrary, patients with KRAS and TP53 mutations and only KRAS mutations had similar progression-free survival (PFS). The median overall survival (OS) (mOS) was 6.4 months in patients with comutations in the KRAS and STK11 genes compared to 16.0 months in patients with comutations in the KRAS and TP53 genes and 16.1 months in patients with KRAS mutations. The risk of death was significantly higher in patients with STK11 mutations compared to the remaining patients (HR =1.99). Furthermore, patients with STK11 protein deficiency (lack of STK11 protein due to the lack of STK11 expression or STK11 inactivation) had a significantly higher risk of progression (HR =1.80) and death (HR =2.03) compared to those with STK11-proficient tumours. It is important to note that abnormal STK11 activity is not always associated with the presence of mutations in the STK11 gene (29).

The authors also analysed the impact of the cooccurrence of STK11 and TP53 genetic alterations in 44 patients with KRAS mutations from the CheckMate-057 clinical trial. Next-generation sequencing was performed using whole exome sequencing technology in patients. Twenty-four patients received nivolumab (anti-PD-1 antibody) and 20 patients were treated with docetaxel. Six patients with mutations in the KRAS and STK11 genes were refractory to nivolumab therapy. However, 4 of 7 patients (57.1%) with mutations in the TP53 and KRAS genes and 2 of 11 patients (18.2%) with only a mutation in the KRAS gene responded to ICIs therapy. Although ORR did not differ significantly between the three subgroups in the docetaxel arm. The small number of patients within the subgroups resulted in the inability to determine whether STK11 mutations are a prognostic or predictive factor for treatment results in the CheckMate-057 data set. Median values of PFS and OS could also not be reliably determined (29).

The analysis mentioned above was deepened by Ricciuti et al. The authors identified 1,261 patients with advanced adenocarcinoma treated with immunotherapy in four cancer centers: Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan Kettering Cancer Centre, and MD Anderson Cancer (14). Among these patients, 873 (69.2%) received second-line immunotherapy. Mutations in the KRAS gene were detected in 536 (42.5%) patients. Cooccurring mutations in the KRAS and STK11 genes, the KRAS and KEAP1 genes, as well as STK11 and KEAP1 were found—respectively—in 10.9% (138 of 1,261), 8.4% (101 of 1,202), and 9.4% (113 of 1,202); 147 patients (11.6%) had mutations in the STK11 gene, and 118 patients (9.8%) had mutations in the KEAP1 gene without coexistence with mutations in the KRAS gene. Gene alterations were determined using the Next Generation OncoPanel (DFCI) and MSK-IMPACT (MSKCC) sequencing platforms (14).

A harmful effect of STK11 mutations on immunotherapy results was observed only in patients with mutations in the KRAS gene. These patients with STK11 mutations had significantly lower median PFS (mPFS) (2 vs. 4.8 months) and mOS (6.2 vs. 17.3 months) and higher risk of progression (HR =1.46) and death (HR =1.73) in multivariate analysis compared to patients with KRAS gene mutations and wild type STK11 gene (wt). The STK11 mutation was associated with significantly worse ORR in patients with KRAS mutations but not in KRAS wt patients. ORR was 11.6% in the first group of patients and 23.8% in the second group of patients. However, in the absence of STK11 mutations, ORR was higher in the group of patients with a mutation in the KRAS gene than in patients with wild-type KRAS (32.4% vs 19.1%). STK11 mutations were associated with significantly worse clinical outcomes in patients mutated with KRAS regardless of PD-L1 expression status and type of KRAS substitution (p.Gly12Cys, p.Gly12Val and p.Gly12Asp) (14).

Similarly, KEAP1 mutations were also associated with decreased survival in ICIs-treated adenocarcinoma patients, but only in those patients with KRAS gene mutations. In multivariate models, patients with commutations in the KEAP1 and KRAS genes had a higher risk of progression (HR =2.15) and death (HR =2.44) compared to patients with only mutations in the KRAS gene. The mPFS and mOS were 1.8 vs. 4.6 months, as well as 4.8 and 18.4 months, respectively. ORR in the group of patients with commutations in the KEAP and KRAS gene was 17.8%, and in the group of patients with only mutations in the KEAP1 gene it was 26.1%. ORR was similar in patients with a mutation in the KRAS gene but without a mutation in the STK11 gene (29.3%) and in patients with mutations in the STK11 gene but without a mutation in the KRAS gene (26.1%). KEAP1 loss was associated with worse immunotherapy results in patients with PD-L1 expression in <50% of TC and did not depend on genetic variants in the KRAS gene. The impact of concurrent STK11 and KEAP1 mutations on ORR, mPFS, and mOS was found in patients with KRAS mutations, suggesting an additive effect of STK11 and KEAP1 comutations on immunotherapy outcomes (14).

The authors also explored the impact of STK11 and KEAP1 mutations on chemotherapy efficacy in The Cancer Genome Atlas (TCGA) cohort. In this group of patients with adenocarcinoma, they found that STK11 and KEAP1 mutations were associated with significantly shorter PFS among patients with KRAS mutants, but not in patients with the wild-type KRAS gene, suggesting that loss of STK11 or KEAP1 may be a poor prognostic factor (14).

Effectiveness of first-line immunotherapy or combined two ICIs in STK11-, KEAP1- and KRAS-mutated NSCLC patients

Mok et al. evaluated the clinical utility of TMB mutations, as well as STK11, KEAP1, and KRAS mutations, as biomarkers for pembrolizumab monotherapy (anti-PD-1 antibody) (30). The authors analyzed 793 patients from the KEYNOTE-042 trial who were treated with pembrolizumab or platinum-based chemotherapy. Patients with advanced NSCLC had expression of PD-L1 in 1% of chemotherapy and mutational status was examined with the next generation sequencing (NGS) technique in the whole exon sequencing (WES) option. STK11 mutations were detected in 7.7% of the patients (33 of 429), KEAP1 mutations—in 14.9% of the patients (64 of 429) and KRAS mutations—in 22.9% of the patients (69 of 301). Twelve patients (2.8%) had both STK11 and KEAP1 mutations. In the STK11- and KEAP1-assessable population, 29.8% were patients with SCC. In patients with STK11 mutations, the expression of PD-L1 was lower and the TMB was higher than in patients with wild-type STK11. PD-L1 expression was similar in patients with and without KEAP1 mutations. However, TMB was higher in patients with KEAP1 mutations than in patients with wild-type KEAP1 (wt). In patients with KRAS mutations, both PD-L1 expression and TMB were higher than in patients without these mutations (30).

An improvement in OS was observed for pembrolizumab vs. chemotherapy regardless of the presence of mutations in the genes analyzed. The reduction in death risk was the following: 63% for STK11-mutant patients (HR =0.37), 17% for STK11 wt patients (HR =0.83), 25% for KEAP1-mutant patients (HR =0.75), 22% for KEAP1 wt patients (HR =0.78), 58% for KRAS-mutant patients (HR =0.42) and 14% for patients of KRAS wt (HR =0.86). A high reduction in the risk of death occurred in patients using pembrolizumab compared to chemotherapy in patients with the p.Gly12Cys mutation in the KRAS gene (HR =0.28). The ORR for pembrolizumab vs. chemotherapy was 31.3% vs. 5.9% in patients with the STK11 mutation and 29.4% vs. 23.6% for wild-type STK11 patients. The ORR was 35.5% for pembrolizumab vs. 18.2% for chemotherapy in patients with KEAP1 mutant and 28.6% vs. 22.9% for KEAP1 wild-type patients. ORR in the pembrolizumab and chemotherapy groups was 56.7% and 18.0% in patients with KRAS mutant, 66.7% and 23.5% in patients with p.Gly12Cys mutation, as well as 29.1% and 21.0% in patients with KRAS wild-type (30).

In the phase 3 MYSTIC study, 1,003 patients with NSCLC were treated with first-line monotherapy with durvalumab (anti-PD-L1 antibody) or durvalumab in combination with tremelimumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody] or chemotherapy (31). Blood TMB and mutations in the STK11, KEAP1, and ARID1A genes were evaluated. Circulatory tumour DNA (ctDNA) was profiled from baseline blood samples using the GuardantOMNI platform. High TMB has been associated with improved OS and PFS with first-line durvalumab or durvalumab with tremelimumab vs. platinum-based chemotherapy. However, specific gene mutations have been associated with resistance (STK11 and KEAP1) or sensitization (ARID1A) to anti-PD-1 monotherapy. In non-squamous NSCLC patients, the mutation frequencies were the following: 19% for STK11 mutations, 20% for KEAP1 mutations, and 11% for ARID1A. However, in squamous-cell tumours, the frequencies were lower and reached 7%, 13%, and 15%, respectively. Patients with STK11 mutations or KEAP1 mutations had a shorter mOS than patients without these mutations. In STK11 or KEAP1 mutated patients vs. non-mutated STK11 patients, mOS was as follows: 10.3 vs 13.3 months in patients treated with durvalumab; 4.4 vs. 11.3 months in patients treated with durvalumab with tremelimumab and 6.7 vs. 13.1 months in patients receiving chemotherapy. Patients without KEAP1 mutations also had a higher mOS, which in each study arm was as follows 14.6, 11.3, 13.3 months. Furthermore, patients with ARID1A mutations receiving durvalumab with tremelimumab had a higher mOS than patients without ARID1A mutations (23.2 vs. 9.8 months) (31).

In the CheckMate-227 Part 1 clinical trial, first-line nivolumab in combination with ipilimumab demonstrated a long-term and durable clinical benefit vs. chemotherapy in patients with NSCLC (32). In non-squamous NSCLC patients, the FoundationOne CDx TM assay was used to identify KRAS, STK11, and KEAP1 mutations. Nivolumab with ipilimumab improved OS compared to chemotherapy in patients with or without KRAS, STK11, or KEAP1 mutations; however, the subgroups with mutations were small [78 patients (16.4%) with STK11 and 38 patients (8%) with KEAP1 mutations]. The reduction in death risk by immunotherapy compared to chemotherapy was the following: 21% (HR =0.79) for patients with KRAS mutations (mOS 17.5 vs. 15.7 months), 27% (HR =0.73) for patients without KRAS mutations (mOS 20.6 vs. 17.9 months), 22% (HR =0.78) for patients with STK11 mutations (mOS 10.8 vs. 11.2 months), 25% (HR =0.75) for patients without STK11 mutations (mOS 21.2 vs. 8.5 months), 69% (HR =0.31) for patients with KEAP1 mutations (mOS 24.4 vs. 8.9 months), and 20% (HR =0.80) for patients without KEAP1 mutations (mOS 20.1 vs. 16.7 months) (32).

The presence of STK11 mutations seems to be a poor prognostic factor regardless of the type of treatment in NSCLC patients. The non-randomised controlled phase 2. The TELMA clinical trial included patients with NSCLC with high TMB (over 10 mutations/megabase) and without alterations in the genes EGFR, ALK, STK11, MDM2, or ROS1. This single-arm study used first-line treatment with atezolizumab (anti-PD-L1 antibody) and bevacizumab [anti-vascular endothelial growth factor (VEGF) antibody]. The results confirm that strict qualification for treatment based on the exclusion of poor predictive genetic factors can improve the effectiveness of immunotherapy. The 12-month PFS rate was 51.3% and the 12-month OS rate was 72.0%. The mPFS was 13.0 months, and the mOS was not reached (33).

Effectiveness of immunotherapy combined with chemotherapy in patients with STK11, KEAP1 and KRAS mutated NSCLC

Data from clinical trials of immunochemotherapy in advanced NSCLC are based on exploratory analyses of subgroups, mainly patients diagnosed with non-squamous NSCLC.

The multi-arm CheckMate-227 trial also included a Part 2 that evaluated the value of combining nivolumab with chemotherapy regardless of PD-L1 expression (34). Pathogenic variants in the STK11 and KEAP1 genes were found in 23% and 8% of patients, respectively. A trend toward prolonged OS with nivolumab plus chemotherapy (vs. chemotherapy) was observed in the overall population analysed regardless of gene status: mOS 18.8 vs. 15.6 months, HR =0.86, 95.62% confidence interval (CI): 0.69–1.08, P=0.18. At the same time, the benefit of immunochemotherapy was similar in the STK11 mutant vs. STK11 wt and KEAP1 mutant vs. KEAP1 wild-type subgroups. However, the small size of the subgroups limits the interpretation of the results (34).

An exploratory molecular profile analysis was also performed in patients treated in the KEYNOTE-407 and KEYNOTE-189 trials (35). The prevalence of high mutations of tissue tumour mutational burden (tTMB) and STK11, KEAP1, and KRAS was assessed. Of the 289 patients evaluated in KEYNOTE-189, 18.7% had STK11 mutations. Pathogenic variants KEAP1 and STK11 were found to be more common in patients with lower expression of PD-L1 (additional differences were observed depending on TMB levels). In the STK11 mutant group, lower percentages of objective responses to immunochemotherapy (30.6% vs. 48.8%), while in the STK11 mutant group, the benefit of immunochemotherapy in terms of PFS was limited HR for PFS 0.81 (95% CI: 0.44–1.47) and HR for OS 0.75 (95% CI: 0.37–1.50). Similar results were observed in patients with KEAP1 mutations. It should be noted that the subgroups analysed were small, which makes reliable conclusions difficult. In the population of the KEYNOTE-407 study, only 2% of the patients had a mutation in the STK11 gene, so no comparative analysis was performed (35).

A publication presenting the results of the CM9LA trial, updated after 3 years, confirmed the superiority of nivolumab and ipilimumab in combination with chemotherapy vs. chemotherapy alone in the total population analysed; mOS was 15.8 and 11 months, respectively (HR =0.74; 95% CI: 0.62–0.87) (36). Comutation status was known in 313 patients diagnosed with non-squamous NSCLC—in this group, pathogenic variants in the KRAS, TP53, STK11 and KEAP1 genes were detected in 39%, 60%, 27%, and 10% of patients, respectively (30). There was a trend toward prolonged OS after immunochemotherapy in the groups of patients with pathogenic variants, but the differences were not statistically significant. The small size of the subgroups limits the value of these observations (36).

An updated analysis of the POSEIDON trial, which evaluated the value of combining chemotherapy (C) with durvalumab +/− tremelimumab (DT + C), showed that patients in the three-drug arm benefited from treatment in terms of OS compared to chemotherapy (HR =0.75; 95% CI: 0.63–0.88); a trend toward longer OS was also observed in the DT + C arm (HR =0.84; 95% CI: 0.71–0.99) (37). The greatest clinical benefit was observed in patients with non-squamous NSCLC: mOS was 17.2 months for the triplet arm compared to 13 months for chemotherapy (HR =0.68; 95% CI: 0.55–0.85). The DT + C regimen was shown to be the most effective (relative to chemotherapy) in both STK11 mutant (found in 87 patients)—HR =0.62 (95% CI: 0.34–1.12) and STK11 wt—HR =0.70 (95% CI: 0.55–0.89) (38). Similar observations were made for patients with KEAP1 mutation (n=51)—HR =0.43 (95% CI: 0.16–1.25) and KEAP1 wild-type—HR =0.75 (95% CI: 0.63–0.89). No data on the efficacy of treatment were presented in patients with the coexistence of two pathogenic variants, of which the coexistence of mutations in the KRAS gene and p53 is the most significant (38).

Among the 920 patients in the IMpower50 study population, 24.5% of the patients had pathogenic KRAS mutations, 14.5% had the STK11 mutant, and 15.5% had tumours of the KEAP1 mutant. At the same time, it was found that in the KRAS mutant patient group, commutations were present in 44.9% of patients (39). A multiagent regimen that includes platinum-based chemotherapy, atezolizumab, and bevacizumab provided clinical benefit in patients with KRAS mutants regardless of commutation status (39).

A summary of the presented clinical data is presented in Table 2.

The real-world data analysis of immunotherapy’ effectiveness in STK11-, KEAP1- and KRAS-mutated NSCLC patients

Sun et al. presented an analysis of a group of 2,593 patients treated daily—patients with non-squamous NSCLC predominated (74.3%), 62.6% of patients received immunochemotherapy based on a single ICI (40). In the whole population analysed, 37.9% had mutations in the KRAS gene—differences were observed in the frequency of abnormalities in the KRAS gene determined by PD-L1 expression (most frequent in the group of patients with PD-1 expression 50–45%). At the same time, it was found that in the group of patients with PD-L1 0% with mutations in the KRAS gene, the presence of KEAP1/STK11 commutation was found more frequently, in a total of 60% of the patients, while in the group of patients with high expression of PD-L1, only 18% of the patients were found. The presence of mutations in the KRAS gene (against the KRAS wt variant) was a negative prognostic factor only in the group of patients without PD-L1 expression in TC (for OS—HR =1.46, 95% CI: 1.18–1.8, P=0.001; for PFS—HR =1.23, 95% CI: 1.01–1.49, P=0.035). However, regardless of PD-L1 expression, the prognosis was particularly unfavourable for patients in whom KEAP1/STK11 commutations coexisted with mutations in the KRAS gene. The risk of death increased for patients with PD-L1 expression in TC for 0%, 1–49% and >50% of TC—HR =2.73 (P<0.001), HR =2.64 (P<0.001) and HR =2.35 (P=0.008), respectively (40).

In an analysis presented by Arbour et al. of a group of 330 patients with advanced and recurrent NSCLC with confirmed KRAS gene mutations, the most common coexisting mutations were in the genes TP53 (42%), STK11 (29%) and KEAP1/NFE2L2 (27%) (41). In a subgroup analysis of patients (n=86) receiving immunotherapy (nivolumab or pembrolizumab in second-line treatment), the coexistence of abnormalities in the KEAP1/NFE2L2 gene appeared to be a negative predictor of OS—HR =1.96 (95% CI: 1.33–2.92, P<0.001). No such association was confirmed for the other commutations (42). Similar, in an analysis of 377 patients treated with pembrolizumab in combination with chemotherapy, the presence of the STK11/LGB1 mutation (n=102) correlated with significantly shorter PFS (mPFS 4.8 vs. 7.2 months, HR =1.5; 95% CI: 1.1 to 2.0; P=0.0063) and OS (mOS 10.6 vs. 16.7 months, HR =1.58; 95% CI: 1.09 to 2.27; P=0.0083). KRAS gene variants were not assessed (42).

Julian et al. presented an analysis of a group of 2,715 patients, 445 of whom had the p.Gly12Cys variant in the KRAS gene (43). The variant p.Gly12Cys variant of the KRAS gene was correlated with a trend toward longer OS, both in patients treated with immunotherapy in the first and second lines. The co-occurrence of STK11 and KEAP1 mutations was associated with significantly shorter OS in both KRAS wt and KRAS mutant patients. In patients with KRAS wt receiving first-line immunotherapy and immunochemotherapy (n=512), a significantly shorter mOS was observed in patients with the STK11/KEAP1 mutant variant, which comprised 10% of the analysed group, compared to the median STK11 wt/KEAP1 wt of 5.8 vs. 10.1 months (HR =1.81; 95% CI: 1.44–2.26; P<0.001). Nonsignificant differences were also observed between STK11 mutant/KEAP1 wild-type patients vs. STK11 wild-type/KEAP1 wild-type patients (7.5 vs. 10.1 months, HR =1.27; 95% CI: 1.00–1.62; P=0.05) and STK11 mutatnt/KEAP1 wild-type patients vs. STK11 wild-type/KEAP1 wild-type patients (8.8 vs. 10.1 months, HR =1.21; 95% CI: 1.00–1.48; P=0.06). Similar observations were made in the KRAS p.Gly12Cys population: STK11 mutant/KEAP1 mutant patients had the least favorable prognosis (19.4% of KRAS p.Gly12Cys patients) compared to STK11 wild-type/KEAP1 wild-type, the mOS was 6.4 vs. 15.0 months (HR =1.93; 95% CI: 1.35–2.75; P<0.001). The authors did not provide detailed information on treatment regimens, although given the analysis based on daily practice and patients treated between 2009 and 2020, it is reasonable to assume that most of the immunochemotherapy cases were based on pembrolizumab (43). In contrast, Papillon-Cavanagh et al. presented the results of an analysis of 574 patients who received immunotherapy in the first-line setting (20). Pathogenic variants of STK11/KEAP1 were found in 20% of patients, more frequently in patients with low expression of tumour PD-L1. The STK11/KEAP1 mutant profile was found in 13% of patients receiving immunotherapy. The authors did not observe a statistically significant predictive value of molecular abnormalities in the STK11/KEAP1 genes for PFS and OS, although a less favourable outcome was observed in patients with the STK11 mutant patients (HR =0.88; 95% CI: 0.43–1.81; P=0.06). Furthermore, pathogenic variants also appeared to be negative prognostic factors in the chemotherapy group.

Conclusions

STK11 and KEAP1 gene mutations have an impact on the prognosis of patients treated for advanced NSCLC, especially if they coexist with mutations in the KRAS gene. It is worth noting that patients with this molecular profile are significantly more likely to have low PD-L1 expression—in group of patients with no PD-L1 (0%) expression, 27% of KRAS mutant patients had comutations in both genes, while in a group of PD-L1 expression over 50%—only 4% (41). The presented results indicate also the prognostic, but not predictive, role of mutations in the STK11 and KEAP1 genes with reduction of the effectiveness of all systemic treatment methods in patients with advanced NSCLC. However, immunotherapy as monotherapy or as a combination of two ICIs in patients with PD-L1 expression or high TMB appears to be more effective than chemotherapy alone, as shown by the results of the KEYNOTE-042, CheckMate-227, and MYSTIC trials. Ongoing prospective clinical trials, for example TRITON, taking into account the molecular profile of patients eligible for ICIs, may clarify the importance of pathogenic variants in the STK11 and KEAP1 genes (44-46).

In conclusion, it is important to underscore that the molecular profiling of patients diagnosed with advanced NSCLC should encompass not only the identification of targetable mutations but also the detection of pathogenic variants in the STK11, KEAP1, and KRAS genes. This comprehensive approach has the potential to significantly enhance the stratification of patients for immunotherapy, thereby improving clinical outcomes.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-552/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-552/coif). M.K.W. reports advisory boards for BMS, MSD, and Takeda; invited lectures for BMS, MSD, Astra Zeneca, Takeda, and Roche; travel grants from Astra Zeneca and MSD. K.W.K. reports invited lectures for BMS, MSD, and Astra Zeneca. P.K. reports lectures, participation in congresses and advisory boards for Roche, Amgen, BMS, MSD, Takeda, Jansen and Astra Zeneca. M.K. reports advisory boards for BMS, MSD, Roche, and Astra Zeneca. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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