Immunotherapy in advanced,KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions

Abstract

Kirsten rat sarcoma (KRAS) mutations are present in up to 25% of non-small-cell lung cancer (NSCLC). KRAS G12C is the most common type of mutation, representing approximately half of the cases in KRAS-mutant NSCLC. Mutations in KRAS activate the RAF-MEK-ERK pathway, leading to increased cell proliferation and survival. Recent advances in drug development have led to the approval of KRAS G12C inhibitors sotorasib and adagrasib. This review explores the emerging therapeutic strategies in KRAS G12C-mutant NSCLC, including dual checkpoint blockade and combinations with checkpoint inhibitors, with a focus on the setting of advanced disease.

Plain language summary

Review on the use of immunotherapy in lung cancer harboring KRAS G12C mutation

In lung cancer, certain genes drive the growth of the disease. One common mutation is in the KRAS gene, specifically the KRAS G12C mutation, which occurs in about half of KRAS lung cancer. This mutation is particularly important because there are treatments that target this mutation. Immunotherapy, a treatment that boosts the immune system to help it recognize and attack cancer cells, has shown to be effective in this type of cancer. This review focuses on the latest treatment options for KRAS G12C, including immunotherapy and targeted KRAS G12C inhibitors.

Keywords

chemoimmunotherapy immunotherapy KRAS G12C inhibitors non-small cell lung cancer

Introduction

Kirsten rat sarcoma (KRAS) oncogene is the most common oncogene driver mutation in cancer and is found in approximately 25% of non-small-cell lung cancers (NSCLC). In the year 1982, it was the first human oncogene to be discovered.¹ Despite its early identification, KRAS is known as the “undruggable target” due to the lack of classic drug target sites, its high affinity for GTP, and its unusual shape. Recent progress in drug development led to the design of small-molecule inhibitors that target KRAS G12C mutations. This game-changer has opened the door for new treatment options with recent approvals of AMG510 (sotorasib) and MRTX849 (adagrasib).^2,3 This review will focus on KRAS G12C-mutated NSCLC, exploring its role in tumor growth as an oncogene driver mutation, as well as current and future therapeutic strategies that involve immunotherapy.

KRAS is a RAS protein that is part of the small GTPase family.⁴ These proteins are intracellular guanine nucleotide-binding proteins (G proteins) that regulate cell growth and survival.⁴ It shifts cyclically between an active GTP-bound state and an inactive GDP-bound state. Two important regulatory proteins control this shifting process: guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs).⁵ When the GEFs interact with the KRAS-GDP complex, the KRAS-GDP complex has decreased affinity to GDP and GDP is replaced with GTP. GTP has higher affinity and concentration than GDP. The KRAS-GTP complex acquires a change in conformation in switches I and II of the G domain leading to KRAS activation.⁶ On the other hand, GAPs promote binding between KRAS and GDP by promoting the GTPase activity of KRAS to maintain the inactive GDP-bound state.

When KRAS is activated, it triggers multiple downstream signaling pathways that drive cancer growth. The RAF-MEK-ERK pathway is the main downstream pathway of KRAS signaling. Activated KRAS-GTP leads to phosphorylation events involving MEK1/2 and ERK1/2. These events regulate the transcription and translation of specific genes, subsequently influencing cell proliferation and survival.⁷

Another pathway involved is the PI3K-AKT-mTOR pathway which is crucial for cellular growth, metabolism with glucose transportation, and apoptosis.⁸ KRAS can activate PI3K which leads to downstream activation of AKT and mTOR proteins. Activation of mTOR proteins leads to cell proliferation and survival. AKT phosphorylates and activates Bcl-XL/Bcl-2-associated death promoters, eventually inhibiting apoptosis.⁹

RAL guanine nucleotide dissociation stimulator is another downstream signaling KRAS protein. It functions as a GTP/GDP exchange factor to promote conversion from RAL GDP to RAL GTP.^10,11 The downstream factors from RAL proteins include Rac/cell division cycle 42 (CDC42) for cell migration, TANK-binding kinase 1 associated with viral immunity, and phospholipase D involved with endocytosis^10,11 (Figure 1).

Figure 1.

Schematic illustration of the KRAS signaling pathway. KRAS activation leads to downstream signaling through the RAF-MEK-ERK, PI3K-AKT-mTOR, and RalGDS pathways.

Mutations in KRAS, particularly at codons 12 (G12), 13 (G13), and 61 (Q61), affect the protein’s GTPase activity. As mentioned above, these mutations lead to continuous activation of the signaling pathways.¹² KRAS mutations are common in NSCLC, pancreatic adenocarcinoma, and colorectal cancer. The KRAS G12C mutation is the most common type of KRAS-mutated lung cancer.¹³ Up to 80% of patients with KRAS-mutant NSCLC have a smoking history, in comparison to KRAS G12D, which is more frequent in non-smokers. KRAS G12C is more common in women who are often younger with less smoking history than men.¹⁴

Rationale for immunotherapy in KRAS-mutated NSCLC

The use of immunotherapy with immune checkpoint inhibitors such as pembrolizumab, nivolumab, cemiplimab, and atezolizumab has transformed the treatment landscape in lung cancer, improving survival in patients with advanced and now early-stage disease.^15–21

The presence of a KRAS mutation is associated with an inflamed tumor microenvironment (TME) and increased tumor immunogenicity.²² KRAS-mutant tumors have greater T-cell infiltration compared to KRAS-wild-type tumors.²² This contributes to enhanced response to immunotherapy. KRAS-mutant tumors have an increased proportion of programmed death-ligand 1+ (PD-L1+)/TIL+ suggesting an inflammatory phenotype and adaptive immune resistance.²² A study has shown KRAS mutation leads to upregulation of PD-L1 through the p-ERK signaling pathway.²³ Mutation profile analysis showed that KRAS mutations are associated with increased tumor mutational burden (TMB) and immunogenicity.²² High TMB reflects genomic instability leading to increased neoantigen production that can attract immune cells.²⁴ In addition, high TMB has been linked to smoking and alteration in DNA replication and damage repair genes in KRAS-mutant NSCLC.^24–26

KRAS mutations are typically mutually exclusive of other actionable alterations such as EGFR and ALK. There is heterogeneity in clinical outcomes of patients with KRAS-mutant NSCLC based on co-occurring alterations. The most common co-mutations in KRAS-mutant NSCLC are STK11 (serine/threonine kinase 11), KEAP1 (Kelch-like ECH-associated), TP53, SMARCA4, and CDKN2A/CDKN2B.²⁷ Each of these co-mutations can influence the biology and immune microenvironment of the cancer (Figure 2).

Figure 2.

Summary of the effects of co-mutations on the tumor microenvironment in KRAS-mutant NSCLC.

STK11, also known as LKB1, acts as a tumor suppressor gene that regulates cell metabolism and growth by phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases.^28,29 Loss of STK11 in KRAS-mutant tumors promotes interleukin-6 (IL-6) production which attracts neutrophils, decreases T-cell infiltration, and leads to higher T-cell exhaustion.³⁰ NSCLCs with STK11-loss also express low levels of PD-L1.³¹ The inactivation of STK11 leads to an “immune-cold” TME and is associated with poor response to immunotherapy.^28,30,32 STK11 co-mutation occurs in approximately 10%–28% of KRAS G12C-mutant NSCLC.³³

KEAP1 protein is a negative regulator of the NRF2 pathway, which is involved in the oxidative stress response by triggering antioxidant and anti-inflammatory effects.³⁴ Mutations in KEAP1 lead to NRF2 activation, promoting cell growth and chemoresistance. KEAP1 mutations occur in about 11% of NSCLC.³⁵ KRAS-mutant NSCLC with concurrent KEAP1 and/or STK11 mutations had worse outcomes compared to those without KEAP1 and STK11 mutations. The presence of KEAP1 mutations alone or in combination with STK11 mutations is associated with worse progression-free survival (PFS) and overall survival (OS), even with the use of chemo-immunotherapy. A study showed that the median OS for patients with KRAS/STK11 double-mutant NSCLC was 12 months compared to KRAS-mutant only NSCLC was 21 months (hazard ratio (HR) 1.7, 95% confidence interval (CI): 1.1–2.4, p = 0.002).²⁷ In the same study, KEAP1 co-mutation had a median OS of 10 months (HR 2.1, 95% CI: 1.4–3.1, p < 0.0001).²⁷

KRAS mutations influence the TME, leading to immune evasion and reduced effectiveness of therapies especially immunotherapy.^36,37 KRAS mutations promote immune escape by producing pro-inflammatory cytokines and chemokines, such as IL-6, IL-8, and GM-CSF.³⁸ These factors attract immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the TME. This inhibits the immune response against the tumor. KRAS-mutant tumors have increased expression of PD-L1, which interacts with the PD-1 receptor on T cells to suppress their antitumor activity.³⁹ These tumors typically have reduced infiltration of cytotoxic T lymphocytes (CTLs) essential for effective antitumor response and have increased infiltration by immunosuppressive cells such as MDSCs and Tregs.^37,40

KEAP1 and STK11 mutations are associated with an adverse immunosuppressive microenvironment, creating resistance to immune checkpoint inhibitors. This microenvironment is characterized by the depletion of CD8⁺ cytotoxic T cells while preserving the CD4⁺ effector subsets.⁴¹ Adding CTLA4 blockade to PD-(L)1 inhibition might mitigate this resistance. The combination of PD-(L)1 and CTLA4 inhibition utilizes two critical aspects of the suppressive STK11MUT and/or KEAP1MUT NSCLC tumor immune microenvironment. The first is the retention of anti-CTLA4-responsive CD4+ T cells, including TH1 T cells. The second is the reprogramming of myeloid-cell-rich tumor ecosystem to inducible nitric oxide synthase (iNOS)-expressing tumors in response to dual immune checkpoint blockade (ICB).⁴¹

Emerging evidence suggests that STK11 and KEAP1 mutations are not equivalent in effect and that predicting immunotherapy outcomes solely based on the presence or absence of these mutations may be insufficient.⁴² For example, truncating mutations in STK11 are more frequent in exons 1 and 2 which are associated with a worse prognosis compared to mutations in exons 3–9.⁴³ KEAP1 mutations are distributed throughout the gene and less clustered in specific hotspot regions.³⁵ The functional impact of these missense mutations remains unknown and suggests the need for more accurate classification based on pathogenicity, protein expression, and downstream effector activity.⁴² Mutation clonality can also impact immunotherapy efficacy. Clonal mutations with loss of heterozygosity in KEAP1, unlike subclonal mutations, are associated with resistance to PD-(L)1 monotherapy and a T-cell-excluded microenvironment.⁴⁴ The observation that some STK11 and KEAP1-mutated tumors may still respond to ICI highlights the importance of identifying factors that can guide clinical decisions. For example, for those without concurrent KRAS mutations with subclonal STK11 or KEAP1 mutations and high PD-L1 expression levels, PD-(L)1 monotherapy may be sufficient. Alternatively, those with low or negative PD-L1 expression, concurrent KRAS mutation, truncating mutations, or clonal mutation may require PD-(L)1 inhibitor combination therapies with chemotherapy or CTLA4 inhibitor.⁴²

A SMARCA4 co-mutation occurs in nearly 6% of KRAS-mutant lung cancers.⁴⁵ SMARCA4 encodes the SWItch/Sucrose NonFermentable complex, which controls gene expression by altering chromatin structure.^46,47 The loss or mutation of SMARCA4 disrupts chromatin remodeling and may dysregulate transcription programming.⁴⁸ Lung adenocarcinomas with KRAS-SMARCA4 co-mutations, treated with or without immunotherapy, have poor survival outcomes.^45,49 These co-mutations were found to have lower proportions of CD8 and activated CD4+ T cells than those found in KRAS-mutant only and KRAS-TP53-mutant lung cancers, indicating an immunosuppressive TME.⁴⁵

Tumors with both KRAS and TP53 co-mutations in NSCLC have demonstrated high TMB, high PD-L1, and high tumor cell proliferation.⁵⁰ Genome-wide expression analysis showed that KRASmut/TP53mut overexpress the CX3CL1 gene. In its soluble form, the CX3CL1 chemokine (additionally termed fractalkine) can attract immune effector cells such as tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells to the tumor leading to antitumor immune effect.^51,52 In lung adenocarcinoma, increased mRNA expression of CX3CL1 was associated with improved OS.⁵² This gene is also associated with increased myeloid diversity and improved response to immunotherapy; thus, it could potentially be a biomarker of response in lung cancer.⁵³

Testing for KRAS mutations by genomic profiling is recommended in NSCLC.⁵⁴ Liquid biopsy for plasma NGS testing can provide a noninvasive option for detecting these mutations. Routine testing for co-alterations such as STK11, KEAP1, and TP53 mutations is not yet recommended by clinical guidelines, though many NGS vendors already include this information in their NGS profile reports. While not yet standard in clinical practice, these mutations are increasingly being recognized as prognostic biomarkers and may eventually guide treatment decisions.

KRAS inhibition

AMG-510 and MRTX849 are the two pioneers of allosteric inhibitors for KRAS G12C. These inhibitors can form covalent bonds with the mutant cysteine in codon 12 to inhibit GDP-GTP exchange and maintain the KRAS protein in its inactive state, preventing downstream signaling pathways.^55,56 The drugs not only have direct anticancer activity but they also exhibit immune-modulatory effects that contribute to their efficacy. Preclinical studies of AMG-510 demonstrated that this drug increases the infiltration of T cells, mainly CD8+ T cells, into the tumor. It induces a pro-inflammatory microenvironment marked by increased interferon signaling, chemokine production, antigen processing, cytotoxic and natural killer cell activity, along with markers of innate immune system activation. The inflamed TME renders the tumor more responsive to immune checkpoint inhibition.⁵⁷

Resistance to KRAS inhibitors represents a challenge in the treatment of KRAS-mutant NSCLC. Many patients demonstrate primary resistance and never respond to the molecules, while other patients may initially respond but subsequently develop resistance leading to treatment failure and disease progression. The mechanisms of resistance to KRAS inhibition are multifaceted. Studies have shown that co-occurring mutations in KEAP1, SMARCA4, and CDKN2A are associated with poor OS in those with NSCLC treated with sotorasib or adagrasib.^58,59 Regarding secondary resistance, in one study by Awad et al.,⁶⁰ genomic and histologic analyses were performed using tumor biopsy samples of those who developed resistance after treatment with adagrasib monotherapy in KRAS G12C-mutant cancer. In 45% (17/38) of patients, a possible mechanism of resistance was identified such as a secondary KRAS mutation including KRAS^R68S, KRAS^H95D/G/N/R, and KRAS^Y96C/D/H/N or amplifications in KRAS. Alternative oncogenic alterations that activate the RTK-RAS signaling pathway, without affecting KRAS, were seen, as were two cases of histologic transformation from lung adenocarcinoma to squamous-cell carcinoma. However, in the majority of patients, no new genomic event was detected to explain the pattern of resistance.⁶⁰

Current strategies: Immunotherapy for KRAS G12C NSCLC

As of the writing of this article, patients with KRAS G12C mutations are treated in the frontline with non-selected, immunotherapy-based treatments, with or without chemotherapy.⁶¹ KRAS G12C inhibitors are currently used in the second line as monotherapy after both demonstrated an improvement in PFS over docetaxel in randomized clinical trials.^62,63 Many retrospective studies have examined the efficacy of currently available immunotherapy-based regimens specifically in the KRAS-mutated patient population.

Single-agent immunotherapy

For patients with metastatic NSCLC with PD-L1 ⩾50%, regardless of squamous or non-squamous histology, there are currently three available single-agent immunotherapies that are approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA): pembrolizumab, atezolizumab, and cemiplimab.^{15,16,18,64–66}

Regarding the efficacy of immunotherapy specifically in the KRAS-mutated NSCLC, a subgroup analysis of patients enrolled on KEYNOTE-042 has been performed.⁶⁷ KEYNOTE-042 randomized patients with PD-L1 expression ⩾1% to either single-agent pembrolizumab or chemotherapy.⁶⁸ A subgroup analysis of outcomes by KRAS mutational status included only 12 patients with a KRAS G12C mutation.⁶⁷ While this group was small, the ORR was 66.7% (95% CI: 34.9–90.1), mPFS 15 months (95% CI: 10–NR), and mOS not reached (95% CI: 23–NR), suggesting these patients did not perform worse than those without KRAS G12C mutations.⁶⁷ Additional retrospective data have suggested that PD-L1 expression, both >1% and ⩾50%, is particularly predictive for ICI efficacy in patients with KRAS mutations.⁶⁹

Several groups have published conflicting results regarding the efficacy of immunotherapy for KRAS G12C versus KRAS non-G12C. One single-center retrospective analysis performed at Memorial Sloan Kettering indicated that patients treated with first-line immunotherapy may have worse outcomes for those with KRAS G12C when compared with those with KRAS non-G12C mutations.³³ Landmark 12-month PFS was 59% (22/37) in patients with non-G12C subtypes, compared with only 29% (11/38) with G12C mutations.³³ This analysis was not designed to compare outcomes with patients without KRAS mutations.

However, additional data have suggested that for patients with a PD-L1 expression ⩾50%, KRAS G12C mutations were associated with improved outcomes with first-line single-agent immunotherapy when compared to either patient with KRAS non-G12C mutations or KRAS wild-type tumors.^70–72 Among 696 patients from the German National Network Genomic Medicine Lung Cancer who were PD-L1 ⩾50%, patients with a KRAS G12C mutation demonstrated a longer PFS (25.3 (14.3–36.2) months) compared with non-G12Cmut KRAS (9.6 (7.1–12.1)) and KRASwt patients (10.3 (8.0 = 12.5) months). For patients with a KRAS G12C mutation, a TP53 co-mutation predicted an increased response rate (69.7% vs 46.5%) for TP53-mutated (TP53mut) versus wild-type as well as PFS (HR = 0.59, p = 0.009), with a trend toward improvement in OS (HR = 0.72, p = 0.16).¹⁹ For patients with KRAS G12C/TP53 co-mutations with a PD-L1 ⩾50%, there was an impressive mPFS and mOS (33.7 and 65.3 months, respectively).¹⁹ An additional data set demonstrated that TP53/KRAS co-altered NSCLC derived significant clinical benefit from PD-1 inhibitors, more than either the KRAS-mutated/TP53 wild-type or KRAS wild-type groups. However, this analysis was not restricted to KRAS G12C specifically.⁷³ A similar multicenter study from France of 681 non-squamous patients with PD-L1 ⩾50%, which included 86 patients with KRAS G12C mutations, demonstrated a mPFS of 7.0 months (3.7–14) for KRAS G12C with a mOS of 18.4 (12.6–NR) months, with similar results seen in both KRAS non-G12C and wild-type KRAS.⁷⁴

We anticipate future data will more accurately describe efficacy outcomes in this patient population, given there are a number of prospectively enrolling clinical trials detailed below of frontline treatment of patients with KRAS G12C with single-agent immunotherapy control arms. In the interim, however, these data cumulatively show that frontline immunotherapy is efficacious for patients with KRAS G12C mutations and that alterations such as TP53 can potentially predict patient outcomes.

Single-agent immunotherapy in combination with chemotherapy

For patients with PD-L1 0%–49%, there are multiple combinations of chemotherapy plus single-agent immunotherapy that have demonstrated significant clinical benefit and are FDA- and EMA-approved. Pembrolizumab plus chemotherapy, cemiplimab plus chemotherapy, and atezolizumab plus chemotherapy with or without bevacizumab all have demonstrated improvements in patient outcomes over chemotherapy alone.^75–79 The majority of patients with KRAS G12C mutations with PD-L1 0%–49% will be treated with one of these regimens, similar to those patients without KRAS G12C mutations. Understanding how patients with KRAS G12C mutations specifically perform using these regimens has never been prospectively studied. However, similar to single-agent immunotherapy, multiple retrospective analyses have been conducted that were either subgroup analyses of clinical trials or multicenter retrospective cohort studies to better inform both our prognostic and predictive understanding of these patients.

A subgroup analysis of KEYNOTE-189 of patients treated with pembrolizumab plus chemotherapy included 26 patients with a KRAS G12C mutation, who demonstrated an ORR of 50% versus 47.5% in patients without any KRAS mutation.⁸⁰ Progression-free survival was 11 months (95% CI: 6–18), while it was 9 months (95% CI: 7–14) for those without KRAS mutations.⁸⁰ Median OS was 18 months (95% CI: 11–NR) with KRAS G12C, while it was 23 months in those without KRAS mutations.⁸⁰

In a multicenter study of 138 patients with KRAS G12C treated with first-line chemo-immunotherapy, ORR was 41% (95% CI: 32–41), mPFS was 6.8 months (95% CI: 5.5–10), and mOS was 15 months (95% CI: 11–28).⁸¹ When compared with patients with non-G12C KRAS mutations, in an adjusted analysis, there was not a statistically significant difference in PFS (HR 0.82, 95% CI: 0.61–1.11, p = 0.2) or OS (HR 0.55, 95% CI: 0.30–1.01, p = 0.053).⁸¹ These data demonstrate that patients with KRAS G12C mutations can derive significant benefits from treatment with combination chemo-immunotherapy. We will obtain prospective data on the effectiveness of chemoimmunotherapy for patients with KRAS G12C mutations from the control arms of the upcoming phase III, randomized, first-line trials investing novel agents in the previously untreated setting, such as the CodeBreak202 trial.⁸²

Doublet immunotherapy with or without chemotherapy

Doublet immunotherapy combinations currently available include nivolumab plus ipilimumab with or without chemotherapy, as well as tremelimumab plus durvalumab with chemotherapy.^83,84 Subgroup efficacy analysis has been performed for patients with KRAS mutations for CheckMate 227, CheckMate 9LA, and POSEIDON, though none of these analyses differentiate between KRAS G12C and non-G12C.^83,85–87

The CheckMate-227 trial compared ipilimumab plus nivolumab to chemotherapy.⁸⁴ In the KRAS mutant population, ipilimumab/nivolumab outperformed chemotherapy with a mOS of 17.5 versus 15.7 months (HR 0.79, 95% CI: 0.55–1.12).⁸⁵ With the addition of two cycles of chemotherapy in CheckMate 9LA, at the 3-year update, patients with a KRAS mutation demonstrated an improvement in mOS at 19.2 versus 13.5 months (HR 0.72, 95% CI: 0.48–1.08).⁸⁷

POSEIDON was a three-arm randomized trial of tremelimumab plus durvalumab plus chemotherapy, durvalumab plus chemotherapy, or platinum chemotherapy alone. In the KRAS-mutated subgroup, tremelimumab, durvalumab, and chemotherapy demonstrated an impressive mOS of 25.7 months compared with 10.4 months with chemotherapy (HR 0.56, 95% CI: 0.36–0.88).⁸⁶ Similarly in the durvalumab, tremelimumab, and chemotherapy arm, mPFS was 8.5 versus 4.7 months with chemotherapy alone (HR 0.57, 95% CI: 0.35–0.92).⁸⁶ Based on the results of these three trials of dual checkpoint blockade, the combination of doublet immunotherapy plus chemotherapy could be considered for patients with KRAS G12C mutations, though with the disclaimer that none of these data sets differentiated between KRAS G12C and KRAS non-G12C.

One of the biggest limitations of using dual checkpoint blockade is the increased risk of immune-related adverse events (irAEs) over single-agent immunotherapy regimens. However, as the science of predicting which patients are at higher risk for adverse events evolves, dual checkpoint blockade may be able to be used with decreased toxicity. As an example, germline single-nucleotide polymorphism data were used in a cohort of patients to develop and validate polygenic risk scores for hypothyroidism, which could predict the development of thyroid irAEs (HR per SD = 1.34; 95% CI: 1.08–1.66; AUROC = 0.6).⁸⁸ In a separate study, distinct human lymphocyte antigen-DR alleles were associated with specific immunotherapy-related adverse events, such as type 1 diabetes or hypophysitis.⁸⁹ Utilizing genetic biomarkers to better understand toxicity risks will allow for informed patient discussions and shared decision-making regarding the optimal treatment strategy.

Effect of co-mutations on immunotherapy efficacy

STK11 or KEAP1, occurring either independently or as co-mutations concurrent with KRAS, is increasingly being recognized as both prognostic and perhaps also predictive.⁹⁰ STK11 co-mutations occur in 28% of patients with KRAS G12C mutations, and KEAP1 occurs in 23%.³³ Co-mutations in STK11 or KEAP1 have both been demonstrated to be associated with inferior outcomes with immunotherapy in patients with KRAS G12C.^27,32,44,58

As a specific example, in a combined cohort from four medical centers of 1261 patients, STK11 was associated with significantly worse PFS (HR 2.04, p < 0.0001) and OS (HR 2.09, p < 0.0001).³¹ Similarly, KEAP1 demonstrated inferior outcomes both of PFS (HR = 2.05, p < 0.0001) and OS (HR 2.24, p < 0.0001).³¹ Interestingly, the inferior outcomes of STK11 and KEAP1 were observed only in patients with co-mutations in KRAS, but not in patients who had KRAS wildtype.³¹ Similar results were found also for patients treated with chemotherapy alone.⁹¹

In KEYNOTE-189, whole-exome sequencing data from both tumor and normal DNA were evaluable for 289 (47%) of 616 patients, of whom 54 (19%) had an STK11 mutation and 68 (24%) had a KEAP1 mutation; 29 (10%) had both STK11 and KEAP1 mutations. PD-L1 Tumor Proportion Score (TPS) tended to be lower in patients with versus without STK11 mutation (median (IQR) 0% (0–16) vs 15% (0–75)), whereas TMB score tended to be higher in patients with mutation (209 (132–265) vs 146 (89–264)). Similar patterns were seen for patients with or without KEAP1 mutation (PD-L1 TPS: 1% (0–13) vs 20% (0–75); TMB: 173 (124–267) vs 147 (89–263)). Although the ORR of pembrolizumab plus chemotherapy was lower and PFS and OS shorter in patients with versus without STK11 and KEAP1 mutation, pembrolizumab plus chemotherapy was associated with numerically better outcomes than placebo plus chemotherapy regardless of mutation status, and the 95% CIs were wide given the modest mutation frequency and the 2:1 randomization in favor of pembrolizumab plus chemotherapy for patients with metastatic nonsquamous NSCLC, regardless of STK11 or KEAP1 status.⁹²

A recent publication from Skoulidis et al.⁴¹ demonstrated that for patients with STK11 and/or KEAP1, the addition of a PD-L1 inhibitor durvalumab did not improve outcomes over chemotherapy; however, dual checkpoint blockade with the addition of tremelimumab, a CTLA4 inhibitor, to the PD-L1 and chemotherapy combination showed clinical benefit.

This strategy will be studied prospectively with the TRITON study, which is enrolling patients with metastatic non-squamous NSCLC with KRAS mutations and/or STK11 and/or KEAP1.⁹³ Patients will be randomized to either tremelimumab, durvalumab, and chemotherapy versus pembrolizumab plus chemotherapy.⁹³

Moving forward, as the next wave of clinical trials is designed for patients with KRAS mutations, consideration should be given to the stratification of patients by specific allele or co-mutation status. Stratifying based on STK11 or KEAP1 co-mutations may allow for a more nuanced understanding of treatment efficacy, as well as a more personalized treatment approach. Prospectively designing trials that are statistically powered to understand the effect of these co-mutations will allow for a greater understanding of small, unplanned, retrospective analyses, to guide future clinical decision-making and design more effective treatment paradigms.

Combining KRAS G12C inhibition with immunotherapy

KRAS G12C inhibitors including sotorasib and adagrasib have demonstrated clinical activity in the second line, with an improvement in response rate and PFS over docetaxel.^62,63 However, sotorasib did not demonstrate a statistically significant improvement in OS over docetaxel.⁶³ Monotherapy use of a KRAS G12C inhibitor is unlikely to provide robust benefit in front line setting due to the resistance mechanism from KRAS G12C inhibition.⁶⁰ Therefore, multiple clinical trials were designed to assess the safety and efficacy of immunotherapy in combination with KRAS G12C inhibitors. As detailed above, there is additionally a strong preclinical rationale for combining a KRAS G12C inhibitor with immunotherapy.⁹⁴

Second line and beyond

Sotorasib is a small-molecule inhibitor of KRAS G12C that binds specifically and irreversibly.⁶³ In the second line, sotorasib demonstrated a response rate of 28.1% (95% CI: 21.5–35.4) and a mPFS of 5.6 months (95% CI: 4.3–7.8).⁶³ The first data presented the combination of immunotherapy with a KRAS inhibitor for patients with KRAS G12C mutations was from the CodeBreaK 100/101 studies, in which patients with KRAS G12C-mutated NSCLC received sotorasib at varying dose levels in combination with either atezolizumab 1200 mg q3w or pembrolizumab 200 mg q3w (see Table 1). Of patients enrolled, 67% had received prior immunotherapy, with a median of 1 prior line of therapy (range 0–7). Patients received sotorasib either concurrent with IO or sequentially with a sotorasib safety lead-in before starting IO. The combination was deemed unsafe to proceed with additional development, given that 57% (33/58) of patients had a grade 3 or 4 treatment-related adverse events, primarily hepatotoxicity. Despite the limiting toxicity, the combination showed that KRAS inhibitors plus immunotherapy could be efficacious, and lead to durable responses. The ORR was 29% (17/58), 83% disease control rate (48/58), and the duration of response was 17.9 months (95% CI: 5.6– not estimable (NE)). Median OS was 15.7 months (95% CI: 9.6–17.8).⁹⁵

Table 1.

KRAS G12C inhibitors in combination with immunotherapy.

Study	Drug combination	Indication, sample size	ORR (%)	Safety profile (common AEs with %)
Treatment naïve
KRYSTAL-7 Garassino et al.¹⁰⁰	Adagrasib + pembrolizumab	Treatment-naïve; any PD-L1 enrolled (n = 148); efficacy data restricted to PD-L1 ⩾50% (n = 54)	RR: 63% (32/51, PD-L1 ⩾50%)	Nausea (51%), diarrhea (44%), ALT increase (38%), AST increase (32%)
NCT05067283 Rojas et al.¹⁰²	MK-1084 + pembrolizumab	Treatment naïve; PD-L1 ⩾1% n = 31	RR 70% (19/27)	ALT increase (26%); AST increase (23%); pruritis (23%); diarrhea (23%)
LOXO-RAS-20001 Burns et al.⁹⁷	Olomorasib + pembrolizumab	Treatment naïve; any PD-L1 expression n = 17	RR: 77% (13/17)	Diarrhea 23%, ALT increase 20%; AST 16%
LOXO-RAS-20001 Fujiwara et al.¹⁰⁴	Olomorasib + pembrolizumab + chemotherapy	Treatment naïve; any PD-L1 expression n = 21	RR: 50% (10/20)	Anemia (43%), nausea (38%), ALT increase (29%), AST increase (24%)
Second line and beyond
LOXO-RAS-20001 Burns et al.⁹⁷	Olomorasib + pembrolizumab	Prior chemotherapy, anti-PD-(L)1, and KRAS G12C inhibitor therapy allowed; any PD-L1 expression; n = 48	RR: 40% (17/43)	Diarrhea 23%, ALT increase 20%; AST 16%
CodeBreaK 100/101 Li et al.⁹⁵	Sotorasib + pembrolizumab or atezolizumab; administered concurrent or with sotorasib lead-in	Received (or refused) prior standard therapies; no prior KRAS G12Ci; n = 58	RR: 29% (17/58)	Any ⩾Grade 3 TRAE: 55% (32/58); hepatotoxicity 53% (10/19) in concurrent arm; 47% (9/19) in lead-in arm
NCT04449874 Sacher et al.⁹⁹	Divarasib ± atezolizumab	At least 1 prior treatment; prior KRAS G12Ci allowed; any PD-L1; n = 39	All patients: 42.1% (16/38); No prior KRAS G12Ci: RR: 55.6% (15/27)	Nausea (64%); diarrhea (62%); vomiting (49%); AST increase (26%); ALT increase (26%)

AE, adverse event; KRAS G12Ci, Kirsten rat sarcoma G12C inhibitor; ORR, overall response rate; PD-L1, programmed death-ligand 1; RR, response rate; TRAE, treatment-related adverse event.

Olomorasib is a second-generation KRAS G12C inhibitor with significant single-agent activity and tolerability.⁹⁶ It has been studied in combination with pembrolizumab in 43 previously treated patients with NSCLC, of which 81% (35/43) had received prior immunotherapy. The ORR was 40% (17/43). The most common grade 3 toxicities observed were diarrhea (13%), ALT (6%), and AST (8%).⁹⁷ Data have not matured sufficiently to know the mPFS or mOS of this group.

Divarasib is a KRAS G12C inhibitor with high potency and selectivity that binds irreversibly in the inactive state.⁹⁸ Single-agent activity in a heavily pretreated patient population demonstrated an ORR was 53.4% (95% CI: 39.9–66.7), with an mPFS of 13.1 months (95% CI, 8.8 to could not be estimated).⁹⁸ Divarasib at a 200 and 400 mg dose has been combined with atezolizumab 1200 mg IV q3w in 39 patients who were previously treated, of which 90% (35/39) had received prior PD-1/PD-L1 inhibitor, 95% (37/39) received prior platinum chemotherapy, and 28% (11/39) had received a prior KRAS G12C inhibitor. The combination was safe, with no dose-limiting toxicities observed, and only 5% of grade 3 AST and ALT elevations were reversible. Confirmed ORR was 42.1% (n = 38), with an ORR of 55.6% (n = 27) for those without a prior KRAS G12C inhibitor.^98,99 These trials taken together demonstrate that the combination of IO and KRAS G12C inhibition can be efficacious, though tolerability varies between KRAS G12C inhibitors.

Immunotherapy combinations in the first line

Given the clinical efficacy of KRAS G12C inhibitors and single-agent immunotherapy in the second line and beyond, there is significant interest in moving the combination up to the frontline. Adagrasib is a KRAS G12C inhibitor that binds irreversibly and selectively to KRAS in the inactive state.³ As a single agent in the second line, it has an ORR of 32% with a PFS of 5.5 months, and a DOR of 8.3 months.⁶² KRYSTAL-7 studied the efficacy and safety of adagrasib plus pembrolizumab in patients with treatment-naïve, advanced NSCLC with KRAS G12C mutations. Safety data were presented for 148 patients; while ALT and AST elevations were still frequently observed (38% and 32%, respectively), grade 3 elevations were uncommon (9% and 13%, respectively). Treatment discontinuations were limited, with discontinuation rates of adagrasib at 6% (9/148), pembrolizumab at 11% (16/148), and 4% discontinuing both (6/148). Of the 51 patients with PD-L1 ⩾50%, ORR was 63% (32/51, 95% CI: 48%–76%) with a disease control rate (DCR) of 84% (43/51; 95% CI: 71–93). Both median PFS and DOR were not reached with a median follow-up of 10.1 months.¹⁰⁰ Efficacy data for PD-L1 <50% have not been presented. Regarding future trials, for patients with TPS <50%, adagrasib will be studied in combination with pembrolizumab plus chemotherapy (ClinicalTrials.gov identifier: NCT05609578).

MK-1084 is a KRAS G12C inhibitor that binds covalently.¹⁰¹ The combination of MK-1084 plus pembrolizumab 200 mg IV q3w was administered in patients with untreated, metastatic NSCLC with PD-L1 ⩾1%. Of the 27 patients who were response evaluable, the ORR was 70% (95% CI: 50%–86%) at MK-1084 doses ranging from 25 to 400 mg daily. Responses were seen both in patients who were PD-L1 1%–49% and PD-L1 ⩾50%. The combination was well tolerated, with grade 1/2 ALT elevation in 26% (8/31) and grade 3–5 in 13% (4/31); grade 1/2 AST elevation in 23% (7/31) and grade 3–5 in 10% (3/31).¹⁰² The combination of MK-1084 plus pembrolizumab versus pembrolizumab plus placebo is being studied in a prospective, phase III trial of patients with KRAS G12C mutations and a PD-L1 ⩾50%.¹⁰³

Two cohorts of the LOXO-RAS-20001 study enrolled previously untreated patients with KRAS G12C to be treated with the combination of olomorasib plus pembrolizumab in the frontline setting, as well as olomorasib plus pembrolizumab plus chemotherapy. For patients treated with pembrolizumab plus olomorasib, there was an ORR of 77% (13/17). The data are not mature enough to be able to estimate PFS and OS.⁹⁷ The combination of olomorasib, pembrolizumab, and chemotherapy similarly showed a tolerable toxicity profile in 21 treatment-naïve patients. The ORR was 50%, with 48% (10/21) of patients having a PD-L1 <1%.¹⁰⁴ Both of these combinations will be pursued in the SUNRAY-01 trial. For patients who are PD-L1 ⩾50%, patients will be randomized to pembrolizumab plus olomorasib versus placebo.⁹⁷ Patients with any PD-L1 expression will be treated with platinum, pemetrexed, and pembrolizumab plus olomorasib versus placebo.⁹⁷

These data demonstrate that combinations of KRAS G12C inhibitors plus single-agent immunotherapy can be tolerable with significant clinical efficacy. We look forward to prospective, randomized data in the next few years. While outside the scope of this review on the role of immunotherapy in KRAS G12C NSCLC, the combinations of chemotherapy plus sotorasib will be studied in the randomized, phase III clinical trial CodeBreaK 202 in patients who are PD-L1 ⩽1%.¹⁰⁵ In addition, KRAS on-target inhibitors, pan-KARS inhibitors, or novel combination strategies may play a role in the treatment of KRAS G12C-mutated NSCLC.¹⁰⁶ It remains to be seen whether a single strategy will maximize efficacy, minimize toxicity, and increase CNS treatment activity, or whether an individualized approach based on patient characteristics, PD-L1, and co-mutations will be the best path forward.

Novel combinations with KRAS G12C inhibitors

As detailed above, there are multiple resistance mechanisms that have been identified after treatment with KRAS G12C inhibitors, including on-target resistance mechanisms, bypass mechanisms, and histologic transformation.⁶⁰ Currently, the genomic and histologic resistance profile following treatment with the combination of immunotherapy plus KRAS G12C inhibitors is unknown. Novel combinatorial strategies will be needed both to treat patients after the development of resistance to KRAS G12C inhibitors, as well as to prevent the initial development of resistance using novel combinations upfront. Many combination strategies with KRAS G12C inhibitors are under development, including the HER2 antibody–drug conjugate trastuzumab deruxtecan, a SOS1 inhibitor BI 1701963, the CDK4/6 inhibitor palbociclib, the PARP inhibitor olaparib, the EGFR inhibitor cetuximab, and the SHP2 inhibitor TNO155.^107,108 Each of these combinations will have variable efficacy and toxicity, and may not be the correct treatment for an unselected, KRAS G12C-mutated population, but rather small subsets of patients. One aspirational goal is the treatment of every patient’s individual resistance mechanism with a combinatorial strategy that also minimizes toxicity, though much work needs to be done for this to be realized.

Conclusion

KRAS G12C inhibitors have demonstrated single-agent efficacy in later lines of therapy, although response rate and durability have been limited in randomized clinical trials. This has led to the investigation of immunotherapy-based strategies combined with KRAS G12C inhibition in the frontline, which have demonstrated promising response rates in multiple single-arm, phase I trials. The toxicity of KRAS G12C inhibitors appears drug-specific rather than a class effect, which has led to tolerability differences with unique combinations. It will be important to incorporate what we know about genomic and phenotypic changes with co-alterations to establish treatment paradigms in different subgroups such as STK11 or KEAP1 co-alterations. As the efficacy and tolerability of these combination strategies improve, moving them into earlier stages will be a viable strategy to improve survival for patients with KRAS G12C mutations.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Nadia Ghazali

References

Barbacid

Ras genes. Annu Rev Biochem 1987; 56: 779–827.

Skoulidis

, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021; 384(25): 2371–2381.

Janne

Riely

Gadgeel

, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med 2022; 387(2): 120–131.

Takai

Sasaki

Matozaki

Small GTP-binding proteins. Physiol Rev 2001; 81(1): 153–208.

Bos

Rehmann

Wittinghofer

GEFs and GAPs: critical elements in the control of small G proteins. Cell 2007; 129(5): 865–877.

Iversen

Lin

, et al. Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science 2014; 345(6192): 50–54.

Martinelli

Morgillo

Troiani

, et al. Cancer resistance to therapies against the EGFR-RAS-RAF pathway: the role of MEK. Cancer Treat Rev 2017; 53: 61–69.

Fruman

Chiu

Hopkins

, et al. The PI3K pathway in human disease. Cell 2017; 170(4): 605–635.

She

Solit

, et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005; 8(4): 287–297.

10.

Schubbert

Shannon

Bollag

Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7(4): 295–308.

11.

Tomasini

Walia

Labbe

, et al. Targeting the KRAS pathway in non-small cell lung cancer. Oncologist 2016; 21(12): 1450–1460.

12.

Hunter

Manandhar

Carrasco

, et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res 2015; 13(9): 1325–1335.

13.

Huang

Guo

Wang

, et al. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther 2021; 6(1): 386.

14.

Dogan

Shen

Ang

, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012; 18(22): 6169–6177.

15.

Reck

Rodriguez-Abreu

Robinson

, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375(19): 1823–1833.

16.

Herbst

Giaccone

de Marinis

, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med 2020; 383(14): 1328–1339.

17.

Borghaei

Paz-Ares

Horn

, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639.

18.

Sezer

Kilickap

Gumus

, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 2021; 397(10274): 592–604.

19.

Bischoff

Reck

Overbeck

, et al. Outcome of first-line treatment with pembrolizumab according to KRAS/TP53 mutational status for nonsquamous programmed death-ligand 1-high (⩾50%) NSCLC in the German National Network Genomic Medicine Lung Cancer. J Thorac Oncol 2024; 19(5): 803–817.

20.

Cascone

Awad

Spicer

, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med 2024; 390(19): 1756–1769.

21.

Forde

Spicer

, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022; 386(21): 1973–1985.

22.

Liu

Zheng

Jin

, et al. 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 immunogenicity. Cancer Lett 2020; 470: 95–105.

23.

Chen

Fang

Lin

, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother 2017; 66(9): 1175–1187.

24.

Rizvi

Hellmann

Snyder

, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124–128.

25.

McGranahan

Furness

Rosenthal

, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016; 351(6280): 1463–1469.

26.

Durham

Smith

, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413.

27.

Arbour

Jordan

Kim

, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res 2018; 24(2): 334–340.

28.

Shire

Klein

Golozar

, et al. STK11 (LKB1) mutations in metastatic NSCLC: prognostic value in the real world. PLoS One 2020; 15(9): e0238358.

29.

Shackelford

Shaw

RJ.

The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009; 9(8): 563–575.

30.

Koyama

Akbay

, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res 2016; 76(5): 999–1008.

31.

Ricciuti

Arbour

Lin

, et al. Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status. J Thorac Oncol 2022; 17(3): 399–410.

32.

Skoulidis

Goldberg

Greenawalt

, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018; 8(7): 822–835.

33.

Arbour

Rizvi

Plodkowski

, et al. Treatment outcomes and clinical characteristics of patients with KRAS-G12C-mutant non-small cell lung cancer. Clin Cancer Res 2021; 27(8): 2209–2215.

34.

Itoh

Wakabayashi

Katoh

, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999; 13(1): 76–86.

35.

Frank

Scheffler

Merkelbach-Bruse

, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res 2018; 24(13): 3087–3096.

36.

Kitajima

Thummalapalli

Barbie

DA.

Inflammation as a driver and vulnerability of KRAS mediated oncogenesis. Semin Cell Dev Biol 2016; 58: 127–135.

37.

Zhao

Wen

, et al. Unveiling the role of KRAS in tumor immune microenvironment. Biomed Pharmacother 2024; 171: 116058.

38.

Taniguchi

Karin

IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26: 54–74.

39.

Coelho

de Carné Trécesson

Rana

, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 2017; 47(6): 1083–1099.e6.

40.

Labani-Motlagh

Ashja-Mahdavi

Loskog

The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front Immunol 2020; 11: 940.

41.

Skoulidis

Araujo

, et al. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature 2024; 635(8038): 462–471.

42.

Ricciuti

Garassino

MC.

Precision immunotherapy for STK11/KEAP1-mutant NSCLC. J Thorac Oncol 2024; 19(6): 877–882.

43.

Pecuchet

Laurent-Puig

Mansuet-Lupo

, et al. Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer. Oncotarget 2017; 8(14): 23831–23840.

44.

Scalera

Ricciuti

Mazzotta

, et al. Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma. Ann Oncol 2023; 34(3): 275–288.

45.

Liu

Ahmed

Petty

, et al. SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: a multi-cohort analysis. Mol Oncol 2021; 15(2): 462–472.

46.

Alessi

Ricciuti

Spurr

, et al. SMARCA4 and other SWItch/sucrose nonfermentable family genomic alterations in NSCLC: clinicopathologic characteristics and outcomes to immune checkpoint inhibition. J Thorac Oncol 2021; 16(7): 1176–1187.

47.

Mittal

Roberts

CWM

. The SWI/SNF complex in cancer—biology, biomarkers and therapy. Nat Rev Clin Oncol 2020; 17(7): 435–448.

48.

Becker

Workman

JL.

Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 2013; 5(9): a017905.

49.

Manolakos

Boccuto

Ivankovic

DS.

A critical review of the impact of SMARCA4 mutations on survival outcomes in non-small cell lung cancer. J Pers Med 2024; 14(7): 684.

50.

Budczies

Romanovsky

Kirchner

, et al. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma. Br J Cancer 2024; 131(3): 524–533.

51.

Park

Lee

Yoon

JH.

High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. J Surg Oncol 2012; 106(4): 386–392.

52.

Liu

Zhu

, et al. Increased CX3CL1 mRNA expression level is a positive prognostic factor in patients with lung adenocarcinoma. Oncol Lett 2019; 17(6): 4877–4890.

53.

Bocanegra

Fernández-Hinojal

Ajona

, et al. Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer. EMBO Rep 2023; 24(8): e55884.

54.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for non-small cell lung cancer V.8.2024, Plymouth Meeting, PA: National Comprehensive Cancer Network, 2024.

55.

Ostrem

Peters

Sos

, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013; 503(7477): 548–551.

56.

Fell

Fischer

Baer

, et al. Identification of the clinical development candidate MRTX849, a covalent KRAS(G12C) inhibitor for the treatment of cancer. J Med Chem 2020; 63(13): 6679–6693.

57.

Canon

Rex

Saiki

, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019; 575(7781): 217–223.

58.

Negrao

Araujo

Lamberti

, et al. Comutations and KRASG12C inhibitor efficacy in advanced NSCLC. Cancer Discov 2023; 13(7): 1556–1571.

59.

Chen

Q-A

Lin

W-H

Zhou

X-X

, et al. Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: a systematic review and meta-analysis. Pharmacol Res 2024; 200: 107060.

60.

Awad

Liu

Rybkin II , et al. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med 2021; 384(25): 2382–2393.

61.

Barghout

Zhan

Raptis

, et al. Treatment patterns and outcomes in KRAS(G12C)-positive advanced NSCLC patients previously treated with immune checkpoint inhibitors: a Canada-wide real-world, multi-center, retrospective cohort study. Lung Cancer 2024; 194: 107898.

62.

Mok

TSK

Yao

Duruisseaux

, et al. KRYSTAL-12: phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. J Clin Oncol 2024; 42(17_suppl): LBA8509.

63.

de Langen

Johnson

Mazieres

, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet 2023; 401(10378): 733–746.

64.

Reck

Rodriguez-Abreu

Robinson

, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019; 37(7): 537–546.

65.

Reck

Rodriguez-Abreu

Robinson

, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ⩾50. J Clin Oncol 2021; 39(21): 2339–2349.

66.

Jassem

de Marinis

Giaccone

, et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. J Thorac Oncol 2021; 16(11): 1872–1882.

67.

Herbst

Lopes

Kowalski

, et al. LBA4 association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042. Ann Oncol 2019; 30: xi63–xi64.

68.

Mok

TSK

Kudaba

, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393(10183): 1819–1830.

69.

Jeanson

Tomasini

Souquet-Bressand

, et al. Efficacy of immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol 2019; 14(6): 1095–1101.

70.

Erhart

Cefali

Mangan

, et al. Prognostic value of KRAS G12C in advanced non-small cell lung cancer with high PD-L1 expression treated with upfront immunotherapy: a systematic review and meta-analysis. Swiss Med Wkly 2024; 154: 3695.

71.

Cefali

Epistolio

Ramelli

, et al. Correlation of KRAS G12C mutation and high PD-L1 expression with clinical outcome in NSCLC patients treated with anti-PD1 immunotherapy. J Clin Med 2022; 11(6): 1627.

72.

Frost

Kollmeier

Vollbrecht

, et al. KRAS(G12C)/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (⩾50%) lung adenocarcinoma. Transl Lung Cancer Res 2021; 10(2): 737–752.

73.

Dong

Zhong

Zhang

, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res 2017; 23(12): 3012–3024.

74.

Justeau

Huchot

Simonneau

, et al. Impact of KRAS G12C mutation in patients with advanced non-squamous non-small cell lung cancer treated with first-line pembrolizumab monotherapy. Lung Cancer 2022; 174: 45–49.

75.

Gandhi

Rodriguez-Abreu

Gadgeel

, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078–2092.

76.

Paz-Ares

Luft

Vicente

, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018; 379(21): 2040–2051.

77.

Gogishvili

Melkadze

Makharadze

, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med 2022; 28(11): 2374–2380.

78.

Socinski

Jotte

Cappuzzo

, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018; 378(24): 2288–2301.

79.

West

McCleod

Hussein

, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019; 20(7): 924–937.

80.

Gadgeel

Rodriguez-Abreu

Felip

, et al. LBA5-KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 2019; 30: xi64–xi65.

81.

Elkrief

Riccuiti

Alessi

, et al. Outcomes of combination platinum-doublet chemotherapy and anti-PD(L)-1 blockade in KRASG12C-mutant non-small cell lung cancer. Oncologist 2023; 28(11): 978–985.

82.

Barlesi

Felip

Popat

, et al. 103TiP Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202). ESMO Open 2024; 9: 102682.

83.

Paz-Ares

Ciuleanu

Cobo

, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22(2): 198–211.

84.

Hellmann

Paz-Ares

Bernabe Caro

, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019; 381(21): 2020–2031.

85.

Ramalingam

Balli

Ciuleanu

, et al. 4O Nivolumab (NIVO) + ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced NSCLC (aNSCLC) in CheckMate 227 part 1: Efficacy by KRAS, STK11, and KEAP1 mutation status. Ann Oncol 2021; 32: S1375–S1376.

86.

Peters

Cho

Luft

, et al. OA15.04 association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: durvalumab ± tremelimumab + chemotherapy in mNSCLC. J Thorac Oncol 2022; 17(9, Suppl.): S39–S41.

87.

Paz-Ares

Ciuleanu

T-E

Cobo-Dols

, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non-small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol 2020; 40(17_suppl): LBA9026.

88.

Luo

Martucci

Quandt

, et al. Immunotherapy-mediated thyroid dysfunction: genetic risk and impact on outcomes with PD-1 blockade in non-small cell lung cancer. Clin Cancer Res 2021; 27(18): 5131–5140.

89.

Akturk

Couts

Baschal

, et al. Analysis of human leukocyte antigen DR alleles, immune-related adverse events, and survival associated with immune checkpoint inhibitor use among patients with advanced malignant melanoma. JAMA Netw Open 2022; 5(12): e2246400.

90.

Skoulidis

Heymach

JV.

Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer 2019; 19(9): 495–509.

91.

Socinski

Nishio

Jotte

, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol 2021; 16(11): 1909–1924.

92.

Garassino

Gadgeel

Novello

, et al. Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC. JTO Clin Res Rep 2022; 4(1): 100431.

93.

Skoulidis

Borghaei

Garon

, et al. TRITON: phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11 and/or KEAP1 and/or KRAS mutations. J Clin Oncol 2024; 42(16_suppl): TPS8655.

94.

Boumelha

de Carne Trecesson

Law

, et al. An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations. Cancer Res 2022; 82(19): 3435–3448.

95.

Falchook

Durm

, et al. OA03.06 CodeBreaK 100/101: first report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. J Thorac Oncol 2022; 17(9, Suppl.): S10–S11.

96.

Heist

Koyama

Murciano-Goroff

, et al. Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors. J Clin Oncol 2024; 42(16_suppl): 3007.

97.

Burns

Dragnev

Fujiwara

, et al. Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. J Clin Oncol 2024; 42(16_suppl): 8510.

98.

Sacher

LoRusso

Patel

, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med 2023; 389(8): 710–721.

99.

Sacher

Miller

Jr Paz-Ares

, et al. OA14.06 divarasib single-agent long-term follow-up and atezolizumab combination treatment in patients with KRAS G12C-positive NSCLC. J Thorac Oncol 2024; 19(10): S42–S43.

100.

Garassino

Theelen

WSME

Jotte

, et al. LBA65 KRYSTAL-7: efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Ann Oncol 2023; 34: S1309–S1310.

101.

Sloman

Duggal

, et al. Discovery of MK-1084: an orally bioavailable and low-dose KRAS(G12C) inhibitor. J Med Chem 2024; 67(13): 11024–11052.

102.

Rojas

Lugowska

Juergens

, et al. 44O updated results from a phase I study evaluating the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC. ESMO Open 2024; 9: 102273.

103.

Cobb

Hochmair

Schuler

MHH

, et al. 1392TiP phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ⩾50%: MK-1084-004. Ann Oncol 2024; 35: S871–S872.

104.

Fujiwara

Reddy Ammakkanavar

Hollebecque

, et al. OA14.04 efficacy and safety of olomorasib with pembrolizumab + chemotherapy as first-line treatment in patients with KRAS G12C-mutant advanced NSCLC. J Thorac Oncol 2024; 19(10, Suppl.): S41–S42.

105.

Barlesi

Felip

Popat

, et al. Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202). J Clin Oncol 2024; 42(16_suppl): TPS8653.

106.

Harris

Thawani

Current perspectives of KRAS in non-small cell lung cancer. Curr Probl Cancer 2024; 51: 101106.

107.

Ozakinci

Desai

Kalos

, et al. Trastuzumab deruxtecan combination strongly enhances responses and overcomes sotorasib resistance in KRAS (G12C)-mutant NSCLC. bioRxiv. 2024.12.17.628751, 2024.

108.

Isermann

Sers

Der

, et al. KRAS inhibitors: resistance drivers and combinatorial strategies. Trends Cancer 2024; 11(2): 91–116.