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Review

A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer

by
Peter Manolakos
* and
Linda D. Ward
Healthcare Genetics and Genomics PhD Program, Clemson University, Clemson, SC 29634, USA
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2023, 13(6), 1010; https://doi.org/10.3390/jpm13061010
Submission received: 6 May 2023 / Revised: 9 June 2023 / Accepted: 12 June 2023 / Published: 18 June 2023
Versions Notes

Abstract

:
The Kirsten rat sarcoma viral oncogene homolog (KRAS) and serine/threonine kinase 11 (STK11) co-mutations are associated with the diverse phenotypic and heterogeneous oncogenic subtypes in non-small cell lung cancer (NSCLC). Due to extensive mixed evidence, there needs to be a review of the recent KRAS and STK11 mutation literature to better understand the potential clinical applications of these genomic biomarkers in the current treatment landscape. This critical review highlights the clinical studies that have elucidated the potential prognostic and predictive implications of KRAS mutations, STK11 mutations, or KRAS/STK11 co-mutations when treating metastatic NSCLC across various types of treatments (e.g., immune checkpoint inhibitors [ICIs]). Overall, KRAS mutations are associated with poor prognoses and have been determined to be a valid but weak prognostic biomarker among patients diagnosed with NSCLC. KRAS mutations in NSCLC have shown mixed results as a predictive clinical biomarker for immune checkpoint inhibitor treatment. Overall, the studies in this review demonstrate that STK11 mutations are prognostic and show mixed results as predictive biomarkers for ICI therapy. However, KRAS/STK11 co-mutations may predict primary resistance to ICI. Prospective KRAS/STK11-biomarker-driven randomized trials are needed to assess the predictive effect of various treatments on the outcomes for patients with metastatic NSCLC, as the majority of the published KRAS analyses are retrospective and hypothesis-generating in nature.

1. Introduction

Lung cancer is the most common cause of cancer mortality globally, with 1.8 million deaths annually, and has one of the lowest five-year survival rates at approximately 23% [1,2]. Non-small lung cancer (NSCLC) predominates among lung cancer sub-types, representing 85% of cases, with over 40% of NSCLC patients having adenocarcinoma [3,4]. In the twenty-first century, identifying the molecular subsets of lung adenocarcinoma characterized by specific oncogenic drivers (e.g., epidermal growth factor receptor [EGFR]) has led to remarkable improvements in the treatments and outcomes for various lung cancers with tyrosine kinase inhibitors (TKI) [5]. However, one of the most prominent oncogenic drivers of lung cancer identified to date has eluded the discovery of effective therapies. KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene mutations are the most frequently reported gain-of-function driver mutations in NSCLC. They are found in 30–35% of NSCLC adenocarcinomas, with the KRAS G12C variant being the most common [6]. In a heterogeneous meta-analysis of 23 NSCLC chemotherapy-based studies, 2631 patients with KRAS mutations and an adenocarcinoma subtype had poor prognoses, with a statistically worse overall survival than patients without KRAS mutations [7]. Instead of solely focusing on chemotherapy, other compounds with various mechanisms of action were evaluated to indirectly target KRAS via downstream pathways [8]. These treatments did not improve survival in prospective studies, suggesting that KRAS-mutated proteins may need to be targeted directly [8].
Since 2016, the National Comprehensive Cancer Network (NCCN) has recommended next-generation sequencing (NGS) for metastatic non-squamous NSCLC [9]. Tumor sequencing has led to improved detection of molecular aberrations and the delivery of precision medicine. One crucial real-world outcome of increased NGS was learning that KRAS G12C commonly co-occurs with other pathogenic variants upon its diagnosis, which differs from the other established NSCLC driver mutations (e.g., EGFR) [10]. In NSCLC, the co-occurrence of KRAS and Serine/Threonine Kinase 11 (STK11) mutations is associated with the diverse phenotypic and heterogeneous oncogenic subtypes in the so-called “KRAS KL” NSCLC subgroup [11]. The KL co-mutation subgroup is designated from the K in KRAS and the L in liver kinase B1 (LKB1), also known as STK11. Unlike KRAS, STK11 is a tumor suppressor gene and is a negative regulator of mammalian targets for rapamycin (mTOR) signaling [12]. Recent prospective and retrospective clinical studies have elucidated the potential prognostic and predictive implications of KRAS mutations and KRAS and KRAS/STK11 co-mutations when treating patients with single or combined agents [13]. For example, the approval of immune checkpoint inhibitors (ICIs) has improved patient outcomes with metastatic NSCLC, regardless of their KRAS mutational status [14]. However, patients with KRAS pathogenic variants may have worse outcomes if they have co-occurring KRAS/STK11 mutations [13].
Due to extensive mixed evidence, there needs to be a review of the current KRAS literature to better understand the potential clinical benefit of identifying prognostic and predictive biomarkers in metastatic NSCLC. As a point of reference, a prognostic biomarker indicates a patient’s survival, independent of the treatment received, because this biomarker is an indicator of innate tumor behavior. A predictive marker indicates therapeutic efficacy because there is an interaction between the biomarker and the therapy that affects a patient’s outcome. Over the past ten years, the KRAS treatment landscape has progressed from standard chemotherapy to more innovative approaches investigating the predictive value of ICIs and new KRAS G12C-targeted therapies. A good method for determining whether KRAS status is a predictive factor is looking at the outcomes of various cancer treatments in randomized controlled trials. Beyond clinical trials, the advent of “real world” multi-variate database analyses has allowed for many clinicians to investigate this topic across the treatment spectrum, early in first-line therapy, and in heavily pretreated NSCLC patients across various standards of care.
KRAS-mutated NSCLC is the most common type of oncogenic-driven lung cancer in Western populations. Most of these mutations occur in exons 2 and 3 [10]. A 15-pack-year smoking history increases the likelihood of a lung cancer diagnosis involving a KRAS mutation by six-fold compared to a never-smoker (p = 0.0001) [15]. Moreover, Calles et al. revealed that smokers with KRAS-mutant tumors were more likely to express programmed cell death ligand 1 (PD-L1) [16]. KRAS G12C is the most common KRAS pathogenic variant, occurring in 40–50% of NSCLC cases, and is a critical oncogenic driver found in ~13% of all lung adenocarcinomas [17]. Within KRAS, G12C transversion mutations are more common in current or former smokers, more common in women and reflect the primary mutagenic signature of the DNA damage caused by tobacco smoke [15]. In contrast, never-smokers have a higher frequency of G12D transition mutations [15].
The prognostic and predictive implications of KRAS mutations have been analyzed across various stages of lung cancer in multiple meta-analyses [14,18,19]. The current NCCN guidelines state that: “the presence of a KRAS mutation is prognostic of poor survival when compared to patients with tumors without KRAS mutations” [20]. The predictive implications of KRAS mutations as markers of outcomes to immuno-oncology agents, cytotoxic chemotherapy, and targeted therapy are of great interest to clinicians treating metastatic NSCLC. Most recently, sotorasib and adagrasib have garnered attention as the first two FDA-approved targeted agents for previously treated patients with KRAS G12C mutations in NSCLC [21,22].
STK11 functions as a tumor suppressor gene. Located on chromosome 19, STK11 encodes for Liver Kinase B1 (LKB1), an enzyme responsible for regulating cell metabolism, motility, differentiation, and metastasis [23]. STK11 inactivation occurs via point mutations or deletions in ~10–30% of NSCLC cancers, ranking STK11 as one of the most common mutated genes in lung adenocarcinoma after TP53, KRAS, and EGFR [24]. Somatic STK11 mutations suppress programmed cell death, possibly leading to cell proliferation via an aberrant activation of the mTORC1 signaling pathway, which promotes cellular growth and tumorigenesis [25]. In addition, STK11 mutations are associated with a reduced density of tumor-infiltrating cytotoxic CD8+ T lymphocytes and an increase in pro-inflammatory cytokine production, leading to a more immunosuppressive tumor microenvironment [13]. Supporting this observation of promoting a “cold tumor” microenvironment, several studies have demonstrated that STK11 mutations are associated with a low or no PD-L1 expression and an accumulation of immunosuppressive cells and cytokines (i.e., IL-6) [26].
Unlike KRAS, the NCCN does not provide guidance on the prognostic value of STK11 mutations in NSCLC. As ICI therapy has become the standard of care in metastatic NSCLC, this biomarker has started to become more relevant. Regarding their predictive implications for outcomes, various large ICI retrospective analyses have provided mixed results on STK11 mutations [13,27].
STK11 is the second most common co-mutated gene in patients with KRAS-mutant NSCLC, occurring in approximately 20–32% of metastatic NSCLC diseases [28,29]. The so-called “KL” subset of concurrent KRAS–STK11 mutations defines a unique subset of NSCLC with an immunologically “cold” microenvironment and a more aggressive form of the disease. Often, STK11 mutations correlate with KRAS activation and promote cell growth, as cells cannot halt the anabolic process during energy stress and metabolic depletion, leading to a potential increase in glutamine dependence [30].
This review highlights the clinical studies that have elucidated the potential prognostic and predictive implications of KRAS, STK11, and KRAS/STK11 co-mutations when treating metastatic NSCLC patients across various treatments (i.e., chemotherapy and immune checkpoint inhibitors).

2. Materials and Methods

This critical review presents an analysis of the current literature specific to the prognostic and predictive implications of KRAS and STK11 mutations and co-mutations, focusing on the outcomes for patients diagnosed with metastatic NSCLC. PubMed and the Web of Science were searched using the keywords: “KRAS”, “NSCLC”, “non-small-cell lung cancer”, “prognostic”, “predictive”, “co-occurring”, “computation”, “STK11”, and “LKB1”. Boolean operators were used to connect specific search keywords. Peer-reviewed reviews and meta-analyses published in English between 2016 and 2021 were included and duplicates were removed. Articles were excluded if they were solely pre-clinical in nature or focused on early-stage disease or diagnostics. Non-NSCLC- (i.e., small-cell), non-KRAS-, or non-STK11-focused studies were also excluded from this review.

3. Results and Description of Studies

Two hundred and three articles from PubMed were identified. In addition, 265 articles were identified from the Web of Science. Ninety duplicates were removed and 428 articles remained. All the exclusion criteria were applied, resulting in forty-four studies becoming a part of this critical review. Table 1 summarizes the study designs for the articles included in this critical review.

3.1. Prognostic Implications of KRAS Mutations in Metastatic NSCLC

Various published chemotherapy-based studies about the prognostic effect of KRAS mutations in metastatic NSCLC have produced mixed results. For example, one large meta-analysis of 13 studies with over 3000 metastatic NSCLC patients reported a significantly worse progression-free survival (PFS) with a hazard ratio (HR) of 1.3; p = <0.05 for KRAS mutant patients compared to those with KRAS wild-type (WT) after receiving first- or second-line platinum-based chemotherapy [19]. Similarly, in a much smaller analysis (N = 127 patients), the overall survival (OS) was significantly shorter for patients taking second- or third-line chemotherapy with KRAS mutations vs. KRAS WT (7.2 vs. 16.2 months, p = 0.008) [31].
In contrast to the aforementioned meta-analysis that reported a worse PFS for patients with KRAS mutations, a more extensive meta-analysis of 43 observational and randomized control trials (RCTs) revealed varied outcomes for patients with this oncogenic driver mutation [32]. The RCTs in this meta-analysis did not show an effect of the KRAS variants on OS. Conversely, the pooled multivariate analysis from the observational studies demonstrated a statistically significant negative prognostic effect of the mutant KRAS (HR, 1.71) [32]. Moreover, in a different meta-analysis evaluating the circulating tumor DNA (ctDNA) in 106 advanced NSCLC patients, the KRAS mutations that were detected signified a worse OS (HR, 2.07; p = <0.01) for the patients treated with chemotherapy [33].
Many studies did not show a prognostic difference across the various KRAS subtypes in NSCLC. When comparing the KRAS G12C vs. KRAS non-G12C mutation outcomes in NSCLC across various chemotherapies, there was no difference in the patients who received first-line platinum-based chemotherapy in three multi-variate KRAS mutant analyses [34,35,36]. In the US-based chart review (N = 218), the median OS was not significantly different among KRAS G12C vs. “all other KRAS mutants” (14.6 vs. 19.6 months, p = 0.43) for the patients who received first-line chemotherapy [34]. The second analysis (N = 346) demonstrated a similar OS among the KRAS-mutated and KRAS-WT patients (p = 0.54), with a similar OS compared to the KRAS G12C patients (p = 0.39) [35]. This analysis also revealed that the prevalence of brain metastases, a negative prognostic factor, was similar between the KRAS-mutant and KRAS-WT patients (33% vs. 40%, p = 0.17). However, a different analysis (N = 756) focusing on G12C vs. KRAS WT uncovered a numerically higher number of patients with brain metastasis (23.4% vs. 14.6%) [37]. In the smallest and third analyses of the KRAS-mutated patients treated with chemotherapy (N = 37), G12C KRAS mutations had no impact on their outcomes versus all the KRAS aberrations [36].
In contrast to the previous studies showing no effect on outcomes across the KRAS sub-types in NSCLC, two chemotherapy-based studies showed survival differences. One European analysis (N = 127) showed a worse overall survival for patients with G12C vs. other KRAS mutations (6.4 vs. 10.4 months, p = 0.011) [31]. When comparing the prognostic implications of KRAS G12D vs. G12C in a different study (N = 84), the investigators found that the survival of patients with KRAS G12D was shorter than that of patients with G12C variants after most patients received first- or second-line chemotherapy (p = 0.0001) [38].
Lung cancer therapies have advanced over the past ten years. The advent of immune checkpoint inhibitors (ICIs) and ICI combinations with chemotherapy has led to many multi-variate analyses analyzing the prognostic effect of various KRAS mutations in metastatic NSCLC and the predictive effects of the newer treatments. In one of the most extensive real-world KRAS G12C analyses (N = 743) ever conducted across multiple lines of therapy (67% of patients received ICI therapy), the OS for the NSCLC G12C sub-cohort was similar to that for all the NSCLC patients (15.2 vs. 14.8 months) [37]. In support of this notion of similar outcomes for metastatic patients with KRAS G12C or KRAS non-G12C mutations, the Arbour et al. analysis of comparable size (N = 770) demonstrated similar outcomes for KRAS G12C (13.4 months) vs. non-G12C patients (13.1 months, p = 0.96) across a heterogeneously treated population with either chemotherapy or ICI [39].
When looking exclusively at ICI monotherapy in a real-world registry via the IMMUNOTARGET study (N = 271), there was no significant PFS difference found between KRAS G12C vs. KRAS G12D or other KRAS mutations (p = 0.47) [40]. Interestingly, a PD-L1-positive expression and having a KRAS mutation were correlated with a longer PFS (7.2 vs. 3.9 months) (p = 0.01) [40]. Across a more heterogeneous prospective German registry of various treatments (N = 411) and a French multi-variate analysis (N = 162), where the majority of patients had received a combination of chemotherapy and ICI or ICI alone, no OS differences were found between KRAS WT, G12C, or non-G12C mutations [41]. KRAS mutational status was not found to be prognostic [41,42].
In contrast, a Dutch multi-variate analysis (N = 1357) demonstrated that KRAS mutations were associated with a decreased median survival compared to KRAS WT after chemotherapy: 19.4 vs. 24.7 months (HR, 1.25) [43]. Regarding KRAS G12D specifically, Aredo et al. (N = 186) revealed a negative prognostic effect with this mutation, as they found a significant association with a worse OS (HR, 2.43; p = 0.021) [44].

3.2. Predictive Effect of KRAS Mutations in Metastatic NSCLC

Several analyses have described whether one type of chemotherapy could lead to better outcomes for patients with KRAS mutations. When comparing combination chemotherapy in the first-line in one of the largest real-world multivariate analyses with KRAS mutations (N = 1190) to date, the investigators found that taxane-platinum combination therapy was associated with an improved time to treatment progression (TTP) (HR, 0.31; p < 0.001), especially in KRAS G13D patients (HR, 0.47; p = 0.05), and pemetrexed was associated with a worse TTP, particularly in KRAS G12V patients (HR, 0.55; p = 0.04) [45]. However, no impact on overall survival was found across the chemotherapy regimens and various types of KRAS mutations. In comparison to Renaud’s study, a significant difference in OS (9.7 versus 26.9 months: HR 1.93, p = 0.002) was found in patients who received first-line pemetrexed-based platinum doublet compared to those who received a non-pemetrexed-based platinum doublet in a retrospective analysis of 138 patients with KRAS mutations [46]. When looking at pemetrexed vs. gemcitabine in a different analysis (N = 334), the PFS HR for pemetrexed-treated patients with a G12C (N = 13) mutation, in comparison to subjects with KRAS WT was 1.96 (p = 0.045) [47]. However, other mutations failed to show significant clinical differences [47].
KRAS-mutation sub-groups analyses have been conducted with three FDA-approved ICIs across multiple lines of therapy, via monotherapy or in combination with chemotherapy, to help explore the predictive effect of KRAS variants in metastatic NSCLC [48,49,50]. Several multi-variate studies have demonstrated multiple outcomes as the treatment landscape has progressed beyond chemotherapy with single-agent ICI in pre-treated patients. In an extensive Italian Expanded Access program (N = 530), where nivolumab was primarily used in the second-/third-line, KRAS status was found not to be a reliable predictor of nivolumab efficacy, as there were no notable differences in the median OS of 11.2 vs. 10 months (p = 0.8) in KRAS-mutated vs. KRAS-wild-type patients (p = 0.86) [48]. A German analysis supported these findings (N = 176), showing that KRAS-mutated patients did not seem to obtain a PFS benefit from ICI vs. chemotherapy when receiving ICI in the second-line with post-chemo progression [49]. In contrast, an analysis from Greece (N = 265)) showed that pembrolizumab prolonged overall survival in comparison to any other treatment (p < 0.001), and this effect was more pronounced in the KRAS-mutated patients compared to those with KRAS WT [50]. Regarding PDL1 expression, one analysis (N = 282) showed that, in KRAS-mutant NSCLC, the efficacy of ICIs was higher, even though this was not statistically significant for patients with a PD-L1 expression >1% vs. <1%. This finding of ICI efficacy was especially true when the PD-L1 expression was high (50% PD-L1 expression) [42].
To explore the potential predictive value of KRAS in immune checkpoint inhibitors (ICI), Liu conducted a heterogeneous pooled analysis of 23 studies and 5326 patients, which showed that KRAS-mutated tumors were more likely to be programmed death-ligand 1 (PD-L1)-positive (p = 0.037) and have a higher tumor mutational burden (TMB) status than KRAS WT tumors (p = 0.0002) [51]. As PDL1 expression is a predictive biomarker of ICI, this was the first reported systematic study to reveal the superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant NSCLC [51].
More specifically, analyses in two large, randomized phase 3 studies uncovered the predictive value of KRAS mutations and improvements in OS when using ICI compared to other standard-of-care treatments in patients with KRAS variants. The first meta-analysis, which included three randomized clinical trials (Checkmate-057 (N = 582), POPLAR (N = 287), and OAK (N = 850)), highlighted how ICIs significantly improved the overall survival in previously treated KRAS mutant NSCLC patients (HR, 0.64; p = 0.03) [52]. Interestingly, the second large meta-analysis of five clinical trials (N = 3025) using single-agent ICIs replicated an almost identical HR as compared to Kim’s analysis when comparing the OS in KRAS-mutated patients (HR, 0.65; p = 0.03) vs. KRAS WT patients [53]. Outside of these meta-analyses, a phase 2 single-arm atezolizumab (BIRCH) trial (N = 659) highlighted the predictive value of ICI in patients who were KRAS mutated vs. KRAS WT across different lines of therapy: not estimable vs. 20.1 months (first-line), 17.7 months vs. 15.1 months (second-line), and 12.1 months vs. 13.8 months (third-line or greater), respectively [54].
Alessi’s univariate analysis (N = 195) study showed no difference in the PFS or OS for KRAS-mutated vs. KRAS-WT patients with a >50% PDL1 expression [55]. Within Sun’s KRAS analysis of patients with a PDL1 expression greater than 50% that were treated with ICI monotherapy (N = 280), KRAS mutation was associated with a superior survival compared to KRAS WT (OS, 21.1 vs. 13.6 months, p = 0.03), and the OS did not differ between the patients with KRAS mutations treated with ICI monotherapy vs. triplet chemo-immunotherapy (OS, 21.1 vs. 20.0 months; HR, 1.03; p = 0.78) [56].

3.3. Predictive Implications of Other Treatments beyond Chemotherapy or ICI in KRAS-Mutated NSCLC

Several KRAS-mutant-focused clinical trials in clinical development have focused on tyrosine kinase inhibitors in combination with other agents and other novel mechanisms beyond chemotherapy or ICI. Major signaling pathways, including mitogen-activated protein kinase (MEK), often characterize mutant KRAS tumor proliferation and survival, so inhibiting their signaling mechanism is a valid approach for overcoming these pathways [57]. However, the majority of the agents studied did not target KRAS directly and did not predict clinical benefits. In a phase II clinical trial (N = 55), defactinib, a selective oral inhibitor of focal adhesion kinase (FAK), demonstrated modest clinical activity in heavily pre-treated KRAS-mutated NSCLC patients [70]. Focusing on the MAPK pathway in a larger phase III randomized study (N = 510), selumetinib (a MEK1 and MEK2 inhibitor) did not show an improvement in combination with docetaxel for the PFS (primary endpoint: 3.9 vs. 2.8 months, p = 0.44) or OS in pre-treated metastatic NSCLC patients [58]. Recent advances in CDK4/6 clinical development led to the phase III Juniper study. In this large, randomized trial (N = 453), abemaciclib (a potent and selective inhibitor of CDK 4 and 6) was compared to erlotinib (EGFR inhibitor) in KRAS-mutated patients who progressed after platinum-based chemotherapy and one additional therapy. Unfortunately, the primary endpoint of the OS was not reached: 7.4 months (abemaciclib) vs. 7.8 months with erlotinib (p = 0.77) [59]. In a smaller 1b clinical trial with abemaciclib in combination with pembrolizumab in KRAS-mutated patients (N = 50), the combination of abemaciclib and pembrolizumab resulted in a more significant toxicity compared to that previously reported for each individual treatment. This combination led to a higher discontinuation rate when compared to those of JUNIPER and KEYNOTE-042 (32% versus 12% and 9%, respectively) [60]. Regarding novel mechanisms, pelareorep (Dearing strain of reovirus serotype immune-oncolytic virus) was studied in the second-line in the randomized Canadian Cancer Trials Group (CCTG) IND211 trial (N = 166) [61]. Pelareorep did not improve the PFS in KRAS-mutated patients in a sub-group analysis [61].
Two agents that have gained FDA approval for metastatic NSCLC patients with KRAS G12C mutations are sotorasib and adagrasib [21,22]. In the phase 2 registrational (CodeBreaK100) trial (N = 126), sotorasib demonstrated a PFS of 6.8 months and an OS of 12.5 months in patients who were previously treated with standard therapies (90% previously treated with chemotherapy and ICI) [21]. The adagrasib approval was based on KRYSTAL-1, where its efficacy was evaluated in 112 patients: the median PFS was 6.5 months, and the median OS was 12.6 months [22].

3.4. Prognostic and Predictive Implications of STK11 Mutation in Metastatic NSCLC

In one of the most extensive STK11 mutational analyses (N = 454) ever published, the authors concluded that “STK11 mutations are prognostic and not predictive biomarkers for ICI therapy and should not be used to exclude patients from ICI therapy”, as there was no significant interaction between ICI and STK11 mutations affecting OS [62]. In support of this conclusion, a second large, real-world study focusing on STK11 in NSCLC showed worse OS outcomes in patients with STK11 mutations (N = 328), regardless of treatment (chemotherapy or ICI therapy), versus STK11 WT metastatic NSCLC [63].
Moreover, a meta-analysis including two atezolizumab clinical trials (N = 165) supported the OS improvement seen with ICI in patients with STK11 mutations [64]. Coefficients from the multivariable logistic regression model were used to create prediction scores. The prediction scores for the OS in the STK11-mutated patients with atezolizumab vs. docetaxel resulted in a statistical difference (HR, 0.21, p = 0.04) [64]. In contrast, Skoulidis et al. concluded in 2018 that STK11/LKB1 genomic changes have a deleterious influence on the clinical responses to PD-1 inhibitors in PDL1-positive NSCLC, suggesting that a lack of response is partially independent of PD-L1 expression [13].

3.5. Prognostic Implications of STK11–KRAS Co-Mutations in Metastatic NSCLC

Beyond STK11 mutations alone, the “KL” subset includes concurrent KRAS–STK11 mutations. This subset defines a unique subset of NSCLC and a more aggressive form of the disease associated with a poorer prognosis and reduced survival [13]. This prognostic effect was further exemplified in two real-world analyses, where KL was associated with a significantly worse OS, regardless of therapy [62,63]. The first analysis of 37 STK11-mutated patients demonstrated the median overall survival of KL (7.1 months) vs. STK11 alone (16.1 months) (p = 0.001) [66]. The second large analysis included 327 patients who had STK11 mutations and were treated with either chemotherapy or ICI. When treated in the first-line with chemotherapy, patients’ OSs were as follows: KL 11.7 months vs. STK11 mutated 11.7 months vs. KRAS/STK11 WT 10.0 months [62]. ICI treatment in the first-line resulted in the respective OSs of: KL 10.0 months vs. STK11 mutated 14.2 months vs. KRAS-STK11 WT 18.2 months [62]. The authors concluded that STK11–KRAS co-mutations confer a poor prognosis in NSCLC, regardless of treatment class, and that these co-mutations were enriched for negative PD-L1 staining (75.8% vs. 60.8%, p < 0.001) [62]. In a large, “real-world” study (N = 7069) across many lines of treatment (first-, second-, or third-line of therapy), KRAS G12C/STK11 co-mutations were not shown to impact the median OS as compared to KRAS WT or all NSCLC patients (including all KRAS mutations beyond G12C): 9 vs. 8.6 months, vs. 8.9 months in the patients [37]. With regard to incidence and OS, there was a significant association between the STK11 (N = 25) and KRAS statuses, where mutations co-occurred 52% of the time (p = 0.008) in Facchinetti’s analysis, but the STK11 status did not impact the OS in the multivariate analysis (N = 302) [66].

3.6. Predictive Implications of STK11–KRAS Co-Mutations in Metastatic NSCLC

Beyond randomized clinical trials, one real-world analysis (N = 95) demonstrated that STK11/KRAS co-mutations were not associated with an improved survival for patients who received nivolumab or pembrolizumab monotherapy (STK11 (HR, 1.3; p = 0.22)) [67]. Arbour et al. determined that TMB was associated with a difference in the OS from the time of initiation of immunotherapy, as patients with co-mutations and a higher TMB were found to have a more prolonged survival from the start of treatment (HR, 0.9; p = 0.02) [67]. This is in stark contrast to a previous, widely cited analysis (N = 174) pointing to the negative predictive effect of STK11 co-mutations as a major driver of primary resistance in relation to ICI [13]. Of note, there were significant differences in the response rates among the KRAS/STK11 (KL) (7.4%) vs. KRAS (28.6%) NSCLC subgroups (p < 0.001) in the Stand Up To Cancer (SU2C) cohort (primarily nivolumab treatment) and patients treated with nivolumab in the phase III CheckMate-057 (RR: KL 0% vs. KRAS 18.2%, p = 0.04) [13]. The lower response rates and trends toward inferior outcomes with ICI in the KL subgroup are thought, in part, to be due to the effects of the LKB1 loss in the tumor microenvironment, despite the presence of an intermediate or high TMB [68]. In addition, other outcomes were significantly impacted in the KL NSCLC group, as these patients exhibited a shorter progression-free (p < 0.001) and overall (p = 0.0015) survival compared to those of the KRAS mutant/STK wild-type patients [13]. In support of these results, an extensive multi-institution, multi-variate, real-world analysis demonstrated that STK11 co-mutations (N = 260) confer a worse OS after immunotherapy among patients with KRAS mutations but not among KRAS WT patients (HR, 2.09; p < 0.0001) [69].
Beyond ICI and chemotherapy, the newest KRAS-G12C-targeted therapies resulted in tumor reductions in patients with KRAS-STK11 co-mutations. Sotorasib (a KRAS G12C inhibitor) demonstrated a 50% response rate (RR) for 11 out of 22 patients with co-STK11 mutations (all the patients had KRAS G12C mutations) [21]. In addition, adagrasib showed a 64% RR for patients with concurrent KRAS and STK11 mutations [22].

4. Discussion

Overall, identifying KRAS mutations in metastatic NSCLC provides some demonstrated prognostic value. KRAS aberrations in three meta-analyses pointed to a statistically significant worse PFS (HR, 1.3) and worse OS (HR, 1.71 and 2.07) [19,32,33]. The authors concluded that “KRAS mutation is a weak but valid predictor for poor prognosis.” [19]. The current NCCN guidelines state, with a more definitive stance: “the presence of a KRAS mutation is prognostic of poor survival when compared to patients with tumors without KRAS mutations” [20].
For patients who received first-line platinum-based chemotherapy, three multivariate analyses did not show a worse prognosis if they had a KRAS G12C variant vs. KRAS non-G12 variants [34,35,36]. The Svaton et al. analysis showed a worse prognosis for KRAS G12C patients than those with KRAS non-G12C (6.4 vs. 10.4 months, p = 0.011) [31]. When analyzing G12D vs. G12C specifically, Cai’s analysis of 84 patients with KRAS mutations demonstrated that the patients with KRAS G12D had a shorter OS than those with G12C variants (p = 0.0001) [38]. However, after controlling for several variables that lead to a worse prognosis (i.e., brain metastases), it might be that the chemotherapy of choice could have led to different outcomes vs. categorizing all chemotherapies as equal in the realm of KRAS mutations [31,38].
In three retrospective studies, chemotherapy selection was possibly predictive of outcomes (taxane vs. pemetrexed vs. gemcitabine) when looking across various KRAS mutations [45,46,47]. In one of the most extensive KRAS mutation analyses to date (N = 1190), Renaud et al. found that taxane-platinum combination therapy was associated with an improved Time to Treatment Progression (TTP) HR, 0.31; p < 0.001) vs. pemetrexed, especially in KRAS G13D patients (HR, 0.47; p = 0.05), and pemetrexed was associated with a worse TTP, particularly in KRAS G12V patients (HR, 0.55; p = 0.04) [45]. In comparison to Renaud’s study, Ricciuti et al.’s study (N = 356) demonstrated a significant overall survival difference (OS 9.7 vs. 26.9 months, HR 1.93, p = 0.002) in patients who received first-line pemetrexed-based platinum doublet compared to those who received a non-pemetrexed-based platinum doublet in a retrospective analysis of 138 patients with KRAS mutations [46]. In Park’s study, the PFS was worse (HR:1.96, p = 0.045), with no difference in the OS for pemetrexed-treated subjects with G12C mutations compared to subjects with KRAS WT, but other mutations failed to show clinical significance [47].
When treating patients with KRAS aberrations using ICI, there are mixed results regarding prognoses. In one of the largest real-world KRAS G12C analyses ever conducted (N = 743), the overall survival for the NSCLC G12C sub-cohort (15.2 vs. 14.8 months) was similar compared to a cohort that included all NSCLC patients (N = 7069), regardless of driver mutation status and irrespective of the type of therapy used [37]. When looking across several meta-analyses that contained large phase III randomized studies (Checkmate-57, POPLAR, and OAK) on pre-treated patients, there was a clear predictive benefit with ICI vs. chemotherapy with regard to OS and patients with KRAS-mutated NSCLC (HR. 64, p = 0.03) [52,53].
Two important analyses from landmark studies support this notion of a KRAS-predictive effect. The KEYNOTE-042 study demonstrated a predictive effect. In this study, the first-line use of pembrolizumab monotherapy for patients with a PDL1 of > 1% and KRAS G12C mutations showed an improvement in their response rates (66.7% vs. 23.5%) and OS (28 vs. 11 months) compared to chemotherapy, but did not show an improvement among KRAS WT patients (OS 15 vs. 12 months with chemotherapy) [71]. The KEYNOTE-189 exploratory analysis demonstrated that triplet pembrolizumab-pemetrexed-platinum (irrespective of PD-L1 expression) therapy “should be considered as a standard first-line treatment for patients with metastatic non-squamous NSCLC, regardless of KRAS mutation status” [72]. There was a numerical improvement in the KRAS-mutation OS: triplet chemo-ICI therapy 21 months vs. 14 months with the chemotherapy doublet (HR, 0.79, (0.45–1.38)) and a statically significant survival benefit among KRAS-mutated patients (PFS 9 versus 5 months, HR, 0.47) [72]. When addressing a higher >50% PDL-1 cutoff, Sun et al. found a higher OS in patients treated with ICI with KRAS mutations vs. those with KRAS wild type (21.1 vs. 13.6 months, p = 0.03) [56].
Looking across various KRAS variants, the IMMUNOTARGET study found no significant PFS difference between G12 aberrations with single-agent ICI, as demonstrated with G12C vs. G12D or other KRAS mutations (p = 0.47) [40]). Regarding KRAS G12D specifically, Aredo et al. revealed a negative prognostic effect with these mutations, as they found a significant association with a worse OS (HR, 2.43; p = 0.021) [44]. Furthering the study’s analysis, a PD-L1-positive expression and positive KRAS status were correlated with a longer PFS (7.2 vs. 3.9 months, p = 0.01) [40]. Across a more heterogeneous population, no OS differences were found between patients with KRAS WT, G12C, or non-G12C mutations. In contrast, one multi-variate analysis (N = 392) demonstrated that KRAS mutations were associated with a decreased median survival in comparison to KRAS WT after first-line treatment: 19.4 vs. 24.7 months (HR, 1.25) [43].
Based on several studies, patients with STK11 mutations prognostically had a worse OS, regardless of treatment, as demonstrated in the KEYNOTE-189 analysis: (10.6 months vs. 16.7 months, HR: 1.58, p = 0.008) [62,73]. In the updated KEYNOTE-189 analysis, the pembrolizumab chemo-platinum triplet was associated with numerically better outcomes than standard chemotherapy, regardless of STK11 mutation status (HR: 0.75 (0.37–1.50)): STK11 mutation: OS 17 months (triplet chemotherapy-ICI) vs. 8 months (standard chemotherapy) and STK11 WT: 23 months vs. 12 months [73]. Interestingly, the PD-L1 Tumor Proportion Score (TPS) tended to be lower in the patients with vs. without STK11 mutations (0% vs. 15%), and the TMB score tended to be higher in patients with STK11 mutations (209 vs. 146) [73].
In one of the most extensive STK11 mutational analyses (N = 454) ever published, there was no significant predictive interaction between ICI treatment and STK11 mutations on OS [63]. The authors concluded that STK11 mutations are prognostic and not predictive biomarkers for ICI therapy and should not be used to exclude patients from ICI therapy. [63]. In contrast, the KEYNOTE-042 exploratory analysis with single-agent pembrolizumab was associated with a better OS in patients with STK11 mutations vs. without and had better outcomes than chemotherapy: 18 vs. 8 months (HR, 0.75) [74].
Patients with co-occurring KRAS and STK11 co-mutations comprise a unique subset with a more aggressive form of NSCLC, which points to a major driver of primary resistance, more so than KRAS mutations or STK11 alone [13]. For example, in Skoulidis et al.’s analysis, there was a significant predictive effect on the response rate (p = 0.001 & 0.04) when comparing KL vs. KRAS-mutated patients in Checkmate-057 (7.4% vs. 28.6) and SU2C (0% vs. 18.2%) [13]. In support of these results, Ricciuti’s real-world multi-variate analysis demonstrated that KRAS/STK11 co-mutations predict a worse OS than KRAS-mutated-STK11 WT (4.4 months vs. 20.8 months, p < 0.0001) [69]. In contrast to Skoulidis and Papillon-Cavanaugh, Spira demonstrated that KRAS G12C/STK11 specifically did not impact the median OS compared to the general NSCLC lung population [37]. More recently, when looking at ICI triplet therapy vs. chemo-doublet therapy in first-line STK11-mutated patients (non-KRAS mutated), the triplet did not improve the PFS (mPFS 4.8 m vs. 4.3 m, p = 0.75) or OS (mOS 10.6 m vs. 10.3 m, p = 0.79) [75]. The response rates with triplet ICI differed significantly between the two groups (STK11 mutated 32.6% vs. STK11 WT 44.7%, p = 0.04) compared to that with chemotherapy-platinum alone [75].
Several trials focusing on mechanisms beyond chemotherapy or ICI did not provide any survival benefit for patients with KRAS mutations. Defactinib, selumetinib, pelareop, and abemaciclib in combination with pembrolizumab, did not result in a survival benefit for patients with KRAS mutations [58,59,61,70]. The FDA approved sotorasib as the first targeted agent for patients with KRAS G12C mutations, as a result of the phase 2 CodeBreaK 100 trial [21]. More recently, in a large, randomized phase 3 study, the CodeBreaK 200 resulted in a PFS advantage (primary endpoint) of sotarasib vs. docetaxel (5.6 vs. 4.5 months) (p < 0.001), but this did not translate into an OS benefit (secondary endpoint: HR, 1.01) [76]. In addition, adagrasib was the second KRAS G12C approved by the FDA as a result of the KRYSTAL-1 study, where patients with KRAS G12C mutations had an ORR of 43% and a median duration of response (DOR) of 8.5 months [77].
There are two apparent limitations of this critical review. There was a single reviewer, increasing the risk of bias, and the dates of the articles were from 2016–2021.

5. Conclusions

The path to precision medicine has increased the use of NGS testing and improved the detection of KRAS and STK11 mutations. KRAS mutations are the most frequently reported gain-of-function oncogenic driver mutations in NSCLC. KRAS mutations are found in 30% of NSCLC adenocarcinomas, while patients with KRAS mutations are KRAS/STK11 co-mutated 15–32% of the time in the metastatic setting. KRAS mutations are associated with poor prognoses and have been determined to be a valid but weak prognostic biomarker among patients diagnosed with NSCLC. KRAS mutations in NSCLC have mixed results as predictive clinical biomarkers for immune checkpoint inhibitors treatment. STK11 mutations are prognostic and had mixed results as predictive biomarkers for ICI therapy in the studies included in this review. However, KRAS/STK11 co-mutations may predict a primary resistance to ICI. Several randomized trials focusing on mechanisms beyond chemotherapy or ICI did not result in any significant overall survival benefit for patients with KRAS mutations. The vast majority of investigators in this review conducted retrospective multi-variate analyses when looking at either KRAS, STK11, or KRAS/STK11 co-mutations. Prospective KRAS/STK11 biomarker-driven randomized trials are needed to assess the predictive effect of these mutations on the overall survival for patients with metastatic NSCLC.

Author Contributions

Conceptualization, P.M. and L.D.W.; methodology, P.M. and L.D.W.; validation, P.M.; formal analysis, P.M. and L.D.W.; investigation, P.M.; resources, P.M.; data curation, P.M.; writing—original draft preparation, P.M.; writing—review and editing, P.M. and L.D.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval was not sought for this literature review.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Special thanks to A.M.

Conflicts of Interest

P.M. is an employee of and a stockholder in Novartis®. L.D.W. declares no conflict of interest.

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Table
Table 1. Summary of study designs for articles included in this critical review.
Table 1. Summary of study designs for articles included in this critical review.
Study TitleStudy Method/
Design		Line of TherapyTreatment ArmsBiomarkerNAuthor/
Reference		Year of Publication
The prognostic role of KRAS mutation in patients with advanced NSCLC treated with second- or third-line chemotherapySingle-center, retrospective medical record review2nd- or 3rd-lineChemotherapy: Pemetrexed or docetaxel KRAS mutation39Svaton et al. [31]2016
KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: a systematic literature review and meta-analysisSystematic literature review and meta-analysis (43 studies)1st-, 2nd-, 3rd-, or 4th-line Various (including chemotherapy and EGFR inhibitors)KRAS mutation701Goulding et al. [32]2020
Prognostic value of EGFR and KRAS in circulating tumor DNA in patients with advanced non-small cell lung cancer: a systematic review and meta-analysisSystematic literature review and meta-analysis (13 studies)1st-line ChemotherapyKRAS mutation 104 Fan et al. [33]2017
First-line chemotherapy responsiveness and patterns of metastatic spread identify clinical syndromes present within advanced KRAS mutant non-small-cell lung cancer with different prognostic significanceMulti-center, retrospective medical record review1st-line ChemotherapyKRAS mutation 218Iams et al. [34]2018
Real-world outcomes in KRAS G12C mutation-positive non-small cell lung cancerSingle-center, prospective Thoracic Malignancies Cohort (TMC)1st-, 2nd-, or 3rd-line Chemotherapy +/− ICI (primarily chemo in 1st line)

Single-agent ICI (primarily in 2nd-line)		KRAS mutation 144Cui et al. [35]2020
Concomitant genomic alterations in KRAS mutant advanced lung adenocarcinomaMulti-center, multivariate analysis 1st-line ChemotherapyKRAS mutation 37Gibert et al. [36]2020
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 diseaseMulti-center (280 sites), retrospective observational cohort study1st-, 2nd-, or 3rd-lineChemotherapy with or without ICI
(67%) ICI 		KRAS mutation 743Spira et al. [37]2021
The prevalence and prognostic value of KRAS co-mutation subtypes in Chinese advanced non-small cell lung cancer patientsSingle-center, retrospective observational cohort 1st-line Chemotherapy: Pemetrexed-platinumKRAS mutation 84Cai et al. [38]2020
Treatment outcomes and clinical characteristics of patients with KRAS-G12C-mutant non-small cell lung cancerSingle-center, retrospective, medical record review Primarily 1st- or 2nd-line (49%) Platinum-doublet chemo (1L or 2L)
(46%) ICI (1L or 2L)
(39%) Single-agent PD-L1 inhibitor
(7%) Chemo combined with ICI (1L) 		KRAS mutation1194 Arbour et al. [39]2021
Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registryGlobal multi-center registry 1st–5th-lineSingle-agent ICI KRAS mutation 271Mazieres et al. [40]2019
KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nationwide CRISP Registry (AIO-TRK-0315)Multi-center (98 sites), prospective, observational registry 1st-, 2nd-, or 3rd-line (55%) Platinum doublet chemotherapy and
(45%) Chemo +/− ICI (1L)

(60%) ICI +/− chemo and (40%) chemo (2L)		KRAS mutation411Sebastian et al. [41]2021
Efficacy of immune checkpoint Inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC)Multi-center (two sites), retrospective, medical record review1st–6th-line. Primarily 2nd- or 3rd-line: 77% of patientsPrimarily 2nd- or 3rd-line single agent ICI

(88%) Nivolumab 		KRAS mutation162Jeanson et al. [42]2019
Programmed cell death ligand-1 expression and survival in a cohort of patients with non-small cell lung cancer receiving first-line through third-line therapy in DenmarkDanish Lung Cancer Registry, medical record review 1st-, 2nd- or 3rd-line ChemotherapyKRAS mutation385Hedgeman et al. [43]2021
Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomesSingle-center, retrospective medical record review NA Chemotherapy, ICI KRAS mutation
KRAS -STK11 co-mutation		202
11		Aredo et al. [44]2019
KRAS-specific amino acid substitutions are associated with different responses to chemotherapy in advanced non-small-cell lung cancer Single-center, retrospective, medical record review 1st-line Chemotherapy KRAS mutation1190Renaud et al. [45]2018
Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancerMulti-center, retrospective, medical record review 1st-line Chemotherapy-platinumKRAS mutation 138Ricciuti et al. [46]2020
KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancerSingle-center, retrospective, medical record review1st-, 2nd-, or 3rd-line ChemotherapyKRAS mutation 45Park et al. [47]2017
Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harboring KRAS mutationsMulti-center (168 centers), retrospective, medical record review. Expanded access program (EAP)2nd-, 3rd-, or 4th-line Nivolumab KRAS mutation 206Passiglia et al. [48]2019
Immune checkpoint inhibitors versus second-line chemotherapy for patients with lung cancer refractory to first-line chemotherapyMulti-center, retrospective, medical record review2nd-line ICI
Chemotherapy		KRAS mutation52Lefebvre et al. [49]2020
Association between PD-L1 expression and driver gene mutations in non-small cell lung cancer patients: correlation with clinical dataSingle center, retrospective, medical record review1st-, 2nd-, or 3rd-line ICI
(39%) Pembrolizumab single agent (1L, 2L, or 3L)
Chemotherapy 		KRAS mutation62Karatrasoglou et al. [50]2020
The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicityMeta-analysis (23 studies) 1st-, 2nd-, or 3rd-line Various
ICI
Chemotherapy		KRAS mutation (first pooled analysis) 1244Liu et al. [51]2019
Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and reviewMeta-analysis: (three trials: Checkmate-057, POPLAR, OAK)2nd- or 3rd-line Atezolizumab
Nivolumab
Docetaxel 		KRAS mutation148Kim et al. [52]2017
Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysisSystemic review and meta-analysis (five randomized trials) 2nd-line (primarily)Nivolumab, Pembrolizumab
Atezolizumab
Docetaxel		KRAS mutation148Lee et al. [53]2018
Phase II trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH)Phase II, single-arm, prospective clinical trial1st-, 2nd-, or 3rd-line AtezolizumabKRAS mutation 137Peters et al. [54]2017
Outcomes to first-line pembrolizumab in patients with PD-L1-high (≥50%) non-small cell lung cancer and a poor performance statusMulti-center (three centers), retrospective, medical record review1st-line Pembrolizumab KRAS mutation 81Alessi et al. [55]2020
Association between KRAS variant status and outcomes with first-line immune-checkpoint-inhibitor-based therapy in patients with advanced non-small-cell lung cancerMulti-center (280 centers), retrospective medical record review via Flatiron Health database1st-line ICI KRAS mutation 573Sun et al. [56]2021
Phase II study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancerPhase II, prospective clinical trial Median number of prior lines of therapy was four (range 1–8)Defactinib (Focal Adhesion Kinase Inhibitor)KRAS mutation 55Gerber et al. [57]2019
Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-Mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trialMulti-national (202 sites), 25 countries, randomized phase II, prospective trial 2nd-line Selumetinib + docetaxel
Docetaxel 		KRAS mutation 510Janne et al. [58]2017
A randomized phase III study of Abemaciclib versus Erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPERRandomized phase III, multi-center, open-label 2nd- or 3rd-line Abemaciclib
Erlotinib		KRAS mutation 453Goldman et al. [59]2020
Abemaciclib in combination with pembrolizumab for stage IV KRAS-mutant or squamous NSCLC: a Phase 1b studyMulti-center, nonrandomized, open-label, phase 1b1st-line Abemaciclib in combination with pembrolizumabKRAS mutation25Pujol et al. [60]2021
Canadian Cancer Trials Group (CCTG) IND211: a randomized trial of pelareorep (Reolysin) in patients with previously treated advanced or metastatic non-small cell lung cancer receiving standard salvage therapyMulti-center, randomized, phase II clinical trial 2nd-line Chemotherapy +/− Pelareorep NA NABradbury et al. [61]2018
Sotorasib for lung cancers with KRAS p.G12C mutationMulti-center, Phase I, clinical trial 2nd-line or greaterSotorasib KRAS mutation
KRAS-STK11 co-mutation 		126
35		Skoulidis et al. [21]2021
Targeting KRAS in non-small-cell lung cancer: Recent progress and new approachesReview that included multiple studies (including Phase I Krystal-1)2nd-line or greater Adagrasib KRAS mutation
KRAS-STK11 co-mutation		116

30		Reck et al. [22]2021
STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world.Retrospective cohort study, medical record review via Flatiron Health database1st- or 2nd-line ICI (1L or 2L)
Chemotherapy 1L 		STK11 mutation

KRAS-STK11 co-mutation 		327


156		Shire et al. [62]2020
STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohortRetrospective cohort study, medical record review via Flatiron Health database1st-line (37%) Platinum-based chemotherapy combinations
(25%) PD-1/PD-L1–based therapies
(21%) Anti-VEGF–based therapies
(14%) EGFR TKIs
(4%) Single-agent chemotherapy 		KRAS mutation

STK11 mutation 		263

454 		Papillon-Cavanaugh et al. [63]2020
Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutationRetrospective analysis of OAK and POPLAR trials and single-center retrospective (74%) 2nd-line
(26%) 3rd-line 		Atezolizumab
Docetaxel		STK11 mutation 38Nie et al. [64]2021
STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinomaRetrospective analysis of SU2C cohort and Checkmate-0572nd-line (Checkmate-057)(78%) Nivolumab KRAS-mutation
KRAS-STK11 co-mutation		218
60		Skoulidis et al. [13]2018
Impact of KRAS and TP53 co-Mutations on outcomes after first-line systemic therapy among patients with STK11-mutated advanced non-small-cell lung cancerSingle-center retrospective medical record review1st-line ChemotherapySTK11 mutation

KRAS-STK11 co-mutation 		18
19		Bange et al. [65]2019
LKB1/STK11 mutations in non-small cell lung cancer patients: descriptive analysis and prognostic valueRetrospective analysis of the MOSCATO and MSN (NCT02105168) studies 1st- or 2nd-line
(72%) 1st-line 		(72%) Chemotherapy STK11 mutation

KRAS-STK11 co-mutation 		13

12		Facchinetti et al. [66]2017
Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancerSingle-center retrospective medical record review1st- or 2nd-line Chemotherapy
Nivolumab or pembrolizumab		KRAS mutation
KRAS-STK11 co-mutation		330
95		Arbour et al. [67]2018
TP53, STK11, and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinomaSingle-center retrospective medical record review1st- or 2nd-line Nivolumab or pembrolizumabKRAS mutation
KRAS-STK11 co-mutation		11
6		Biton et al. [68]2018
Diminished efficacy of programmed death-(Ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation statusMulti-center retrospective medical record review1st- or 2nd-line (31%) ICI 1L
(69%) IC1 2L		KRAS mutation
STK11 mutation		536
260		Ricciuti et al. [69]2021
1L, 1st line; 2L, 2nd Line; ICI, Immune Checkpoint Inhibitor; VEGF, Vascular endothelial growth factor; chemo, chemotherapy; PD1, Programmed Cell Death; and PDL-1, Programmed Cell Death Ligand-1.
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Manolakos, P.; Ward, L.D. A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer. J. Pers. Med. 2023, 13, 1010. https://doi.org/10.3390/jpm13061010

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Manolakos P, Ward LD. A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer. Journal of Personalized Medicine. 2023; 13(6):1010. https://doi.org/10.3390/jpm13061010

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Manolakos, Peter, and Linda D. Ward. 2023. "A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer" Journal of Personalized Medicine 13, no. 6: 1010. https://doi.org/10.3390/jpm13061010

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