First-line treatment strategies and potential prognostic factors in patients with KRAS G12C-mutant non-small cell lung cancer

Introduction

Lung cancer remains the leading cause of cancer-related death in the US (1). The Kirsten rat sarcoma (KRAS) mutations are present in approximately 25% of non-small cell lung cancer (NSCLC), particularly in lung adenocarcinomas, with the G12C variant being the most frequently observed subtype. KRAS G12C accounts for 40% of overall KRAS mutations in this tumor type (2,3). KRAS mutations are found predominantly in lung, pancreatic, and colon cancer (4). They usually arise from single amino acid substitution—most frequently seen at exon 2 codon 12, where glycine (G) is substituted to either cysteine (C), aspartic acid (D), or a valine (V). The mutations can also arise at exon 2 codon 13, and exon 3 codon 61 (5).

KRAS mutations have been colloquially referred to as “undruggable” cancer targets due to historical difficulty in developing competitive inhibitors given the high affinity of KRAS to GTP (3,6,7). However, advancement in targeted therapy for NSCLC have been rapid and ongoing, highlighted by the approvals of sotorasib and adagrasib. Additionally, several other KRAS inhibitors are currently in development, showing promising results in preclinical and clinical studies. While previous reviews have primarily focused on KRAS G12C, and G12D mutations, mechanisms of resistance to KRAS inhibitors, and the pre-clinical development of next-generation KRAS inhibitors (8,9), this review summarizes approved KRAS inhibitors, addresses co-mutations and biomarkers on treatment response, discusses KRAS inhibitors under development, examines first-line treatment strategies, and presents potential strategies to overcome resistance.

Molecular background and current treatment

KRAS proto-oncogene produces a protein known to function as a GTPase, playing a vital part in a signaling pathway within the cell cycle known as the RAS/MAPK pathway (10). Under normal physiologic conditions, GTPase acts as a molecular switch to convert the cell from an activated, GTP-bound “ON” state to its inactivated guanosine diphosphate (GDP)-bound “OFF” state. When a mutation occurs in the KRAS gene which affects its GTPase function and/or disrupts the guanine exchange cycle, mutant KRAS is then locked in its activated GTP-bound form, driving uncontrolled cell proliferation and survival (11,12). It is to be noted that several other proteins, such as neurofibromin 1 (NF1), are important in facilitating GTP hydrolysis aside from the intrinsic GTP hydrolysis mediated by the KRAS protein itself (13). KRAS G12C is unique among the KRAS variants in that it retains near normal level of intrinsic GTPase hydrolytic activity, hence is able to generate the GDP-bound state of KRAS relative to other KRAS variants.

Current standard of care first-line therapy for KRAS p.G12C-mutant NSCLC

KEYNOTE-024 (NCT02142738) was the first study in NSCLC to establish a new paradigm shift during the past decade in first-line therapy for metastatic NSCLC (14). It demonstrated superiority in treatment outcomes compared to platinum-based chemotherapy, including overall survival (OS), with the anti-programmed cell death protein-1 (PD-1) immune checkpoint inhibitor (ICI) pembrolizumab as monotherapy in EGFR and ALK wildtype (WT) tumors with high programmed death-ligand 1 (PD-L1) expression defined as tumor proportion score (TPS) ≥50% by immunohistochemistry. KRAS G12C mutations are common in smokers (either current or former), associated with higher PD-L1 expression and tumor mutation burden (TMB) compared to other oncogenic drivers (6), and potentially higher likelihood of deriving benefit from therapies using ICIs (15,16). A descriptive analysis of 590 patients with non-squamous NSCLC histology enrolled into two phase III trials, KEYNOTE-042 (NCT02220894) (15), and KEYNOTE-189 (NCT02578680) (17,18), provided helpful insights (19). KEYNOTE-042 evaluated pembrolizumab vs. platinum-based chemotherapy in PD-L1 positive (TPS ≥1%) NSCLC, while KEYNOTE-189 compared pembrolizumab plus platinum-based chemotherapy vs. platinum-based chemotherapy irrespective of PD-L1 expression. Both trials investigated first-line treatment in stage IV EGFR and ALK WT NSCLC, with KRAS G12C mutations identified in 11% of the patients. Notably, KRAS G12C tumors represented the highest proportion (28.4%) of KRAS-mutant NSCLC that exhibited both high TMB (TMB ≥175 mut/exome) and PD-L1 TPS ≥50% (19). Conversely, PD-L1 ≥50% can be found in up to 60% of patients with KRAS G12C-mutant NSCLC in this combined analysis (19).

A meta-analysis of randomized controlled trials further confirmed these findings. It included data from first-line ICI-based studies such as IMpower150 (NCT02366143), which evaluated atezolizumab, in combination with chemotherapy and bevacizumab (20) aside from KEYNOTE-189 (NCT02578680) (17,18) and KEYNOTE-042 (NCT02220894) (21,22). Additionally, second-line trials were analyzed, including atezolizumab in OAK (NCT02008227) (23), and POPLAR trials (NCT01903993) (24), as well as nivolumab in CheckMate-057 (NCT01673867) (25). Among 1,313 patients with NSCLC (386 KRAS-mutant and 927 KRAS WT tumors), ICI with or without chemotherapy significantly improved OS [hazard ratio (HR): 0.59; 95% confidence interval (CI): 0.49–0.72, P<0.00001] and progression-free survival (PFS) [HR: 0.58; 95% CI: 0.43–0.78, P=0.0003] compared to chemotherapy alone. Moreover, ICI with or without chemotherapy was shown to be more effective in KRAS-mutant NSCLC than WT KRAS (26). Thus, ICI-based regimens are currently the standard of care for the treatment of advanced stage KRAS G12C-mutant NSCLC.

Approved targeted therapies for KRAS G12C-mutant NSCLC in 2^nd line and beyond

To provide an overview of evolving therapeutic approaches KRAS G12C in NSCLC, we provide key highlights on the CodeBreak and KRYSTAL studies, which led to the FDA approval of the KRAS G12C inhibitors sotorasib and adagrasib in the 2^nd/3^rd-line treatment setting. Additionally, we explore current insights into the predictive and prognostic value of co-occurring mutations and discuss the evolving landscape of KRAS G12C inhibition. Figure 1 summarizes the main results of relevant CodeBreak and KRYSTAL studies discussed below.

Figure 1 Comparison between FDA approved KRAS G12C Inhibitors. 2L, second-line; 3L, third-line; DCR, disease control rate; DOR, duration of response; HR, hazard ratio; IC, intracranial; m, months; mPFS, median progression-free survival; NR, not reported; ORR, overall response rate; OS, overall survival; TRAE, treatment-emergent adverse event.

Sotorasib

In recent years, major breakthroughs have been achieved in drugging mutant KRAS, primarily driven by the discovery of an allosteric regulatory pocket that can be targeted in its mutated form (12). The mutated cysteine of KRAS G12C resides in a pocket of the switch II region, called the P2 pocket, which is only present when KRAS is in its inactive GDP-bound form. Sotorasib (AMG 510) is the first-in-class covalent inhibitor of KRAS G12C mutation to be approved by US FDA for clinical use (27). Sotorasib interacts with the allosteric regulatory site within the P2 pocket, trapping KRAS G12C in its inactive GDP-bound conformation and thereby inhibiting downstream signaling pathway and the resulting uncontrolled cell proliferation (28-31). In addition, preclinical evaluation suggests that sotorasib resulted in a pro-inflammatory tumor microenvironment, potentially enhancing the activity of ICIs (32).

The phase I/II CodeBreak 100 (NCT03600883) trial investigated sotorasib in patients with locally advanced, or metastatic KRAS G12C-mutant NSCLC previously treated with at least one line of systemic treatment. Combined analysis of the phase I and phase II portions of the studies wherein patients received 960 mg once daily dose demonstrated duration of response (ORR) of 41% of patients, a median duration of response (DOR) of 12.3 months, median PFS of 6.3 months, median OS of 12.5 months and 2-year OS rate of 33%, with long-term clinical benefit from sotorasib observed irrespective of PD-L1 expression levels (27,33). These compelling findings led to the accelerated approval of sotorasib by the US FDA on May 28, 2021, for the treatment of patients with advanced stage KRAS G12C-mutant NSCLC who have received at least one prior systemic therapy.

Building on these promising findings, the open label, multicenter, randomized phase III CodeBreak 200 (NCT04303780) trial was launched to evaluate the efficacy and safety of sotorasib compared to docetaxel in patients with KRAS G12C-mutant NSCLC previously treated with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. The trial demonstrated improved PFS as the primary endpoint and a better safety profile for sotorasib than docetaxel, with median PFS of 5.6 months for sotorasib compared to 4.5 months for docetaxel (HR: 0.66; 95% CI: 0.51–0.86, P=0.0017) (34). It is important to note that as part of the FDA Project Optimus, sotorasib dosing was also evaluated in the randomized CodeBreak100 phase II trial (NCT03600883) (35) comparing the efficacy of the approved dose (960 mg once daily) to a lower dose (240 mg once daily) based on the rationale that sotorasib has non-dose proportional pharmacokinetics and ORRs were seen similarly at the lower dose. The study however was not powered for formal statistical hypothesis testing. Final results of the study indicated that 960 mg dosing showed numerically higher ORR, disease control rate (DCR) and OS compared to 240 mg. Specifically, ORR was 32.7% vs. 24.8%, DCR was 86.5% vs. 81.9%, median PFS was 5.4 vs. 5.6 months (HR: 0.95; 95% CI: 0.67–1.35), and OS was 13 vs. 11.7 months for 960 and 240 mg (HR: 0.75; 95% CI: 0.53–1.07), respectively. Treatment-emergent adverse events (TEAEs) were observed at a higher rate in the 960 mg dosing, namely diarrhea (39.4% vs. 31.7%) and nausea (23.1% vs. 19.2%), along with higher rate of grade 3 treatment-related adverse events (TRAEs) (35.6% vs. 19.2%) compared to 240 mg dosing. Interestingly, hepatotoxicity rates were similar between the two doses (35). While the FDA upheld the 960 mg daily dosing on the current approved label (36), this issue remains controversial (37). Although sotorasib was the first-in-class KRAS G12C inhibitor to be approved, the high rates of hepatotoxicity observed, either in combination with immunotherapy or in sequence within 3 months of antecedent immunotherapy, represented a roadblock to the development of this agent in the first-line setting for most KRAS G12C-mutant NSCLC. Currently, it is being explored in combination with chemotherapy only as first-line therapy in PD-L1 negative NSCLC in the phase III CodeBreak 202 study (NCT05920356) (38).

Adagrasib

In December 2022, the US FDA approved adagrasib (MRTX849) for patients with advanced KRAS G12C-mutant NSCLC after at least one prior line of systemic therapy. Adagrasib is another covalent inhibitor that binds to the KRAS G12C locking the protein in its inactive GDP-bound conformation, and thereby inhibiting KRAS-dependent signaling. The phase II component of the KRYSTAL-1 trial (NCT03785249) evaluated adagrasib (600 mg taken orally twice daily) in patients with KRAS G12C-mutant NSCLC who were previously treated with platinum-based chemotherapy and either anti-PD-1 or PD-L1 therapy. The primary endpoint, ORR, was achieved in 42.9% of patients. The median DOR was 8.5 months, median PFS was 6.5 months, and median OS was 12.6 months at 15.6 months of follow-up (39). This trial also included a separate treatment subgroup specific to patients with asymptomatic untreated central nervous system (CNS) metastases to evaluate the intracranial (IC) efficacy of adagrasib. In KRAS G12C-mutant NSCLC patients with untreated brain metastases, the IC ORR was 42%, the median IC PFS was 5.4 months, and the IC DCR was 90% (40) with adagrasib. In comparison, patients with treated, stable brain metastases at enrollment for the KRSYTAL-1 phase II study, the IC ORR was 33%, IC PFS 11.2 months, and IC DCR was 85% (39). In the CodeBreak100 study, patients with active untreated brain metastasis were excluded. However, a post-hoc analysis of 16 patients with stable brain metastasis showed IC DCR of 88%, similar to that observed in KRYSTAL-1 (41). Moreover, an exploratory analysis of patients with treated, stable brain metastasis from CodeBreak200 (NCT04303780) trial demonstrated longer IC PFS with sotorasib compared to docetaxel: 9.6 vs. 5.4 months (HR: 0.84; 95% CI: 0.32–2.19, P=0.37). The ORR was also higher with sotorasib compared to docetaxel (33% vs. 15.4%) (42-45).

Finally, in the phase III KRYSTAL-12 (NCT04685135) comparing adagrasib to docetaxel for patients with advanced KRAS G12C-mutant NSCLC after at least one prior line of systemic therapy, adagrasib showed improvement in PFS 5.49 vs. 3.84 months (HR: 0.58; 95% CI: 0.45–0.76, P<0.0001), improved ORR 31.9% vs. 9.2% and DOR of 8.3 vs. 5.36 months, respectively. However, it is important to note that patients with untreated brain metastases were also excluded (46). In contrast to sotorasib however, rates of hepatotoxicity in combination with immunotherapy were lower, hence the ongoing investigation of its front-line use in combination with pembrolizumab compared to pembrolizumab in KRYSTAL-7 (NCT04613596) study for patients with advanced KRAS G12C-mutant NSCLC and high PD-L1 TPS ≥50% (47).

The crucial role of tumor biology and tumor heterogeneity: co-occurring mutations as prognostic and predictive biomarkers

Tumor biology plays a significant role in influencing treatment outcomes for KRAS G12C-mutant NSCLC, particularly the heterogeneity of co-occurring genomic alteration in tumor suppressor genes such as tumor protein p53 (TP53), serine-threonine kinase 11 (STK11), and kelch-like ECH-associated protein 1 (KEAP1), with evidence emerging that these co-mutations may impact treatment outcomes to ICIs and KRAS G12C inhibitors (48). Both STK11 and KEAP1 co-mutations have been linked to worse prognosis and poor outcomes to anti-PD-1/PD-L1-based regimens in KRAS-mutant NSCLC, compared to patients with WT STK11/KEAP1 NSCLC (48-52). Conversely, patients with TP53 co-mutations have shown an enhanced response to anti-PD-1/PD-L1-based regimens. This is attributed to tumor instability, high TMB and increased PD-L1 expression in tumors with TP53 co-mutations, all of which contribute to prolonged PFS with ICIs (52,53). In contrast, KEAP1, STK11, and TP53 co-mutations have a different impact on clinical response to sotorasib and/or adagrasib. NSCLC patients derived treatment benefit from either KRAS G12C inhibitors regardless of TP53 status (27,39). In the CodeBreak100 study (NCT03600883), long-term treatment benefit with sotorasib was seen in patients regardless of STK11 mutation status as long as KEAP1 is WT, whereas those with co-mutated KEAP1 had higher proportion of patients with early disease progression independent of STK11 co-mutation (33). Real world analyses affirm the same observation (32,54). Furthermore, in an analysis of the CodeBreak200 (NCT04303780), sotorasib showed superior clinical benefit compared to docetaxel regardless of PD-L1 expression and across all prespecified subgroups (e.g., STK11, KEAP1, TP53), although patients with KEAP1-mutant NSCLC had shorter PFS compared to WT KEAP1 regardless of treatment (55). Aside from KEAP1 co-mutations as a major determinant of sotorasib antitumor efficacy, exploratory analyses of biomarkers from the phase II CodeBreak100 and phase III CodeBreak200 studies reveal that low expression of TTF-1 was associated with low response rate to sotorasib whereas low inflammatory subtype and PD-L1 low (<1%) status may identify patients with long-term benefit with sotorasib treatment (56). Therefore, molecular profiling is essential to identify co-mutations, particularly predictive markers of poor response such as KEAP1 mutation. While sotorasib remains an appropriate option for those patients, expectations need to be tempered and patients monitored closely.

Therapies in development of relevance to KRAS G12C-mutant NSCLC

Other KRAS G12C inhibitors, pan-RAS inhibitors, dual-state KRAS inhibitors, dual RAF-MEK inhibitors, PI3Kα: RAS breakers in the development

Currently, multiple small-molecule inhibitors targeting KRAS G12C are under development, with ultimate plans to transition to first-line therapy in combination with immunotherapy-based regimens. Some of these inhibitors function similarly to sotorasib and adagrasib targeting the “OFF” state of KRAS G12C. Several have demonstrated greater potency preclinically as well as potentially greater efficacy signals based on ORR in phase I and II trials (57-68). However, due to intense competition in this space, developmental plans were discontinued for some such as with opnurasib. Table 1 summarizes KRAS G12C roman inhibitors currently in development.

Another class of KRAS G12C inhibitors operates via a distinct mechanism by targeting the “ON” state of KRAS G12C. For instance, RMC6291 is a tri-complex KRAS G12C “ON” inhibitor in clinical development utilizing a ubiquitous chaperone protein (in this case, cyclophilin) as a molecular scaffold to block downstream signaling of KRAS G12C in its active GTP-bound form. Early phase dose-escalation trials demonstrated activity among NSCLC patients who had acquired resistance to KRAS G12C “OFF” inhibitors (65). This approach has led to generation of other KRAS-mutant “ON” inhibitors, including pan-RAS inhibitors as exemplified by RMC6236 (66,69). This agent has shown clinical activity in early phase trials.

Preclinical studies have shown that combining pan-KRAS inhibitors with KRAS G12C inhibitors enhances anti-tumor activity by suppressing compensatory pathways and by reducing the likelihood of resistance. This combination strategy is being actively investigated in clinical trials including for lung cancer (70). A number of other non-covalent pan-KRAS inhibitors (undisclosed mechanism of action) with preclinical activity against common as well as uncommon mutations (e.g., acquired resistance against KRAS G12C “OFF” inhibitors) such as PF-07934040, JAB-23E73, LY4066434, are in early phase clinical testing. Additionally, inhibition of KRAS G12C aiming at blockade of both “ON” and “OFF” conformations with a single drug is also being explored. BBO-8520 is the first-in-class dual inhibitor of KRAS G12C designed to engage with both active and inactive confirmations, with increased potency and benefit of overcoming future adaptive resistance mechanism seen after treatment with KRAS G12C “OFF” inhibitors. It is currently being studied in early phase study (NCT06343402) (71) alone or with ICI.

Targeting additional components vertically through downstream inhibition of RAS pathway represents another approach. For instance, preclinical in vivo studies have shown synergistic effects in reducing tumor cell viability by combining both sotorasib or adagrasib with avutometinib (VS-6766), a small molecule inhibitor of RAF and MEK kinase signaling (72). VS-6766, a dual RAF/MEK inhibitor, demonstrated promising early clinical activity as monotherapy and in combination with defactinib, a focal adhesion kinase (FAK) inhibitor, in low-grade serous ovarian cancer (LGSOC) in the phase II RAMP201 study (NCT04625270) (73). Updated results investigating the combination of avutometinib with defactinib in LGSOC showed overall ORR of 31%, with ORR of 44% in KRAS-mutant LGSOC, and ORR of 17% for patients with KRAS WT LGSOC (74). RAMP202 (NCT04620330) is a phase II trial evaluating the efficacy and safety of avutometinib +/− defactinib in previously treated KRAS G12V NSCLC. In contrast to RAMP201, limited clinical activity was observed with the combination therapy in this trial and hence further evaluation of avutometinib +/− defactinib in KRAS G12V-mutant NSCLC was not pursued (75). RAMP 203 is a phase I/II trial investigating triplet combination cohort of avutometinib, sotorasib plus defactinib in advanced stage NSCLC patients previously treated with a KRAS G12C inhibitor. Initial results this study revealed no dose-limiting toxicities in the safety cohort for the triplet combination, with early signs of clinical benefit showing tumor reductions in 2 out of 3 patients enrolled to date whose cancer previously progressed on a KRAS G12C inhibitor (76). The study is continuing its enrollment for efficacy evaluation. Other dual RAF/MEK complex inhibitors in early phase clinical testing include IK-595 and NST-628.

Another approach under development is the use of “RAS PI3K breakers” which are small molecules designed to disrupt RAS-driven activation of phosphatidylinositol 3-kinases (PI3K)-AKT-mTOR signaling pathway (77). This selective blockade abrogates on-target toxicity of hyperglycemia seen with direct PI3Kα tyrosine kinase inhibitors while demonstrating preclinical activity in tumor models exhibiting RAS pathway activation. BBO-10203, a first-in-class PI3Kα: RAS breaker that binds to the RAS-binding domain (RBD) of PI3Kα without directly affecting the enzymatic function of PI3Kα (78), is currently being evaluated in the phase I BREAKER-101 (NCT06625775) (79) study evaluating safety and efficacy of BBO-10203 alone or in combination with trastuzumab across multiple solid malignancies including KRAS-mutant advanced NSCLC.

Combination therapy—what is the “optimal strategy”?

Beyond combination strategies with chemotherapy, a multitude of ongoing trials of combination therapies investigate specific KRAS G12C tumor biology (e.g., KEAP1/STK11 co-mutation), and/or broadly incorporate drugs that encompass various mechanisms to overcome treatment resistance to KRAS G12C inhibitors. These acquired resistance mechanisms may include KRAS amplification, acquired mutation in the RAS pathway or activation of bypass signaling through other pathways (80). As previously mentioned, pan-KRAS inhibitors targeting a broader spectrum of KRAS mutations beyond G12C, including G12D, G12V, and G13D are emerging as a promising strategy to address resistance mechanisms associated with KRAS-targeted therapies.

To vertically modulate RAS pathway activation, inhibition of the interaction with other proteins in the RAS activation complex have been attempted. BI 1701963 is an orally available pan-KRAS SOS1 inhibitor that binds to the catalytic domain of SOS1, preventing its interaction with KRAS by impeding the exchange of GDP to GTP. This inhibition reduces the formation of active KRAS, subsequently suppressing MAPK pathway signaling in KRAS-dependent cancers. The development of this agent however has been terminated, likely due to lack of efficacy and/or poor toxicity profile. Attempts to combine KRAS G12C with inhibitors of SHP2, a protein phosphatase that promote RAS activation through regulating SOS1 activity have been challenged by toxicities without apparent improvement in efficacy with certain drug combinations, such as the combination of sotorasib with RMC4630 but other combinations demonstrate potential feasibility, such as opnurasib with TNO155 KontRASt-01 trial (NCT04699188) (81), and the combination of glecirasib with JAB-3312 (discussed in the next section).

Another combinatorial approach is via parallel inhibition of other bypass signaling pathways. For example, adaptive reactivation of KRAS signaling maybe mediated through EGFR pathway, underlying the rationale of combinations with EGFR pathway inhibitors such as cetuximab, of which the combination with adagrasib received accelerated approval as treatment in colon cancer. In NSCLC, the ongoing KROCUS trial (NCT05756153) (62) is an open-label single arm phase II study evaluating fulzerasib (KRAS G12C “OFF” inhibitor) as a first-line therapy with cetuximab in previously untreated advanced NSCLC, with encouraging interim results showing the study met its primary endpoint with confirmed response rate of 69% in 45 patients enrolled, with responses similarly observed regardless of STK11 or KEAP1 co-mutation, with median PFS of 12.6 months (82).

Lastly, given the non-overlapping mechanism of action and preclinical rationale for combination strategy is the use of ICI together with KRAS G12C inhibitors. KRAS mutations are known to modulate tumor microenvironment, and KRAS G12C inhibitors can in turn improve antitumor immunity, as discussed earlier, making such combination a compelling strategy. However, this approach is beset by concerns of potential increased toxicity, such as hepatotoxicity particularly for sotorasib (29). Notably, the risk of hepatotoxicity does not appear to be a class effect as the combination with other KRAS G12C inhibitors such as adagrasib, olomorasib, opnurasib or glecirasib revealed lower rates of grade 3 or higher liver enzyme elevation but remains challenging for other agents as well (e.g., garsorasib). Table 1 summarizes key findings from ongoing trials and reported rates of hepatotoxicity.

Evolving first-line therapeutic options for KRAS G12C-mutant NSCLC

Given the established role of ICIs in the first-line setting for patients with KRAS-mutant NSCLC as discussed above, the race is on to demonstrate best-in-class KRAS G12C inhibitor that can be safely and effectively combined with immunotherapy and/or chemotherapy. As alluded to in the earlier section regarding the prohibitive hepatotoxicity seen with sotorasib in combination with ICI, the potential role for sotorasib in the first-line setting is thus currently limited to patients who are not eligible for or less likely to benefit from the use of ICI. Thus CodeBreak 201 is designed as an open-label phase II study to evaluate the efficacy and safety of sotorasib (960 or 240 mg once daily) as first-line therapy in KRAS G12C-mutant metastatic NSCLC with PD-L1 TPS <1% and/or with the presence of STK11 as a co-mutation. A competing strategy is the evaluation of dual CTLA4-PD-1/PD-L1 pathway inhibition being investigated in this subgroup of patients (TRITON study, NCT06008093) (83).

Multiple other KRAS G12C-targeted therapies are currently being investigated in the first-line setting. For example, olomorasib in combination with pembrolizumab in any treatment line demonstrated an ORR of 63% and a DCR of 93% in 50 patients enrolled to receive this combination in an ongoing phase I/II trial (NCT04956640) (58). In the same trial, in subgroup analysis for those in the first-line setting, ORR was 78% and DCR was 100% among 9 patients (58). The KRYSTAL-7 trial (NCT04613596) (47,84) is evaluating the combination of adagrasib with pembrolizumab in the first-line setting of advanced KRAS G12C-mutant NSCLC. Early results show that in patients with PD-L1 ≥50%, ORR was 59% (32/54) and DCR was 81% (44/54) with median PFS of 27.7 months. NCT05288205 evaluates the efficacy and safety of KRAS G12C “OFF” inhibitor glecirasib also known as (JAB-21822) combined with JAB-3312 (an SHP2 inhibitor) as first-line treatment for patients with KRAS G12C-mutant NSCLC (85). The confirmed ORR in 102 enrolled patients with NSCLC was 70.6% (95% CI: 60.7–79.2%), with higher ORR in PD-L1-expressing tumors (ORR was 78% and 82.4% in PD-L1 ≥50% group and 1–49%, respectively) compared to PD-L1 <1% group (ORR 65.9%). The median PFS was 12.2 months (95% CI: 0.3–17.1) with 12-month PFS rate of 50.5% (95% CI: 39.4–60.5%). Presence of co-mutations in SMARC family members were associated with a low ORR (25%) (86,87). A phase III trial in NSCLC evaluating this combination compared to carboplatin, pemetrexed and tislelizumab as standard of care first-line therapy in China has started enrolment recently (NCT06416410) (88).

Limitations

This review is limited by the scope of the available citations, particularly due to the retrospective nature of some of the included studies. Additionally, the review focuses on key aspects of KRAS G12C inhibitors, intentionally excluding in-depth discussions of their molecular mechanisms and side effects profile and doesn’t cover the scope of molecular and mechanism of actions of each of the KRAS G12C inhibitors. Finally, given the fast-paced advancement in targeted therapies, the information presented reflects the state of knowledge and key developments at the time of submission, with new findings likely emerging shortly thereafter.

Conclusions

After decades of drug development failure, we now have targeted therapies available for KRAS-mutant NSCLC, specifically with KRAS G12C “OFF” inhibitors as therapeutic options among advanced stage disease progressing on first-line systemic regimen based on chemotherapy and/or immunotherapy. Despite the clinical heterogeneity due to differing co-mutation and PD-L1 biomarker status, given the prolonged durable benefit that can be achieved with ICI, the most successful first-line approaches need to include immunotherapy in the treatment backbone. Interim results reported from KRYSTAL-7 demonstrates higher PFS compared to historical or expected estimates with pembrolizumab or adagrasib alone. Whether this longer PFS is cost-effective or translates to superior OS compared to sequential use has yet to be demonstrated. Yet at the same time, given the anticipated risk of adverse events with combination strategies with targeted therapies, incorporation of adaptive trial designs and additional biomarkers [circulating tumor markers such as circulating tumor DNA (ctDNA), tissue-based assays such as transcriptional analysis, biomarker-based imaging including positron emission tomography (PET) imaging, etc.] will be needed to enhance and refine patient selection to identify those who would benefit the most from a triplet or quadruplet regimen incorporating KRAS G12C inhibitors in the first-line setting.

Finally, personalized treatment is essential, and next-generation sequencing remains a critical first step toward achieving this goal. Identifying predictive biomarkers such as PDL-1 expression and co-mutation status helps guide treatment decision is important. Additionally, clinical factors such as the presence of brain metastases should also be considered, as they may warrant local interventions following systemic disease stabilization.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-63/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-63/coif). M.A. reports receiving honoraria for participating in Targeted Oncology Clinical Congress Consultants at ASCO. G.K.D. reports receiving consulting fees from Amgen, Mirati, Regeneron, Eli Lilly, Janssen, AstraZeneca, and Novartis. The other authors have no conflicts of interest to declare.

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

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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